ORIC Pharmaceuticals Inc Aktie

Great. Good morning, everyone. Thanks for joining us here at the Goldman Sachs Global Healthcare Conference. And good morning on our second day of event for everyone who's joining us online as well. And we're thrilled to have the team from ORIC here this morning, and we'll just get right into it.

Maybe to start, there was some news last week, not from you guys, but from Fulcrum, which was an update that has obviously been top of mind given the mechanism of action overlap. Maybe you could speak to the Fulcrum update on pociredir and any potential implications for your program in prostate cancer rinzimetostat.

Yes. Firstly, thanks for having us here at the conference. So it's a great conference. We're just talking about the long flight across the country. So at a high level, last week, Fulcrum announced the discontinuation of their PRC2 inhibitor, which they were studying in sickle cell disease. If you read the press release, the press release kind of states that the FDA's position was really based on 3 things. One is the risk-benefit profile for sickle cell disease, which is obviously very different than it is for oncology. Two was the previously disclosed malignancies they saw in their preclinical tox work. And third was the ongoing secondary malignancies that tazemetostat is seeing in various indications as well.

So obviously, that was -- people think that's a read-through to us. When we take a look at this, we think the implications are limited when we look at rinzimetostat. And again, that's really for 3 reasons. One is that we've dosed over 100 patients, both as a monotherapy and in combination with AR inhibitors. We have not seen any instances of secondary malignancies. Based on the preclinical work we've done, which is a 4-week tox and a 13-week tox in 2 species, which is a requirement for oncology, which is different from non-oncology. We have not seen any signs of malignancies as well. And third, I think most importantly is, as I said before, the risk profile for prostate cancer is very different than sickle cell disease. So that's, I think, first and foremost, when you think about any drug, it does come down to the risk-benefit profile, taking into consideration therapeutic area, taking into consideration the overall patient population as well.

We also went on to say that over the last 6 months, obviously, we've had a number of interactions with the FDA as we imminently look to start our Phase III study. And there's been no change to our base case plan. Now as you can imagine, with the news on tazemetostat, which I think happened in the first quarter, secondary malignancies was a topic that came up as well, but there was no delay or anything in our timing. And lastly, last week, we did announce that we have completed the end of Phase I meeting.

The 3 objectives of that meeting were first was to finalize the protocol. The second was to confirm the dose selection that we picked for the Phase III study, which is 400 mg once a day of rinzimetostat in combination with darolutamide. And third was to determine any other prerequisites that were required for the initiation of the Phase III study. So we did announce last week that the protocol is finalized, the dose is confirmed and there's nothing else kind of precluding us from starting that Phase III study. So we expect to start that study imminently.

At the end of the day, I think our view is this all comes down to the risk-benefit profile of the drug. Even if you look at some of the prostate cancer drugs today like docetaxel, some of the PARP inhibitors some of the radioligands, there is some small percentage of patients that see these secondary malignancies. So again, it all just comes down to the risk-benefit profile, which, again, oncology is very, very different than sickle cell disease.

Great. So maybe we can talk about a more relevant comp within the prostate cancer context, which is mevrometostat. And could you just speak to like the mechanism of action differences and distinctions between rinzi and mevro?

Yes. So going way back, I think PRC2 inhibitors in general have been studied in prostate cancer for a number of years. I think the #1 issue has been the first-generation PRC2 inhibitors have been plagued with poor drug properties, poor in-vivo potency, very, very short half-lives, call it, 1 to 2 hours. And some of these also had CYP auto induction where you actually saw a decrease in exposure with repeat dosing. We think mevrometostat call it a second-gen PRC2 inhibitor. We think they've improved on a number of those. They've got good in vivo potency. They've increased the clinical half-life from about 1.5 to call it, 5 hours. And they don't appear to have the CYP auto-induction issue. And as you can see, that has translated into a pretty profound benefit based on the randomized data they presented at ASCO GU in 2025.

What we bring to the table, I think, is we continue to have good in vivo efficacy. We have a clinical half-life of 20 hours. And we think that could be a key differentiator for us because with these epigenetic modifiers, what you want to do is cover Cmin for 20, 24 hours, and we're able to do that with that. Now Pfizer's half-life being 5, 6 hours does require BID dosing. So you do have this kind of peak to trough. And our view, and I think Pfizer's view as well is that a lot of the on-target toxicities is Cmax driven. So we're able to prevent that with the once-a-day dosing.

Great. You started to allude to this, but as you think about that differentiation, how would you expect to show up in like clinical benefit? And what maybe tie that into what you've actually seen in the clinical data you put today?

Yes. That's a great segue. And I think what we expect that to see is in the safety side of things. And I think we have seen that. As you know, we had a pretty comprehensive Q1 update. The Q1 update was really -- the objective of the Q1 update was really threefold, is one to select the patient population that we're going to study the first Phase III and select the dose of rinzimetostat that we're going to move forward with. And thirdly, to determine which AR inhibitor we're going to pick for the first Phase III study.

As you know, we're studying both with apalutamide and with darolutamide. We did that. We selected a dose of 400 mg of rinzimetostat, and we've decided to go with darolutamide for the first Phase III study. So if you look at that data update, I think, first and foremost, the efficacy that we've shown primarily on the PFS because that's ultimately the regulatory endpoint. It's highly competitive to what rinzimetostat has shown compared to mevrometostat. If you look at the landmark analysis at 5 months and we look at 5 months because the average follow-up we had -- the median follow-up, I should say, was 5 months. We had a landmark analysis of about 84%, which is right on top of what Pfizer showed at 5 months, both at the ASCO GU data in 2025, I think it was about 80% and then ASCO GU 2026 showed about 84%.

So the differentiation really comes on the safety side. So we were able to show that competitive -- highly competitive efficacy with a differentiated safety profile. So if you look at the adverse events and safety events us versus Pfizer, you can see both in the frequency and the severity of events were significantly less. If you look at Grade 3 treatment-related adverse events, we had mid-single digits. I think depending on which data set you look at, the 875 BID in the Fed or the 1250 in the fasted state, they had somewhere in the mid-30s to high 40s.

So we think safety at the end of the day will win out here, obviously, dealing with older men that are on therapy for an extended period of time. So I think that's the key differentiator so far what we've shown. Now could that translate into longer PFS longer term? We'll have to run that out to see what that looks like.

Great. One of the things that's come up in our conversations kind of subsequent to the data was just like nonspecific discontinuations in the Phase I trial. Maybe you could just contextualize that for us. and help us think about what you guys saw in your early Phase I update relative to apples-to-apples comparison versus mevro or other prostate cancer trials?

Yes, I think that's a good question. That's something that we've gotten a lot of questions about since our last data update. I think a couple of things. We addressed that in a few ways. I think, one, what we saw in our study is no different than what you typically see in other Phase I studies for prostate cancer. Just to remind people, it is a Phase I study, the primary endpoint is safety and PK. It's not an efficacy endpoint. I think that's kind of one.

When you look at other Phase I studies in prostate cancer, there's been many that's been reported recently, including mevrometostat and some of the other T cell engagers and other things like that. It's very common that you have early kind of non-related discontinuations. So I think that's kind of one. In these early Phase I studies, you don't always have perfect clarity on exactly why there are discontinuations, short of something definitive like a safety or an adverse event. And so patients can discontinue for a variety of reasons. Often, it's attributed to something like withdrawing consent or physician's decision.

What's a little bit unique in prostate cancer studies, you also have the phenomenon of increasing PSA. And so often patients can come off the study, especially in a Phase I study where the endpoint safety can come off early, not for radiographic progression, but just to move on to other studies or other therapies. And so that's something that you typically see in Phase I studies with prostate cancer, even though the prostate cancer guidelines discourage that, they encourage you to stay on treatment until radiographic progression, which is a key kind of regulatory endpoint.

As we move forward, thinking about a Phase III study, a lot of times that resolves itself usually because the primary endpoint is something efficacy in the case of mevrometostat it's radiographic progression-free survival or overall survival. Patients, physicians are often blinded to PSA response to not have any bias in the study. And so you see that as kind of typical in the way the progression of clinical studies for prostate cancer trials are conducted.

You've guided to providing another update from the program later this year. And maybe you could just talk about the scope of update that you're going to provide? What kind of things should we be expecting there?

Yes. So we provided updated guidance in January of each year, which we do on a regular basis. And at that time, we specifically intentionally called it a program update to give us full optionality or flexibility on what we provide there. So that could be a number of things. That could be just an update on where we are with the first Phase III study, which we refer to as Himalayas-1.

It could be our thoughts on a second Phase III study in prostate cancer, could be potentially a third -- another study outside of prostate cancer or it could be some additional data update as well. Now obviously, we're expecting the MEVPRO-1 data update as well. So it could also be some color on the results of that study and anything we learned from that study as well. So that's kind of broad. Obviously, we'll provide additional details at a later point.

Within that range of things you just said, one of them is data in the post ARPI population. And so what do you think you need to have to be able to provide a robust update such that it would be worth sharing in the second half of the year in terms of patient numbers, et cetera?

Yes. Specifically on the post-AR inhibitor population, I think, one, we're obviously excited by the data we've shown so far. I think when you look at radiographic progression-free survival, it looks fairly consistent to what we've seen in the post-abiraterone setting. I think you asked a good question, what do we need to see to kind of move that one forward. I think, one, we want to see a little bit more patients responding the same way that we have in our initial bolus of data. And then two, I think a little bit longer duration is what we want to see.

And so again, as Dominic said, similar to the post-abiraterone patients, we had a median follow-up of about 5 months. And so the 5-month PFS actually stands out pretty well compared to other therapies in the space at that landmark. So I think we want to see a few more months of duration to see if that holds. And I think that we will get pretty excited by that moving forward since there is a significant unmet need there.

And remind us what the benchmarks are for rPFS 5 months?

Yes. It's relatively similar to the post-abiraterone setting and that you see a lot of patients, either 1 in clinical studies or 2 in the real world getting AR switch. And so this would be the opposite. So instead of patients having received abiraterone and getting an AR inhibitor, this is kind of the vice versa. They're getting an ARPI, so the AR switch would be abiraterone. And in that setting, there's been some recent Phase III studies that reported data. You typically see an rPFS of about 3 months. And so the AR switching is typically shorter as patients do worse, having seen an AR inhibitor switching to abiraterone. So I think that's one.

Chemotherapy is about the same, so about 7 to 8 months. That is a 5-month landmark PFS in the 60%, whereas we're tracking about 85%. And I think the other interesting benchmark there, it is a relatively small data set. It's a population that Pfizer has not been focused on with mevrometostat, but they did report Phase I data in one of their earlier updates a couple of years ago in that setting. And there, they showed a 5-month landmark PFS in the high 60s. And so again, there's some separation there. Again, it's small data sets to compare, but I think what we're seeing so far is very encouraging.

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You covered it.

You got it. All right. Okay. Let's talk about the registrational study Himalayas-1. Maybe first speak to the dose selection at 400 mg. And are you confident kind of with that selection? And it sounds like you've had these regulatory conversations that you've satisfied any sort of Project Optimus or other requirements?

Yes. I think on -- I think we disclosed this on the Q1 update. We did complete an extensive exposure response analysis across a number of different measures, looking at the correlation to exposure to both the efficacy and safety. And the key takeaway there is that from an efficacy standpoint, there was no statistical difference in the dose on the safety there was. So that was a key driver. So this is actually the ideal scenario for Project Optimus, right? You want to maintain the efficacy without pushing the dose too much from a safety standpoint.

And as you pointed out, we did complete the end of Phase I study and the FDA was satisfied with the completion and the way we approach Project Optimus. So 400 is our dose going forward. We feel good about it. And we'll have data probably in early 2028 from the Phase III study.

One of the key strategic questions you answered with the update earlier this year was the decision on combination agent of darolutamide. Maybe you could talk about the advantages you saw partnering in that direction, both with respect to the drug and Bayer as a partner.

Yes. I think at the end of the day, we think both apalutamide and darolutamide are both great drugs. I think what we've said to date, there's really been no drastic difference between the 2 agents combining with apalutamide or with darolutamide. I think at the end of the day, and we know this, right, we know enzalutamide and apalutamide are CYP inducers. And when you're combining it with our drug as well as mevrometostat, you have this kind of CYP interaction of CYP DDI, which decreases the dose or the exposure, I should say, of our drug and mevrometostat as well, which requires you to increase the dose. And I think that's why Pfizer is required to push their dose as well.

So that's a big difference, I think, when you look at the difference between going with darolutamide and apalutamide. Again, we think they're both great drugs. We just think from a differentiation standpoint, this further differentiates us from Pfizer in the first Phase III study. Now to be clear, the decision to proceed with the first Phase III study, darolutamide does not preclude us from using a different AR inhibitor in the second Phase III study in prostate cancer that we choose to go. So I think that was the key driver. They're both great drugs. And then if you ask a number of KOLs, I think they stack rank the 3R inhibitors, they'd say the cleanest from an efficacy standpoint, I think most people would say they're generally the same.

I think from a safety standpoint, first, they'd say darolutamide is the safest drug of the 3. And if you look at some of the darolutamide, just kind of rehash history here, but enzalutamide was launched back in 2012. Apalutamide came 6, 7 years late in 2018 and darolutamide came a year after that. And darolutamide is a run rate, call it, $3 billion, $3.5 billion, and they're growing at 50% to 60%. So they're kind of one of the leaders in the space, and they're growing exponentially there. So I think that's another factor we think about. Obviously, we want to hitch your wagon to is the key driver there. And the further differentiation on safety here, we think the better it is for us for this indication.

Great. So you mentioned that you've reached FDA. I guess what can you share about the parameters in the registrational program that you're going to start here in the near term?

Yes. So I think obviously, we don't go into intimate detail on our FDA interactions. But at a high level, the study design is a 600-patient study, 300 in the treatment arm, 300 in the control arm. The dose we selected, as we said, is 400 of rinzimetostat plus the approved dose of darolutamide. The control arm will be a physician's choice of AR inhibitor or docetaxel. And again, the primary endpoint will be radiographic PFS. Now we're expecting to start that study imminently. We think it will take about 15, 16 months to enroll that study, and we could have top line data as early as early 2028.

Okay. What would you expect the mix of docetaxel versus AR inhibitor to be based on real-world utilization trends?

Yes. I think generally speaking, we'd say the range is close to 50-50, maybe it's 40-60 on the extremes. But depending on which KOL you speak to, there's definitely a preference that each KOL has on what they like to do and some of that may be regional or their experience with the drug as well. So I think, yes, I think that's generally the rule. Now if you look at Pfizer, I think they're generally assuming -- it appears there they're kind of assuming a similar split between AR inhibitor and docetaxel as well.

Right. All right. That's a great transition to MEVPRO-1 data, which is away from you all technically, but is a big catalyst for the cost this year. Maybe just remind us briefly of the trial design relative to the Phase III that you guys are taking forward.

Yes. To be honest with you, we've obviously done our own independent work around our stats and our trial design. And it is very similar to MEVPRO-1. And just to remind everybody that, again, it's 600 patients, they're using 875 BID in the fed state of mevrometostat plus the approved dose of enzalutamide versus the control arm, which again is physician's choice between docetaxel and enzalutamide. That study is powered to show a hazard ratio, I think, about 0.66 or 6.5. They're assuming the control arm does 6.75. And if you do rough math, it appears they're assuming around 6 months for enzalutamide and about, call it, 7-ish months for docetaxel.

So if you assume a 50-50 split between the 2 agents, you get to this blend of 6.75 in the control arm. For the treatment arm, they're assuming 10.2. And as you know, they showed about 14 months at ASCO GU in 2025 in their randomized data set and the more recent update at ASCO GU 2026, they showed about 14 months. So they're assuming some level of degradation. So we think that study is well powered. We think that study has a good chance of being positive as well.

It's pretty common to assume some level of degradation from early studies into later studies in oncology. But I guess, how would you guys think about that level of 14 months to 10 months in transition from a smaller study to later-stage trial?

Yes. I think generally speaking, I'd say that's maybe a little bit on the conservative side based on -- we've seen multiple data sets that they presented where they've confirmed the 14 months. But again, we think it's an appropriately powered study. And even if you're able to show 10 months, I think 10 months in that setting is a big win for the class for Pfizer and then direct read through to us. I mean if you look at other agents in the space, Pluvicto, for example, in a pre-chemo patient population is probably close to 10 months. So this -- as you guys know, in this study design, you're looking at metastatic CRPC patients. These are patients that had failed abiraterone, and they could have seen up to 1 round of chemo as well. So in theory, these are more heavily pretreated patients than the Pluvicto pre-chemo patient population.

I think the other maybe small point to mention as well as side effects using improved dosing regimen and formulation in their Phase III. So they are switching from the 1250 BID in a fasted state into the 875 fed. And I think the data they've shown on that, obviously, one, way more tolerable than their original regimen that they used in their Phase II randomized. And then two, the data they presented earlier this year at ASCO GU, the efficacy seems like it's tracking a little bit better as well. The PSA response is a little bit better. The PFS hasn't been reached yet. And so there's actually potential for that it could exceed. In their earlier Phase I study, they also showed 17.1 months.

And I think as Dominic said, I think we believe if it is a positive study, that should be very commercially relevant when you look at the benchmarks. There are not many therapies in prostate cancer that have beaten the chemotherapy control arm. So I think that's one really interesting thing that, that is the standard to actually beat. And so if they are able to do that, that would be fairly significant. The only other benchmark out there is Pluvicto that is doing very successful, competing well against docetaxel that has an rPFS about 9 months. And so we think if Pfizer can post results in the 10 months is kind of what they're assuming with an oral therapy that's relatively generally well tolerated, we think that would be very successful for the program and the class.

Great. Is there anything that you might take into consideration on seeing your data that could inform Phase III kind of at the margin in your own design?

That may be difficult. Obviously, we don't know when the MEVPRO-1 data will be released. I think the guidance is mid-'26 or second half '26, which basically means the rest of the year. I mean we're early June, so we don't know when that's coming. As I said before, we're imminently starting the Phase III study. So it may be highly unlikely that we'd be able to kind of read into that.

The other thing I'd say is that Pfizer typically will present top line data, just telling you the study is positive and maybe very little color around that. So we won't know the details about that as well. So I mean, realistically, it may be very difficult to kind of see what -- get any color on what they've disclosed other than whether the study hits or not.

Okay. Maybe you could just talk about like a world in which, obviously, your base case is that it succeeds on efficacy and it looks reasonable from a profile perspective. Is there a world in which the trial disappoints but you guys still feel confident in rinzimetostat? And what would that look like?

Yes. We kind of think about it in 4 buckets. One is there's a big win where they just kind of knock it out of the park. Two is where they barely win. Three is where they barely miss and 4 is where they really totally dismissed, which I'd say 4, based on the data that we've seen based on the powering of their Phase III study, we think is kind of off the table. In the middle 2, I think it's interesting because we really would need to understand why they barely made it or why they barely missed.

Again, we think the key differentiator for us to date based on the data that we presented really comes in the form of safety, right? Better safety, you get better compliance, you maybe get longer duration as well. So I think that's the key part. Now again, when Pfizer presents that detailed information, we'll be telling. They obviously have 3 studies ongoing with MEVPRO 1, 2 and 3. So we'll have to just see obviously what they present when they give the top line data update.

Okay. Maybe you could talk about the market opportunity in this first indication that you selected? And could you provide like a high-level view of what you think the opportunity is there?

Yes. So we -- I mean, I think, one, just to start off, we think it's a very significant commercial opportunity. Again, we're kind of going into patients that have previously failed an ARPI, specifically abiraterone. One thing to point out, if you look at the kind of prescriptions in the U.S., abiraterone right now is tracking about 50% of prescriptions in the ARPI market. So there's very significant abiraterone use in the U.S. global as well. And so we think there are a lot of patients that have failed abiraterone, roughly half the market. And I think there's pretty good statistics out there that kind of cite 35,000 to 40,000 metastatic prostate cancer patients. A majority of them have had seen a prior ARPI, potentially up to half of those would have seen abiraterone is their ARPI of choice.

And again, one of the benefits with the PRC2 inhibitor, what we're starting to see with our data and the mevrometostat data is you have the potential for really long duration of therapy with mevrometostat in the randomized Phase II, a 14.3-month PFS. If you kind of add those numbers together using kind of typical pricing for an ARPI, you can easily get to a $3.5-plus billion, a year opportunity just in the U.S., just in the post abiraterone setting. Again, if we were to move forward in a post AR inhibitor setting, that would be essentially about the same market size, again, just in the U.S. alone. So it's a very substantial market opportunity with a very significant unmet need.

Yes. And again, it sounds like your expectation is you'd share this market. So how do you think about kind of share?

Yes. And again, as Matt said, like we think the TAM is $3.5 billion in the U.S. if you just do some rough math based on number of patients and duration and using some average price. When you look at the ex U.S. market, if you look at prostate cancer, it's probably 90% or 100% of the U.S. market. So overall, we think worldwide, that could be close to a $7 billion opportunity. I think when we think of market share, I kind of look at it 2 ways. One is you have the perfect analogy with darolutamide, right? You have a drug that came out 7 years after enzalutamide. The only difference is really on the safety front, and that's doing $3.5 billion, and that's growing 50% per year.

I think the other thing is we've done -- actually, Matt and our Head of Commercial have kind of done an independent market research with the party. And based on that market research, if you just kind of put the profiles of our drug versus mevro and the only differentiation is safety, we should share. So safety does matter here is the point, and we think that could be a huge differentiator, especially as you kind of move up into early lines of therapy like castrate-sensitive prostate cancer, where patients are not on drug for months, but they're on drugs for 4 years or so.

Great. Maybe we can pivot for the last couple of minutes here to the EGFR program. It's specifically designed for potency against exon 20 and atypical mutations in that drug is ORIC-114. And I know there's a new name, but it easier for me to say. So let's start with how the agent is theoretically differentiated versus the range of other EGFR programs.

Sure. Yes, we call it enozertinib is kind of the new name. So yes, preclinically, the molecule, I think a couple of things was designed specifically for exon 20. So prospectively screened and designed for that. I think that's one differentiator. That is not true for most of the EGFR exon 20 inhibitors today. And then two, also prospectively designed to be brain penetrant. And so we thought that, that is a key feature preclinically that was missing in the marketplace. I think there's been a number of companies, a number of therapies that have been going after EGFR exon 20 for a while. We always felt the landscape was missing like a truly good brain-penetrant drug, which is extremely relevant in lung cancer.

As you see from studies and other prevalence reports that at least 1/3 of patients will actually present with baseline brain mets at diagnosis or the time they enter clinical studies and a majority of them will actually progress with brain lesions over the course of their therapy. And so what we've seen with other targeted therapies for the other oncogenic drivers is that you really need a brain-penetrant drug to be very successful, to have very long duration of therapy. And so we think that, that is kind of the key differentiator.

That was early preclinical data and how it's designed. We have presented clinical data now where we're actually seeing that. And so those were the things that we really wanted to see in the clinic. And so I think, one, that we look at the potency and selectivity, which is what it was designed for, and we're actually seeing that in the clinic. From a safety perspective, some EGFR kind of toxicities where we've seen none of the off-targets that other therapies have, such as cardiotoxicity and QTc prolongation, CPK elevations, liver enzyme elevations, things like that. We haven't seen any of that. So I think that's one very good.

Two, we're enrolling an extremely heavily pretreated patient population. We're allowing extremely broad enrollment criteria for CNS criteria. And so one of the distinguishing features is that we allow patients to come into our study with so-called active brain metastases. And so they do not have to have been treated. They can come with full active CNS metastases. That's very different from other studies that will restrict patients from having brain metastases at all. Some studies allow it, but they have to be treated with things like radiation. And so that's kind of key.

And what we have seen from our early data, we're actually seeing really dramatic responses in those patients. And so we think Again, that is the differentiating feature that we have presented so far. We think that, that will translate into kind of long duration of therapy that has the potential to do that. And so we're excited to kind of continue to update folks with the progress of that program.

Great. You did share an update in December and you, I think, anticipate sharing another update kind of midyear this year. Maybe you could talk about the data to date and the scope of the update we could expect.

Sure. I can cover the data, and then I think Dom can kind of point you to what to expect going forward. So I think a couple of the things that we've shared is we are really prioritizing first-line patients. And so we initially started enrolling patients that were previously treated. Now we're really focused on the first-line patients, both in the EGFR exon 20 side and the atypical side. what we've seen just from a high level so far, I think the efficacy in terms of initial ORR seems to be as good, if not better, than what other therapies have reported in both in terms of EGFR exon 20 and atypicals. The safety profile as well looks as good or better than anything else. And so I think we feel extremely excited by that.

And then I think the one thing that is extremely differentiated is what we've seen on the CNS side. So again, in both of those patient populations, that's the first-line EGFR exon 20 and the atypicals, we enrolled patients with active CNS mets. Patients had measurable CNS mets. And in both of those populations, we had 100% CNS ORR in those patients with measurable disease. That has been something that has not been reported yet. And so we think, again, that one speaks to the differentiation and I think leaves us hopeful that we'll see a long-term duration of benefit there.

Other companies that have reported data, especially in the exon 20 side, most of them actually do not see a benefit in patients with CNS metastases, which is why a lot of times, those are excluded from clinical studies. And so we're seeing activity in patients that aren't even allowed to be enrolled in other studies. We saw a couple of updates at ASCO. There's a company, Dizal reported data with sunvozertinib. They had extremely restrictive CNS criteria. But when you look at the data, they actually had no benefit in patients that actually had CNS metastases even though they were required to be treated. And so that was kind of the third study. We've seen that with others as well is that there's just no benefit with some of the other therapies out there. Patients have any sort of history with CNS disease.

And I'll take the second part. So we have a pretty comprehensive update in the second half of the year. This will be at the 80 mg dose, which is kind of the recommended dose we're going forward with. So in first-line EGFR exon 20 as a monotherapy, we have 20 to 25 patients worth of data. In first-line EGFR atypical, we'll have another 20 to 25 patients of data, and then we'll have about 20 patients or so in exon 20 first line with combination with amivantamab as well.

So it's a pretty comprehensive update you'd expect to see there is obviously systemic response rate, CNS response rate, safety, tolerability and a look on durability as well. When we think about the benchmarks in each of those respective areas, we think more or less it's at 60% plus from a systemic response rate.

Maybe briefly, you could touch on what you see as the market opportunity or the size of the market in this population, particularly given the competitive landscape?

Sure. Yes. I think when we think about this space, it's a smaller opportunity in terms of patients wise than prostate cancer, but there is the potential for really long duration of treatment. What's been pretty well characterized is both of the EGFR populations we're targeting. Exon 20, people typically cite about 2%, maybe a little bit higher of lung cancer, and that will get you several thousand patients in the U.S., about 4,000 patients. The atypical side seems to be a little bit bigger. I think it's commonly cited about 3% of lung cancer. And so again, that will get you kind of another 6,000 patients. So with about 10,000 patients, the potential for long duration of therapy, typical drug pricing, you can easily get to multibillion dollars just in the U.S. for both of those is a TAM.

The one thing that's a little bit different with targeted therapies in our view is you really want to have a best-in-class therapy. It is rare that you see markets kind of split evenly in targeted therapies. So again, we want to have a best-in-class profile. If that is true, that's a very substantial commercial opportunity for both of those populations we're targeting. Again, if you add both of them together, it's about 5% of lung cancer. That is kind of in the ballpark of an ALK market. And we've seen that market in the U.S. is about -- or globally is about $4 billion to $5 billion split between kind of the 2 leading therapies there.

Okay. Maybe in our final minute here, you could talk about cash runway and the clinical activities that are embedded in that guidance.

Yes. So we ended the first quarter with $420 million in cash and investments. That gives us cash runway into the second half of 2028. That does assume, obviously, the Phase III study for rinzimetostat, Himalayas-1 that we're starting imminently. That also assumes us starting a Phase III study for enozertinib in early 2027. So that's fully burdened in there.

I think the other key takeaway, as I said before, we're expecting top line data from the first Phase III study with rinzi in early 2028. So we've got cash runway well past that going into the second half of 2028. So we feel we're well capitalized at this point in time.

Beautiful. Well, it's great having you. Thanks for the conversation today, and thanks to everyone who joined us. And with that, we can turn it off.

Thanks.

Thank you. Great.

Good day, and thank you for standing by. Welcome to the ORIC Pharma Update Conference Call. [Operator Instructions]. Please be advised that today's conference is

being recorded. I would now like to hand the conference over to your speaker today, Dominic Piscitelli. Please go ahead, sir.

Welcome to the ORIC Pharmaceuticals rinzumetostat dose optimization data update call. Earlier today, we issued a press release highlighting new clinical data and details for our first Phase III trial. We have prerecorded our prepared remarks, after which we will host a live Q&A session. A replay of the webcast, along with the accompanying slides will be available on the Investor Relations section of our website for 90 days.

Before we begin, during this call, we will be making forward-looking statements, including forward-looking statements based on our current expectations and projections about future events. Our actual results may differ materially from those indicated by such forward-looking statements. For a description of risk factors, please refer to our recent filings with the SEC. ORIC specifically disclaims any obligation to update any forward-looking statements.

Now turning to Slide 3. During today's call, we'll discuss rinzimetostat's preclinical differentiation, clinical data supporting selection of the recommended Phase III dose design of rinzimetostat's first Phase III trial and an overview of its commercial potential, followed by Q&A.

Joining me on the call today, we have Jacob Chacko, CEO; Lori Friedman, CFO; Pratik Multani, CMO; Matt Panuwat, CEO; and Keith Louis, Senior's Vice President, Commercial and Medical Affairs.

Now let me turn the call over to Jacob.

Turning to Slide 5. At ORIC Pharmaceuticals, our late-stage pipeline is centered on 2 potentially best-in-class programs, each targeting large commercial opportunities. The first is rinzimetostat, a PRC2 inhibitor being developed for prostate cancer in collaboration with our partners at Bayer and Johnson & Johnson.

The second is enozertinib, a brain-penetrant EGFR inhibitor being developed for non-small cell lung cancer also in collaboration with Johnson & Johnson. Today's presentation will be focused on rinzimetostat and specifically the dose optimization data that supports our selection of a Phase III dose and the path forward into our first Phase III registrational trial, IMBAS1.

Turning to Slide 6. Let me take a moment to frame the key takeaways from today's data update before we walk through the details. First, PRC2 inhibitors have demonstrated significant clinical benefit in metastatic CRPC with far longer radiographic progression-free survival than approved and emerging therapies in this setting.

Second, rinzimetostat is a next-generation PRC2 inhibitor that was rationally designed to have best-in-class drug properties, including superior potency and a 20-hour clinical half-life that provides strong target coverage and pharmacokinetics that successfully minimize Cmax-related toxicity. Third, we have selected rinzimetostat 400 milligrams once daily in combination with darolutamide as our recommended Phase III dose, or RP 3D for this first Phase III trial.

This dose demonstrated a highly competitive emerging efficacy profile as measured by early landmark radiographic PFS, PSA response and ctDNA reduction, while also demonstrating a highly differentiated safety profile with significantly lower frequency and severity of adverse events compared to competitor regimens. Finally, we expect to immediately initiate our first Phase III trial, which will be called HIMALAYAS 1 in post abiraterone metastatic CRPC, a population that is a $3.5 billion total addressable market annually in the U.S. and has a lack of oral well-tolerated therapies. We are simultaneously evaluating multiple additional potential registrational trials with the intent of starting our second Phase III trial in 2027.

Now turning to Slide 7. To appreciate the opportunity ahead for its it's helpful to first understand the competitive landscape in post ARPI metastatic CRPC. Currently available therapies in this setting, including enzalutamide, docetaxel, cabazitaxel, and [ levicto ] have demonstrated median RPFS ranging from roughly 6 to 9 months and often come with meaningful associated toxicity and administration challenges.

By contrast, rinzimetostat meets Pfizer's PRC2 inhibitor in combination with an AR inhibitor has demonstrated impressive median RPFS in the range of approximately 12 to 14 months, which is far longer than these other therapies. Given the alternative, even a double-digit RPFS would be a game changer for patients in this setting, especially considering that the PRC2 regimen is an all oral therapy. However, the mevrometostat regimen carries with it meaningful toxicity challenges.

As we will discuss shortly in the slides ahead, our early data for rinzimetostat in combination with darolutamide is tracking quite favorably relative to the MEBro-PFS benchmarks while also offering a substantially cleaner safety profile.

Turning to Slide 8. This slide provides a snapshot of the key efficacy and safety data for rinzimetostat at 400 milligrams once daily in combination with darolutamide in the far right column and places it side-by-side with 2 key comparators. Enzalutamide monotherapy in the far left column and the combination of mevro with enzalutamide in the middle column.

Starting with efficacy. The early RPFS landmark data for [ vinci ] plus darolutamide is highly competitive. As 3, 4 and 5 months, our combination achieved landmark RPFS percentages that are essentially identical to the mevro combination and far higher than those of AR inhibitor monotherapy.

For that matter, the rinzimetostat landmark RPFS percentages outperformed those of the various alternative therapies listed on the prior page like pluvicto and chemotherapy as well. What is even more remarkable though is that rinzi's strong efficacy is accompanied by an exquisitely clean safety profile.

The safety profile for our 400-milligram dose in combination with darolutamide is markedly cleaner than what has been reported in the mevro regimen with pluvicto or with chemotherapy. The most common treatment-related adverse events for the rinzi daro combination are fatigue, diarrhea and nausea, all of which occur at relatively low rates and critically, all are grade 1 or 2. Treatment modifications of any kind were exceedingly rare. The contrast versus our competitor safety profile and versus other alternatives in this space is stark.

Finally, turning to Slide 9. I want to briefly review the magnitude of the opportunity that lies before us. In prostate cancer alone, we estimate that rinzimetostat has the potential to reach approximately 70,000 patients in the U.S. annually across 3 distinct indications. The initial target population post abiraterone metastatic CRPC is today roughly a $3.5 billion annual total addressable market in the U.S. alone, with additional prostate populations like post AR inhibitor metastatic CRPC and metastatic castration-sensitive prostate cancer, the opportunity grows substantially, with the metastatic CSPC setting alone being a potential market of greater than $10 billion annually in the U.S.

Beyond prostate cancer, we also see meaningful future development opportunities for Rinse in other settings, including non-small cell lung cancer, colorectal cancer and breast cancer, where the biology of PRC2 inhibition may similarly enable combination strategies with various approved and investigational therapies.

With that, let me hand the call over to Lori to walk through the preclinical rationale for rinzi before Pratik walks us through the clinical data. Lori?

Thanks, Jacob. It's my pleasure to talk about PRC2 and our excitement for developing rinzimetostat in prostate cancer. Turning to Slide 11. PRC2 has been a target of interest for many years. However, the first-generation inhibitors such as CPI-1205 and tazemetostat had multiple shortcomings as shown in the left side of the table.

mevrometostat, a second-generation inhibitor addressed some of these issues including cell potency and SIP auto induction, yet fall short in other drug properties such as solubility and half-life. Rinzimetostat shows improvement in all categories, including drug properties that result in a 20-hour half-life in the clinic, thus, rinzi has potential as a best-in-class PRC2 inhibitor that addresses all the limitations of earlier generation inhibitors.

On Slide 12 are 2 examples of preclinical in vitro data demonstrating the superior potency of rinzimetostat to first-generation PRC2 inhibitors. In these dose-ranging studies, AR-positive prostate cancer cell lines were treated head-to-head with 4 different drugs and assay for effects on cell growth and viability. The cell potency for first-generation inhibitors shown in black and dark blue curves are right shifted due to their weaker potencies. Rinzimetostat demonstrates comparable potency to mevrometostat in prostate cancer cell lines and superiority to the first-generation PRC2 inhibitors.

The graphic on Slide 13 summarizes how therapeutically targeting PRC2 reverses the evolution of prostate cancer. As prostate cancers are treated with hormone blockade or with AR targeted agents, they evolve to evade these therapies. Going from left to right, the illustration shows prostate tumors progressing from castration sensitive to insensitive and from AR dependent to AR independent. Epigenetic reprogramming is the mechanism by which prostate cancer cells transition to change their cell state to escape therapeutic pressure.

PRC2 inhibition can reverse this process and even prevent the transition. So that prostate cancer cells regain and maintain their luminal cell state and their dependency on AR. This mechanistic rationale supports the combination of PRC2 inhibitors with AR inhibitors and suggest that the therapeutic potential of rinzimetostat in prostate cancer will be maximized in combination with AR inhibitors.

On Slide 14 is an example of preclinical data supporting the mechanistic rationale, where PRC2 inhibition with rinzimetostat sensitizes prostate cancers to AR inhibition through epigenetic reprogramming, in the 2 experiments shown here with the CRPC model on the left and the CSPC model on the right, prostate cancers were treated with either rinzimetostat or the vehicle control and tumors were then assessed for transcriptional changes using RNA sequencing. 2 consistent changes were observed, a significant increase in AR signaling and a significant increase in luminal cell state markers. These transcriptional shifts result in the prostate tumors having an increased dependency on the androgen receptor.

Slide 15 shows how rinzimetostat further controls epigenetic reprogramming at the level of chromatin modifications in experiments using ATAX sequencing. These volcano plots depict transcription factor sites on chromogen that are either significantly opened, shown in orange or significantly closed shown in blue.

On the prior slide, I showed how luminal and AR transcriptional signatures were increased following rinzi treatment. In these experiments, we also see that important transcription factor sites are closed. And notably, these closed sites are known to drive lineages statement in prostate cancer, such as [ 1 CAT II and FOXA1 AR ] half sites. Visibility of rinzimetostat to reduce accessibility to lineage escape factors means that rinzi has the potential to prevent resistance from arising. And again, like the prior slide, we see the same mechanism in both CRPC and CSPC models.

Moving forward to in vivo efficacy on Slide 16. On the left is an example of a study where castration-resistant prostate cancer xenograft were treated with darolutamide with and without PRC2 inhibitor. The combination of rinzimetostat with darolutamide impressively improved progression-free survival in this castration-resistant setting. On the right is a similar study. Only this time, the combination was assessed in castration-sensitive prostate cancer xenograft. Once again, adding rinzimetostat to darolutamide increase the progression-free survival. Thus, rinzimetostat has been shown to combine with AR inhibition in prostate cancer xenograph to improve survival in both CRPC and CSPC studies. And importantly, with rinzimetostat's improved drug properties, it stands out as the potential best-in-class PRC2 inhibitor. We're excited to see rinzi's progress in the clinic, as Pratik will tell you about.

Thank you, Lori. Turning to Slide 18. It's my pleasure to provide an update of the dose optimization data from our Phase Ib trial of rinzimetostat and the extensive work we've done to select the recommended Phase III dose to take into our first registrational trial.

This trial is a multicenter study being conducted in 4 countries in patients with metastatic prostate cancer. Initially, we explored rinsimetostat as a single agent at doses ranging from 100 milligrams to 900 milligrams once daily. These data established rinzi's strong pharmaceutical properties, including dose proportional exposure, no evidence of SIP auto induction and a 20-hour clinical half-life allowing once-daily dosing. We also demonstrated robust target engagement at doses as low as 200 milligrams and a well-tolerated safety profile with a single agent maximal tolerated dose of 800 milligrams giving us a wide therapeutic window and making rinzi is highly suitable for drug combination.

Collectively, these properties differentiated rinzimetostat from other PRC2 inhibitors, and positioned it as a potential best-in-class molecule. We then proceeded to combination dose finding conducted in parallel with both darolutamide and apalutamide and have previously presented data from this experience last year.

After determining the candidate RP 3Ds for each AR inhibitor combination, we then embarked upon comprehensive dose optimization randomizing patients to receive 1 of the 2 RP 3Ds selected for each AR inhibitor, respectively. This dose optimization was conducted in 2 separate patient populations with metastatic prostate cancer. One in patients who have previously received abiraterone and the other in patients who had previously received a second-generation androgen receptor inhibitor, namely apalutamide enzalutamide or darolutamide.

Today's update will focus on our dose optimization work with rinzimetostat in combination with darolutamide in the post abiraterone patient population. Before I get into the new dose optimization clinical data, turning to Slide 19, I wanted to spend a minute talking about the pharmacokinetics and pharmacodynamic results that underpin our decision-making around optimal dose and RP 3D selection.

On the left of this slide is a PK plot of rinzimetostat over 24 hours for the 2 doses selected for dose optimization with darolutamide. 400 milligrams and 600 milligrams once daily. You can see that both blue curves peak at 4 hours with a gradual decay over 24 hours demonstrating rinses 20-hour half-life and well-behaved pharmacokinetics. Superimposed on these 2 curves in shades of gray are the single agent PK curves for the same doses of rinzimetostat highlighting the lack of drug-drug interaction between rinzi and daro. The

2 dotted red lines superimposed on this PK plot represent target minimum concentrations from our preclinical work. The key point here is that both doses cover the target exposure for the full 24 hours. On the right, we have pharmacodynamic data, looking at the level of H3K27 trimethylation levels in PBMCs both as a single agent or in combination with darolutamide, we maximize the PD signal in this readout at both 400 and 600 milligrams. And from our single agent work, you can see that we even cover the target at 200 milligrams.

So these data collectively support our choice to take 2 dose levels into dose optimization that were both predicted to be efficacious. Turning to Slide 20 and our clinical data. You can see the demographics and baseline characteristics of the patients treated with rinzimetostat at 400 and 600 in combination with darolutamide in patients with mCRPC post abiraterone.

Overall, these patients were more heavily pretreated than those from recent competitor data sets. The median baseline PSA was 26 for the 400-milligram dose and 12 for the 600-milligram dose. While the median baseline PSA of 12 is comparable to what's been seen in other MCRPC data sets, the median of 26 in the 400-milligram group is considerably higher. In terms of treatment history, patients at both doses had a median of 2 prior therapies, not counting ADT. They all had received prior abiraterone with many receiving prior docetaxel as well as additional therapies such as immune therapy, radium-223 or PARP inhibitors.

This prior treatment history makes our population more heavily pretreated than the disclosed mebrometostat experience which only allowed prior abiraterone and up to one prior chemotherapy and no other therapies. Finally, tables like these conventionally show median age in the first row with little comment. But I think it's important to point out that the median age here is in most studies in metastatic prostate cancer was 70 years overall, meaning that this is a more fragile elderly population with less tolerance for drug-related toxicity.

Slide 21 shows the safety profile of rinzimetostat at 400 and 600 milligrams in combination with darolutamide. You can clearly see that almost all adverse events are either grade 1 or 2. In fact, across all 33 patients at both dose levels, there was only 1 grade 3 event. There were also no grade 4 or 5 treatment-related adverse events at either dose. The most frequent adverse events include fatigue, which can be attributed not only to rinzimetostat, but also the AR inhibitor darolutamide and to the patient's cancer itself.

Next on the list are GI-related toxicities, diarrhea and nausea. These side effects can be particularly troublesome if they are chronic, even at grade 2 in severity because they can significantly impact a patient's quality of life. They'll note that at the 400-milligram dose, most of these events were Grade 1, whereas it's 600 milligrams, there was a generally higher rate of grade 2 events. This safety trend can be seen more clearly on Slide 22, where we pull back and include 39 additional patients from the post AR inhibitor dose optimization cohorts.

The overall safety experience here is larger with 37 patients at the 400-milligram dose level and 35 patients at the 600-milligram dose level. Again, there are a few grade 3 events overall but there remains a trend towards fewer grade 2 versus grade 1 adverse events at the 400-milligram dose level versus 600, especially with the important potential quality of life toxicities of diarrhea and nausea.

In keeping with this observation, the rate of diarrhea at 400 is also just about half the rate at 60, 19% versus 37%, respectively. Nausea is also lower at 400 milligrams and entirely grade 1 compared with 600 milligrams. From a safety perspective, both those levels appear to be well tolerated. However, for a drug where long-term dosing is expected for months and even years, minimizing the incidence of even grade 2 events can be critical to patient adherence.

For the treatment to work, patients need to stay on therapy and the need to maintain that therapy without frequent interruptions for toxicity since interruptions can lead to loss of target coverage and compromise efficacy. Furthermore, these factors become even more critical if you intend to move the drug earlier in the course of disease, for example, into the CSPC setting, where we are planning future potential Phase III trials.

Turning to Slide 23. We have additional safety data, specifically various types of treatment modification events, rates of dose interruptions, dose reductions and treatment discontinuations presented for both the post abiraterone population and the broader post ARPI population. The general trends that we just saw with the adverse event tables are also evident here.

Both the 400 and 600-milligram dose groups have event rates that are lower than competitor regimens, but the 400-milligram remains more favorable than the 600 milligrams with lower rates of treatment modifications across the board.

With that in mind, let's turn to Slide 24, which outlines the work we did to satisfy the requirements of FDA's Project Optimus and formally select the rinzimetostat recommended Phase III dose in combination with darolutamide. To do this, we performed an extensive set of exposure response analysis that look for correlations between drug exposure and a range of measures of both safety and efficacy. Drug exposure was quantified multiple ways. We looked at Semen the lowest concentration over 24 hours. We looked at Cmax, which is the highest concentration, and we looked at AUC a measure of overall exposure, including accounting for individual patient dose modifications.

Safety measures we examined included the rate of grade 2 or higher adverse events, grade 3 or higher events or serious adverse events. We also look for correlations between exposure and specific subsets of adverse events of interest such as gastrointestinal or hematologic toxicities. And finally, we look at the relationship between exposure and rates of treatment modifications.

On the efficacy side, we looked at correlations with radiographic progression-free survival with PSA reduction, both categorically as a response rate and as a continuous variable. We also looked at reduction in ctDNA, and a pharmacodynamic readouts such as changes in H3K27 trimethylation. Overall, this in-depth analysis showed that both 400 and 600 milligrams provided comparable efficacy. There was substantial overlap and exposure distributions between responders and nonresponders on any measure of efficacy, including progression-free survival without statistical significance.

Thus, the 600-milligram dose was statistically comparable to and not superior to the 400-milligram dose. In terms of safety, however, the ER analysis showed statistically significant relationships between exposure and clinically meaningful toxicities as well as statistically significant correlations between higher exposures and higher rates of treatment modifications.

Thus, on the basis of safety, the 400-milligram dose was clearly favored over the 600-milligram dose. Overall, the conclusions from this ER analysis were unambiguous with no advantage in efficacy at the higher dose but a clear statistically significant advantage in safety at 400 milligrams. Therefore, the definitive conclusion from this work is that 400 milligrams is the preferred RP 3D for rinzimetostat in combination with darolutamide. With 400 milligrams selected as our recommended Phase II dose of rinzimetostat in combination with darolutamide.

Let's now take a look at its efficacy profile over the next few slides, beginning on Slide 26. We would hope to replicate this efficacy profile in the upcoming Phase III trial, which if we do, would yield a therapy that is more effective and yet safer than options currently available to these patients today. In fact, we may even be able to improve upon this profile given the more heavily pretreated nature of the patients we treated in dose optimization versus those we would be enrolling in our upcoming Phase III trial.

On this slide, we have a PSA waterfall plot of the best percentage change in PSA from baseline for the 15 patients with mCRPC post abiraterone, who had a PSA measurement by the data cutoff. You can see strong clinical activity with a 47% unconfirmed and 33% confirmed PSA 50 response rate. Multiple of these patients remain on treatment, offering the potential for further deepening of responses.

Slide 27 depicts a waterfall of the best percentage change in circulating tumor DNA fraction and shows a similar impressive molecular response. 71% of patients had a 50% ctDNA reduction and 29% had a 90% reduction. To put this into context, this 71% rate of reductions is meaningfully higher than what was seen with enzalutamide in the Ambassador 250 study, for example.

Of note, these rinzimetostat ctDNA responses were seen across a variety of AR alterations, including point mutations, AR amplifications as well as the wild-type setting. These impressive data are important, especially given the established strong correlation between ctDNA reduction and long-term durability.

Finally, Slide 28 depicts the time on treatment swimmer plot for the 18 patients in dose optimization at the 400-milligram dose. The plot depicts which patients have had radiographic progression events and their timing as well as which patients remain on study. On the left, along the y-axis, we have listed the prior treatment history outside of ADT for each of the patients as well. Follow-up is still early, but with a median follow-up of 4.9 months, you can see in the embedded table on the right, the landmark radiographic progression-free survival at 3 time points where we have reliable data 3, 4 and 5 months.

At 3 months, an impressive 93% of patients remain progression-free which has been 84% at the 4- and 5-month landmarks, meaningfully higher than what you would expect from an ARPI switch alone. With further follow-up, we will be able to extend our estimate of long-term durability. But at this early stage, we are excited by the durability that we're seeing.

Now to put all these data that I presented into context, Slide 29 compares the safety profile that we have developed for rinzimetostat 400 milligrams in combination with darolutamide versus the disclosed safety profile for best both at 1,250 milligrams BID fasted and their more recent data at 875 milligrams BID Fed. We can't do a complete comparison because for rinzimetostat we only know the adverse events that occurred with a 20% or higher incident.

You can see that the adverse event profile of rinzimetostat stacks up very well against the mevrometostat results. regardless of whether you're looking at the fasted or fed mevro regimen. Specifically, for all the adverse events disclosed for mevrometostat, the incidents with rinzimetostat is lower in each case with the one exception of a slightly higher overall rate of fatigue versus the mevro 875 bed regimen. But even here, there are no grade 3 events with Rinse while there are with mevro. In addition, there are a number of adverse events reported with mevro that we don't see to any appreciable degree with rinzi, such as alopecia, neutropenia, thrombocytopenia or vomiting.

Slide 30 extends these safety observations summarizing the rate of grade 3 adverse events, serious related adverse events, dose reductions and treatment discontinuations for rinzi with darolutamide versus mevro with enzalutamide. You can see that across all of these tolerability metrics, the 400-milligram rinzimetostat dose in combination with darolutamide demonstrated a clearly differentiated safety profile from both mevrometastat plus enzalutamide dosing regimens with a lower rate of Grade 3 adverse events no serious related adverse events, no dose reductions and few discontinuations. This differentiated profile, we feel is highly compatible with long-term dosing and sustained patient adherence.

Slide 31 summarizes the important elements of safety and efficacy from the rinzimetostat data with a benchmark comparison to the same results for the mevrometostat combination, both with their fasted and fed regimens as well as enzalutamide single agent. But before I walk through this, I wanted to again point out that our study was conducted in patients who are more heavily pretreated than in the Mero studies, and they had a higher baseline PSA, 26 for the rinzi patient population compared with 15.5% and 16.7% for the 2 mevro groups.

Now in terms of radiographic progression-free survival, we have less follow-up than the mevrometostat patients approximately 5 months median follow-up compared with 9 to 11 plus months for mevro. But for the RPFS landmarks that are available for comparison at 3, 4 and 5 months, the rinzimetostat data are nearly identical to the mevro data and superior to the enzalutamide single-agent data.

In terms of safety, on the other hand, any way you look at it by the rate of grade 3 adverse events or the rate of dose reductions or discontinuations, rinzimetostat appears to be markedly safer than the competitor benchmark. Overall, we feel very good about the safety and efficacy profile we have developed for rinzimetostat at the 400-milligram dose in combination with darolutamide, a profile that positions it well for success as we now move to Phase III development.

Turning to Slide 33. With this strong rinzimetostat profile in hand and having selected the RP 3D of 400 milligrams in combination with darolutamide, I'm excited to unveil our first Phase III trial, which we are calling Himalayas-1. You can see the design of Himalayas-1 here. This study will be conducted in patients with metastatic castration-resistant prostate cancer who have previously been treated with abiraterone and have had up to 1 prior chemotherapy in the CSPC setting. Patients will be randomized 1:1 between a combination of rinzimetostat and darolutamide versus physician's choice of an AR inhibitor or chemotherapy. The primary endpoint of the study will be radiographic progression-free survival with overall survival as a key secondary endpoint.

We are far along in study startup activities, having selected over 250 sites in over 20 countries in North America, South America, Europe and across Asia Pacific. And to help us in the conduct of this study, turning to Slide 34, we have engaged many of the world's leading experts in the treatment of prostate cancer as members of the Himalayas-1 steering committee. The Committee Chair is Matthew Smith of Massachusetts General Hospital and the Vice Chair is Karim [ Pozzi ] of Gustavo. Additional members include Johan de Bono of the Royal [ Marsden ], Arun Azad of Peter Mac. Elizabeth Heat of the Mayo Clinic, Joaquin Matteo of [ ValdeBran ]; Rahul Agarwal of UCSF and [ Wasim Abita ] of Memorial Sloan Kettering. Basically a who's who of international thought leaders in the field of new therapies for prostate cancer.

With the expertise of our steering committee and the partnership with many GU oncologists and urologists around the world, we have agreed to participate in our trial. We have strong momentum to initiate Himalayas-1 in the first half of this year.

Now turning to Slide 35. As a final step to our regimen selection, one that is required by FDA, we are conducting a food effect study. We did look at food effect of rinzimetostat as a single agent and didn't see a significant impact of dosing with food on rinzi exposure. We're now repeating this with the rinzi-daro combination. And so far, we are not seeing a significant food effect here either. Of note, the early data in the food effect cohort continues to look good on efficacy and safety.

In the first 5 patients in this cohort who are evaluable for PSA response, we have observed to confirm PSA 90 as well as 2 confirmed PSA 50 and all safety events noted thus far are grade 1 with 1 Grade 2 related event. This obviously gives us further confidence in our choice of the 400-milligram dose for Phase III development.

Finally, on Slide 36, while we are hyper focused on near-term initiation and execution of our Himalayas-1 Phase III trial, we are simultaneously exploring additional indications in which we may conduct future Phase III studies. Earlier in the presentation, Lori presented compelling preclinical data suggesting that the therapeutic benefit of a PRC2 inhibitor may translate to the CSPC setting.

In addition, as I stated earlier, with our ongoing Phase Ib trial, we are currently generating clinical data looking at rinzimetostat with darolutamide in the post AR inhibitor mCRPC patient population.

Here on this slide, we have a preliminary look at the time on treatment swimmer plot in these post AR inhibitor patients at the 400-milligram RP 3D dose. Follow-up is still early with a median of 4.8 months, but the 3, 4 and 5 month landmarks are very encouraging with 93% progression-free at 3 months going to 85% at 4 and 5 months and 8 of these 19 patients are still on treatment. This performance is particularly striking, given that an AR inhibitor alone after a prior AR inhibitor would be expected to give a PFS of 2 to 3 months at best. These data leave little out in our minds as to the potential of rinzimetostat more broadly in patients with prostate cancer.

Now let me hand it over to Keith, who will outline rinzi's commercial potential. Keith?

Thanks, Pratik. Turning to Slide 38. As Pratik highlighted earlier, based on the highly differentiated rinzimetostat RP 3D efficacy and safety profile, we are excited about the upcoming initiation of Himalayas-1 in post abiraterone MCRPC.

From a commercial perspective, the next logical question is how large is that market? And the answer to that question is driven by the widespread use of abiraterone both in the U.S. and globally that makes it by far the world's most prescribed ARPI. As the first ARPI approved by the FDA for prostate cancer, abiraterone remains the leading ARPI, accounting for approximately half of new ARPI prescriptions annually as evidenced by real-world clinical trial and prescription data.

Turning to Slide 39. This is how we think about the total addressable market in post abiraterone and CRPC. In the U.S., we estimate that the annual incidence of MCRPC patients previously treated with abiraterone is approximately 17,000, then based on mevrometastat Phase II combination data, we estimate a treatment duration of about 14 months. Finally, factoring in the current day pricing of advanced prostate cancer therapies, we arrived at an addressable market in the U.S. of over $3.5 billion and a total global addressable market of around $7 billion for this first indication alone.

As Jacob and Pratik noted earlier, PRC2 inhibitors have demonstrated significant clinical benefit in MCRPC with far longer radiographic PFS than approved and emerging therapies in this setting. Rinzimetostat, albeit early, thus far is tracking to the same long durability. But importantly, rinzi is already well on its way to establishing a highly differentiated safety profile that would stand in a class of its own.

And so as we model out future share scenarios, we are really looking at 2 potential future cases, both of which assume that rinzi continues to demonstrate a best-in-disease safety profile. In a minimal case, rinzi achieves equivalent efficacy to other PRC2 inhibitors, which, as stated earlier, is far longer than other currently available therapeutic alternatives. And in a scenario more akin to our base case, rinzi is able to achieve differentiated efficacy as well. Obviously, either case results in substantial rinzimetostat share of the $7 billion post abiraterone MCRPC market.

Turning to Slide 40. To pressure test the minimal case where rinzi maintains its highly differentiated safety advantage, but achieved only equivalent efficacy to other PRC2 inhibitors, we conducted independent market research with U.S.-based academic and community urologists and oncologists. The physicians assess blinded target product profiles of rinzimetostat noted in the research as product-wide, in combination with darolutamide against a competitor PRC2 inhibitor noted as product Z in combination with enzalutamide in post-abirateron MCRPC.

The TPPs reflected similar efficacy but a more favorable safety profile for the rinzi plus daro combination that was similar to the 400-milligram safety profile Pratik shared earlier in his presentation. The key insight from our research was that physicians indicated they would describe the blinded rinzimetostat profile, 80% share of the PRC2 class, reinforcing the notion that a differentiated best-in-disease safety profile alone can drive prescribing decisions and significant market share, especially considering the demographics of this patient population. This prescribed preference is reflected in multiple quotes throughout the research where prescribers expressed strong preference for product wide based on the safety benefit alone.

Turning now to Slide 41. I want to revisit the commercial potential that Jacob spoke to earlier in the presentation. In the U.S., our initial launch indication in post abiraterone MCRPC represents approximately 17,000 patients per year alone, with a total addressable market of greater than $3.5 billion annually. With additional development potential in prostate populations like post AR inhibitor MCRPC where we showed promising early landmark PFS data in metastatic castration-sensitive prostate cancer, where Lori showed strong preclinical data, the commercial opportunity grows significantly with the MCSPC indication alone representing a potential market of greater than $10 billion just in the U.S.

Beyond prostate cancer, we also see multiple future development opportunities for rinzimetostat in other tumor settings where PRC2 inhibition combined with various approved and investigational therapies may address various unmet medical needs.

I'll now hand it back over to Jacob to discuss next steps and close out our session. Jacob?

Thank you, Keith. We'll wrap up our prepared remarks on Slide 43. We continue to be excited about the development prospects for both our clinical programs and their emerging best-in-class profiles. Within prostate cancer, we believe the dose optimization data presented today build a strong case that rinzimetostat in combination with darolutamide in our upcoming Himalayas-1 registrational trial has the potential to yield profound benefit for patients in a market that is large, but woefully underserved today by oral well-tolerated therapies.

Before we begin Q&A, I'd like to thank our investigators as well as the entire ORIC team who worked diligently to tackle our mission on behalf of patients. And most importantly, I want to thank our patients and their families who we hope to help overcome resistance in cancer.

With that, let's open it up for Q&A.

[Operator Instructions]. Our first question comes from the line of Anupam Rama with JP Morgan.

Thanks so much for the comprehensive update and congrats on the update. So based on physician feedback, we previously laid out these win scenarios, right, which -- what it would take to -- that was sort of a best-in-class profile, and it was really driven by safety differentiation alone.

Today, in your update, you repeatedly talked about a best in disease profile. What gives you confidence that rinzimetostat profile is tracking to a best-in-disease profile that can be replicated in later-stage studies? That's the first question. And the second one is, can you give us any color on any FDA feedback you got on the Phase III study? And how this impacts your start time for the Phase III.

Okay. Sorry, I don't know what happened with the audio on -- thanks for your question. I'll do your first question and then I'll ask Pratik our CMO to cover your second question. Short answer is we're super excited about the profile that we're seeing from rinzimetostat right now, frankly, in combination with either of the AR inhibitors, but right now, we're focused on the rinzimetostat plus daro update. As the programs advance and now we're months away from initiation of the first Phase III trial, we're seeing an emerging profile in that post ARPI metastatic CRPC setting that is highly differentiated for not only mevrometostat, but all the other alternatives that a patient in that space could have today available to them.

So the only other PRC2 inhibitor, as you know, that's currently in prostate Phase III trials is Mevro,and they've shown RPFS from a randomized trial that's substantially better than all the available standard of care therapies for these patients. We laid that out early in the deck with rinzi, while we don't yet have a mature RPFS number, the landmark PFS rate, obviously, are tracking nicely. They're essentially identical to those from mevro. And that's despite, as Pratik said, our population be more heavily pretreated and with a meaningfully higher baseline PSA. So, obviously, intuitively, you can draw a strong correlation between Landmark, RPFS and eventual mature RPFS performance. And again, Slide 7 in our deck shows exactly that across a whole variety of treatments in first-line metastatic CRPC.

So we believe that means that rinzi is tracking to have the same kind of durability, if not better than Mero. And hopefully, that gets better once we get to a like-for-like population with mevro in a Phase III study. But on top of that, this is what's really important to note Anupam is mevro stellar RPFS comes with a tox profile that obviously leaves significant room for improvement with high rates of GI and heme tox as well as things like [ viscusi ] and alopecia. So far, the safety profile of rinse looks markedly better than that.

And for that matter, it looks -- the safety profile looks better than what you see with pluvicto, chemo, T cell engagers, you name it. So if this profile continues to hold into the Himalayas-1 trial, it would set up rinzi to have a combined efficacy and safety profile that's obviously head and shoulders above any of the mechanisms available to these patients today. So that's -- that's why we're so excited about the potential for rinzi and its potential to become a best in disease therapeutic option for these patients.

Now let me have Pratik cover your second question.

Sure. So happy to do so. So your second question was about FDA feedback in the Phase III. So we've had regular communication with the FDA, as you can imagine, all along as the program has progressed. I can't get into specifics, but we are planning an end of Phase I meeting in Q2 to get their final sign-off on the RP 3D selection, the 400 milligrams that we presented today as well as the final design of the Himalayas-1 protocol. There's also some other topics in terms of clinical pharmacology studies, et cetera, but we feel really good going into that end-of-phase meeting. And that should put us on the time line and take outline to start still in the first -- second quarter this year.

[Operator Instructions]. Our next question comes from the line of Prakhar Agrawal with Cantor.

I had a couple. So maybe just if you can expand on the baseline of the patient population in this readout compared to the Mero population. I think you entered at that during the prepared remarks and specifically as it relates to the implications on efficacy on PSA as well as PFS and secondly, CTDNA reductions that you have observed could you contextualize that as well, the 71% ctDNA molecular response out of that compared to some of the other prostate drugs?

Yes. Thanks, Prakhar. We'll have Pratik take your first question. And then Lori, our CFO, will take your second question.

Sure. Thanks. So I take I've already sort of hinted at. As a headline, I'd say that our patient population is more advanced has a higher baseline PSA and on media and then more prior therapies. So our post abiraterone 400-milligram dose group, the median baseline PSA was 26. This is meaningfully higher than the baseline for either of the mevrometastatic data sets. As you'll recall from the randomized experience with the 1250 BID-fasted regimen. They had 41 patients post abi in the median baseline PSA was 15.5%. And then their more recent update at ASCO GU last month with the 875 BID Fed regimen, the regimen they're taking into all of their Phase III there in 14 patients post abi, the median baseline PSA was 16.7.

So ours is meaningfully higher at 26 than theirs in the mid-teens. In terms of prior therapy, our data set includes patients who have had additional prior therapies beyond abi and possibly docetaxel. So the Mero data set on the other hand, was restricted to just prior abi and possibly docetaxel alone.

One other thing I would just point out is that in our study, we enrolled far more African-American patients. 30% of our patients in dose optimization were black or African American and as you probably know, prostate cancer is overrepresented in this population. And so I would say we did a good job of reflecting the real-world demographics of prostate cancer. Mevro just had 5% in the randomized data set, none in their more recent update. So as I said, our patient population is more advanced. It has a higher baseline PSA and more prior therapies.

Okay. For the second question, just doing a sound check. All right. So this question, Prakhar, you asked about ctDNA reductions and how to contextualize those given that we know rinzimetostat mechanism, of action is to enhance the luminal cell state and increase AR signaling. ctDNA reduction is even a better read-through of treatment effect on tumor burden than PSA. While we do see strong PSA responses, we're even more excited to evaluate the ctDNA reduction in clearance, which have been shown to associate with long-term PFS and overall survival, even more strongly than PSA.

In this dose optimization cohort of 400 mg of ready plus darolutamide, the molecular response rate is an impressive 71%. We have no way to compare this ctDNA response to Pfizer's mevrometastat, they've measured ctDNA reductions, but they haven't publicly released it. So to give context to rinzi's 71% molecular response, this result is superior to other active therapies in similar patient populations. For example, in the Ambassador 250 and conrad studies assessing AR inhibition and Radium-223, the molecular response rates were at 28% and 44%.

In treatment-naive metastatic CRPC populations that receive standard of care, the reported rates of molecular response range from 65% to 78%, making our ctDNA response of 71% in the pretreated population that much more notable. So I'm very pleased with this.

[Operator Instructions]. Our next question will come from the line of Brad Canino with Guggenheim.

It would be good to hear the key factors that led to the selection of darolutamide instead of apalutamide. And then you've shown some strong early durability with the landmark RPFS that you put in the slides, but can you also provide some additional color on what you saw or stuff like PSA kinetics or resist responses to help support that RPF as well.

Thanks, Brad. I'll take your first question on the choice of AR combo partner, and then Pratik will cover your second one. So obviously, we've generated a lot of data over the last several years with both -- and apa as combination regimens for rinzi. Both daro and apa are great drugs and great combo partners for rinzi. So I can't say enough good high compliments about both of those programs.

As we've commented many times in the past, we see similar efficacy and similar safety with both combo agents obviously, one big difference. It's not a surprise for folks is that apalutamide and for that matter, enzalutamide has the same factor going forward, which is their well characterized as -- inducers. And so they will push down the exposure of other drugs, most other drugs that are co-administered with them, just given how many drugs are metabolized by the -- times.

So mevrometostat is clearly going to experience that same DDI when they're dosed with apalutamide and while that type of DDI can be overcome through higher dosing, obviously, we're taking higher doses into our dose optimization with rinzimetostat with apalutamide and darolutamide, we chose for this first Phase III study to just go with a simpler path of no DTI. And so that's to combine it with darolutamide. And I should say, obviously, choosing darolutamide for this first Phase III study. We're quite excited about that, but it obviously doesn't preclude us from using apalutamide in subsequent Phase III studies.

And let me ask Pratik to take your second question.

Sure. So Yes. As we progress through the rinzi program to a later stage and as the data mature and more follow-up, the most important end point clearly is radiographic progression-free survival. It's the main regulatory end point for this patient population and it's going to be, as I said, the sole primary endpoint of Himalayas-1, overall survivals and implant secondary.

So we focus today's presentation on the landmark, RPFS through our median follow-up of 5 months since we don't yet fully have a mature PFS for the later time points. And as just to reprise some of what I presented, looking at the 5-month landmark in the post abi population, it's 84%, which is right on top of the mevrometastat data. And if you look at the same 5-month values for other approved agents for these patients, they range from 60% to 75%. So well south of what we're seeing in our patient population.

And then although near the end of my presentation, I also gave a preview of what we're seeing in the post AR inhibitor population with the rinzi-daro combination. And here, again, the 5-month landmark is -- of PFS is 85% where you'd expect the median to be something like 2 to 3 months only. So really much better than conventional therapy. So this gives us a lot of confidence both in terms of the activity, the mechanism and the dose that we picked to go forward into Phase III.

Now with respect to RECIST responses, yes, we definitely looked at additional points of correlation, but most of our patients have bone-only disease, as typical for this patient population. And so for the few patients that have soft tissue disease of those only subset have lesions large enough to be RECIST measurable. So that leaves us just a handful of patients with measurable at 400 milligrams. And we have 100% disease control rate in those patients, and we have seen confirmed RECIST responses at both 400 and 600. So we do see tumor shrinkage, but the low number of patients who are RECIST evaluable makes calculating an ORR not terribly informative.

In terms of PSA kinetics, PSA is actually kind of interesting with respect to the mechanism of PRC2 inhibition. If you go back when we were doing our preclinical work and the effect of PRC2 had on increasing AR signaling, one of the side effects of that is it can drive up PSA because it increases the expression of the gene for PSA. So we initially expected actually that PSA would go up. And that's basically what we saw in our single agent experience.

The PSA went up in all the patients. So we wondered actually what might happen when we combined with an AR inhibitor, whether PSA actually go down or would it even be uninterpretable. So we were glad to see the initial Pfizer data in their combination that the PSA could go down. And as you can see, we're seeing that in patients as well.

So the net effect of the combination regimen can drive down PSA, but it does take time to develop. In our experience, many patients, the reductions can happen over the first 2 or 3 cycles in 2 or 3 months, but we've seen further reductions out past 6 months and even 9 months. And so really because of the locations of looking at RECIST response, not a lot of patients and the limitations of PSA, given the PS2 mechanism, it's why we've actually looked hard at ct DNA, which is a direct -- a more direct measure of disease burden and can be evaluated for most patients. They're all evaluable for ctDNA except for a few exceptions. And so that ctDNA response has been correlated with long-term durability. And on this measure, our molecular response rates are higher than what's been reported for all the active agents this patient population.

[Operator Instructions]. Our next question will come from the line of Maurice Raycroft with Jefferies.

Congrats on the update. You mentioned that 400 mg and 600 mg doses had comparable efficacy. Is there any additional color you can provide on what you observed on efficacy at 600 mg and do you have an update to know for sure that there's no additional benefit on our RPFS with the 600 mg dose?

Yes, Pratik, you can handle that more. Thanks for the question.

Sure. So the objective of the presentation today was delayed the groundwork for our first Phase III study. So we wanted to identify the patient population, identify the AR inhibitor that we were going to combine with and then complete dose optimization and select the dose going forward. And so the bulk of the presentation was then focused on this RP dose selection and the regimen. And that selection, as you heard, is 400 milligrams once a day with darolutamide.

But we did do, as I went into a bit of detail in the presentation, what's called an ER analysis, an exposure response analysis. And with this -- through this analysis, we looked at a broad range of variables that captured exposure, a bunch of different ways, efficacy, a bunch of different ways and same for safety. And the bottom line for the efficacy analysis is that there was no statistical relationship between exposure and efficacy.

It's not really surprising because both of the doses that we took into dose optimization were above the minimum concentrations that we were projecting from a preclinical work. and pharmacodynamic signal that we were looking at maxed out, even at 200 milligrams. So the 4 and 6 were, in our minds, highly likely to be clinically active.

But anecdotally, if you look at any individual readout for the various efficacy measures that we looked at in some of them, the 400 was numerically higher than 600 and others, the 600 value is higher, but the confidence interval is overlapped. And so you can't draw a conclusion from any single comparison as to which dose would be better.

It's the ER analysis that really makes that assessment. But that wasn't the case with respect to safety. There, we saw a clear relationship between exposure and multiple measures of safety, adverse events, adverse events of interest, treatment modifications. And it shows up when you look at the side-by-side safety tables for 400 and 600, 600 has more toxicity, mostly Grade 2 or Grade 1, and it also has more dose modification.

So the bottom line was that there was no advantage in efficacy, but there was an additional toxicity burden with the 600, which is why we concluded the 400 would be the RP 3D. And frankly, that's kind of what FDA wants companies to do when we do these project optimist type of exercises is to move away from just assuming that higher is always better. So I think we have conclusive evidence to support the 400 milligram dose as the RP 3D, and we want to sort of look forward and plan for our first Phase III study and potentially others as well after that.

Got it. That's really helpful. And you're showing low rates of progression and low discontinuation rates. What are some of the other reasons for stopping drug as observed in your consumer plot data? Or how should we contextualize that?

Sure. So the events in a radiographic progression-free analysis that you capture as events are radiographic progression on imaging or death from any cause. So if patients are live in progression-free they're censored at their last visit or the last time they had imaging done. But patients can also be censored if the loss to follow-up or come off of treatment for other reasons other than progression. And these can be a variety of reasons like the patient withdraws consent because they don't like the study visits.

PSA progression where they may want to go on to another therapy even before they progress radiographically or tolerability issues, they don't like the side effects. Consumer plot, we do have some patients like this, and it's typical in prostate cancer trials. Actually, if you look at the Mero swimmer plot from ASCO GU, many of those patients are off treatment, but without a progression event defined 6 of their 14 are off for this reason. So it's not unexpected in this patient population in these kinds of studies.

[Operator Instructions]. Our next question will come from the line of Kelsey Goodwin with Piper Sandler.

Congrats on the update. Maybe first, question. For this combo data, maybe just remind us that this was the facet, I believe. And then in terms of this food effect cohort that you're running now, maybe just tell us what the purpose of that is did the FDA require it? Or are you doing that on your own? And then is that in response to Pfizer also running a food effect study dosing at the -- or looking at the higher dose fasted and then a lower dose wellhead? Maybe just some more color there would be helpful for us.

Thanks, Kelsey. Yes, Pratik can take that one.

Sure. So it's a good question. But before I answer that, let me provide some context and you were actually covering some of those points already. There's a couple of reasons to do food -- studies, as you said. So first, it's an FDA requirement. They want to know whether dosing with food with or without food affects the exposure of your drug. And if there's any meaningful effects of those changes in exposure on the safety and efficacy profile ideally, you wouldn't want to have a food effect. That would give you much more flexibility and a more convenient dosing regimen, the patient can take it however they want.

But if there's a true food effect, then you may have to revisit dose and stricter in terms of patient instructions on how to take the drug. But as you said, the other reason to look at the food effect is that it may improve the safety profile of the drug mostly GI toxicities like nausea or vomiting and diarrhea. And you might want to do this even if there's no meaningful food effect on drug exposure.

So if we start with our drug, rinzimetostat, so we're mostly conducting our food effect to satisfy the FDA requirement. And as I said during the presentation, so far, we don't see meaningful food effect, we looked at this initially as a single agent, and now we're doing this again in the combination with the rinzi-daro combination. And part of the reason is that since darolutamide is taken with food, we want to see if we can make sure that rinzi can just be taken at the same time, which will be more convenient for patients. And so, so far, we aren't seeing a the way a true food effect.

In terms of just the effect on safety so far in the first patients that we've treated on this little cohort, we've only seen Grade 1 treatment-related adverse events except for 1 grade 2 event of decreased appetite. So maybe there's some potential for incremental improvement in GI tox beyond the clean profile we have, but it may stay very much the same and then in terms of efficacy, you saw from the initial PSA data, it looks very consistent with our faster data, the early activity that we're seeing out of the 5 patients, we have 2 PSA 50 and 1 PSA 90, all of them are confirmed. So that's our story. Mevro missed that, the story is a bit different because it does seem to have a meaningful food effect. Since their faster dose of 1250 is if you do the math 44% higher than the Fed dose of 8.75, but you get to the same exposure in each of those instances because of the food.

So there is a meaningful food effect but I think they really chose the dosing with food to improve the GI tox. They had a nearly 80% regimen or rate of diarrhea with their fasted regimen and it dropped to just below 50 with dosing with food. But as you might notice, it doesn't affect the other adverse events like heme tox, which comparing the 1250 to the 8.75 million is about the same, if not maybe a little higher with the Fed regimen. So our reasons and Pfizer reasons for doing the food effect are actually pretty different.

Okay. Got it. And then maybe 1 follow-up. In terms of the second half program update that you guided to earlier this year, now that we have this first quarter data set out, I guess are you providing any more color on what that might look like?

I can take that one, Kelsey. No, not at the moment. I'd say we do have that second half program update, but right now, it's TBD in terms of what that additional -- what additional data, if any, we would plan to disclose during that update, we'll just -- we'll refine that thinking in the coming weeks and months and let you know.

[Operator Instructions]. Our next question comes from the line of Colleen Kusy Hussey with Baird.

A couple on safety for us. Can you just comment on any rate of cytopenias or alopecia that you're seeing? I believe that's something that we saw program? And then on the blood creatinine increases that you saw with -- can you just provide a little more color there? Do you think that's a drug effect of rinzi class effect? Any color there?

Thanks, Colleen. Appreciate you can take both of those.

Sure. So your first question was on the cytopenias or alopecia that Pfizer C. So in terms of cytopenias, we do see both neutropenia and thrombocytopenia, but at a low rate, less than 5% -- CCI inhibition as a class does lead to hematologic toxicity. And it was the dose livering toxicity in our single-agent dose escalation experience. But that only occurred when we pushed the dose up really high. We have a wide therapeutic index with a great sort of long half-life. So we don't have to deal with a high Cmax, and we were able to work within dose ranges that limit the cytopenia complication. And then in terms of alopecia, we've seen a grand total of 1 treatment-related alopecia event of Grade 1 at the 600-milligram dose. So we see maybe a smidgen of it.

And then in terms of the blood creatine increase. So our rate from the table we presented at the 400 is 16%, mostly grade 1 the increase in blood creatinine in older patients, most often is an indicator of dehydration. And if you look at the other adverse events that these patients are experiencing around the same time. You see these events track with some sort of concomitant or preceding GI adverse events like nausea or diarrhea, which leads to decreased oral intake and they get dehydrated and then the creatinine goes up. Good news is that it resolves easily with hydration and the creatinine rise reverses.

In terms of whether this is seen with mevrometostat, it's hard to say because in terms of the mevrometastat profile, we only have insight into the adverse event that they've disclosed in over 20% of patients. So we don't know what the adverse event profile looks in the short of 20% of patients. So they very well could be seeing it, but it just hasn't been disclosed.

[Operator Instructions]. Our next question comes from the line of Derek Archila with Wells Fargo.

This is Simone for Derek -- just 2 from us. One, will you have a drug supply agreement in place before initiating the Phase III. And two, can you walk us through expectations for timing of the Phase III top line data readout and what assumptions go into that?

Thanks, Simone. I'll take your first question on the drug supply agreement and then Pratik can cover your second one. So I think probably all I can say is this, we continue to have excellent working relationships with our partners at both Bayer and J&J. Obviously, we can't comment on the specifics of any ongoing confidential discussions. So it's probably best if I just leave it at that for now, and we'll provide a pick update at the appropriate time.

And I can answer the second one. So as we said in the call, we expect to start the first Phase III Himalayas-1 in the first half of this year. So depending on the exact timing of the study start, we'd expect top line data in late '27 or early '28. So that assumes a 16-month time to fully enroll the study. which would be actually a couple of months longer, a bit of a buffer than what we believe. Pfizer to enroll their mevro-1 study in the same patient population. And then you need to add some additional time for us to get to the necessary number of events for the final analysis. So that's kind of the general time frame.

[Operator Instructions]. Our next question will come from the line of Corinne Johnson with Goldman Sachs.

This is Eric on for Corinne Johnson. I have 2 questions. And first is, is there a corresponding Kaplan-Meier curve that you use to generate the landmark PFS analysis? And if so, any color would be helpful. And second, we're hearing anecdotes that abiraterone usage may be slowly decreasing. How do you reconcile that with the approximately 50% stable market share data you presented in one of the previous slides.

Yes. Great. Thanks, Eric. I'll ask Pratik to take your first question on the Kaplan-Meier curve and then our head of -- and Medical Affairs, Keith Louis, can take your second question on the much -- the rumored attrition of abiraterone.

Yes, sure. So on the Kaplan-Meier curve, so we have a median follow-up of just about 5 months. And so a Kaplan-Meier curve would be immature past that point. So that's why we focused on landmark analysis through the time point where we have our median follow-up. So with immediate follow-up of 4.9 months, that's why our landmark goes out to 5 months. But we have multiple patients approaching or beyond this median that are still ongoing. So the curve is going to be unstable past that point. And so you're not going to get a good read on the later time points.

But you can -- with the tumor plot and bit of graph paper and make -- what the draw out what the Kaplan-Meier curve is going to look like. I would just say that it's going to be unstable far less helpful beyond the immediate follow-up time points.

Yes. And then maybe to comment on the second question. This is Keith. Given that the abiraterone population is going to be the focus -- the [ post-return ] population be the focus of Mason we pressure tested our assumptions about market size from multiple different angles, both quantitatively and qualitatively. And so to develop our market assumptions, we've gathered numerous data points from real-world clinical trial and third-party prescription data, you saw some representative examples of those data in today's presentation. We then triangulate those data with our own market research efforts and then even further validate our insights by speaking with dozens of health care professionals and user professionals, not only in academic settings, but importantly, in community settings where about 80% of prostate cancer patients are treated in the real world.

We also spoke with a wide swath of both oncologists and urologists and we continue to hear from those conversations that there's a strong preference for abiraterone and its usage continues to be highly sticky which is why it's still by far the most prescribed ARPI and has maintained a relatively stable share of new ARPI prescriptions at around that 50% that I presented over the last 5 years, and the reason, I cited are given that it has widespread and long-standing physician experience with the drug, payer preference given that abi is generic, and evidence-based medicine report that starting abi first in the sequencing of RPIs results in longer durability than abi is sequenced later. And so based on all this, we feel really good about the market prospects for that patient population we're setting in Himalayas-1.

[Operator Instructions]. Our next question comes from the line of Yigal Nochomovitz with Citigroup.

Congrats on all the updates. Just a few things. So you mentioned, of course, there's the potential for another Phase III trial -- and I think, Jacob, you said what you've shown today doesn't preclude using apa next. But I guess the question is, is the preference still for daro for the second Phase III, say, in the post AR setting especially since you showed some of that post ARPI data already today. So that's the first one.

And then second, just with regard to the safety, of course, I appreciate the comments and the survey data you showed with the preference for 80% of the time for rinzi. My question was just with regard to exposure times and whether you had to do any normalization or adjustments for median follow-up, given it's obviously about half the amount for Renzi versus what you have for Mero? And then the last question is anything you can say with respect to other feedback from the prostate cancer KOL community, you noted some of the luminaries on the slide at the beginning of the presentation. Anything else that people are commenting on with regard to what you're showing today.

Thanks for the question, Yigal. Yes. I'll take your first one, and then I'll ask Pratik maybe to comment around your questions on safety and the investigator feedback. The we're generating great data. We've continued to generate great data with both of the combo partners, Yigal,both of the AR inhibitors, so darolutamide and apalutamide I would say even though the data that we flashed up today was all focused on the darolutamide combination, including in that sort of experimental population where we're signal-seeking, frankly, for the post-air inhibitor population, which might be a future Phase III study, all of that focused on darolutamide today.

But we don't have a preference for what we might do for that or third Phase III study as well. Obviously, for simplicity's sake, we chose to focus on darolutamide for this first Phase III study, but we're kind of keeping the door open on what we would use for future Phase III studies.

Maybe let me have Pratik take the other questions.

Yes. So in terms of the Kaplan-Meier comparisons, you're absolutely right. We have a different amount of follow-up. We have less follow-up than Pfizer does for their patients, which is why we stuck to the landmark analysis. So the 3, 4, 5 months with our median follow-up of just about 5 months, those comparisons, we think are fully valid because at that point, that curve is quite stable. It's when you get past the median follow-up that comparisons, I think, then become sort of tricky and not really tenable. So that's -- I think we stuck to that just to be strict in terms of where the curves are comparable versus where they're not. Not yet, more follow-up will push out that analysis. In terms of the...

I guess I was referring to more on the safety side, though, that would apply as well on the safety side of things in terms of looking at the rates of different as...

Yes. But the safety develops -- we don't have new safety events that sort of develop in the 5-, 6-month time frame. If they're going to develop toxicity, it happens in the first, if not the first, the second cycle. So I don't feel like the safety profile is going to worsen over time.

Yes, Yigal, the safety kind of is what it is. And one of the reasons why we and pulled back the curtain even a little bit more here on the safety side to show the full experience, not just the post abi, but even the post air inhibitor patients was to really bolster the end that you all were looking at to give everyone confidence that the profile that we're showing you for safety in that post abi population is, in fact, the safety profile for the drug because you obviously see the trends don't change when you look at the full post ARPI population. And then Pratik can just comment quickly on the investigator feedback.

Yes. So I mean, I think the long and short of it is our investigators are very excited to be part of this new study. You already cited, I think the most visible proof is that we've got a top flight steering committee with thought leaders from around the world. World top institutions are represented. But to be more specific, I think they are -- everybody is looking for an all-oral therapeutic option for these patients with MCRPC. There's a lot of -- even though it may not always be on the guidelines, there's so much ARPI switch because physicians and patients want to maximize their time on an oral regimen. And so this whole class PRC2 inhibition potential to have an all oral regimen that may be better, at least have a potential for a long PFS, I think, is very exciting.

And then just to distinguish between the 2 programs, I think the safety profile that we're seeing with our program has -- our current investigator is very excited, and they've signed on from the Phase I on to the Phase III for that very reason because I think that this drug is highly competitive to what's out there.

Our next question comes from the line of Corey Kasimov with Evercore ISI.

So curious if there's anything to read into the RPFS flattening from months 4 to 5? Is it just too small of an end to kind of extrapolate there. And then a follow-up is I'm curious, is there any reason that there are different cutoffs for the efficacy analysis, at least in the swimmer plot, which I think is like March 9 and then the safety data, which has a cutoff in January.

, Cory. I'll have Pratik take both of those.

Yes. So I mean, I think you already answered the first question, which is, yes, there's a few patient numbers. So it's just -- it remains flat, the curve remains flat over that interval. And in terms of the cutoff, yes, so what we -- the cutoff is really January 16, but then we extended the follow-up of those patients to the March date so that we could have more PFS to look at.

Basically, Corey, just trying to eke out as long of a landmark PFS as we could, just to give everyone confidence in how it's tracking.

[Operator Instructions]. Our next question comes from the line of Matthew Biegler with Opco.

I just wanted to ask about Descovy because it doesn't seem like you're seeing much, if any, of it. And it's been flagged by a lot of KOLs we talk to as a big tolerability issue with mevrometostat. So any idea kind of why the low rates? Because I always thought it was more of an on-target tox, but maybe it's just reflective of the lower doses that you're using here?

Thank you, Matt. I'll have Pratik take that.

Yes, sure. So we do see it at a low rate, again, probably like less than 5%. I think actually I wouldn't say that we're using a lower dose I just want to be careful about that. So Pfizer in their -- some of their presentations have correlated safety with a Cmax. And the Cmax is -- for their drug because it has a short half-life, they still have to give very high doses in order to get coverage above a minimum concentration over 24 hours.

So it's dosed BID with still even with food, 75 milligrams twice a day. So they're going to get big swings from peak to trough -- and that is potentially going to drive the toxicity. We have a lower dose. I mean it's a different molecule, but since we have a full 20-hour half-life we have a much lower swing between peak to trough. And so our Cmax, relatively speaking, doesn't go as high. And so we're able to essentially cover the target without necessarily incurring the safety liability from the Cmax.

And so I think that explains a lot of the issues that we don't see with heme tox in particular. We see less GI tox. And so I think that's that would be the explanation I have for those differences.

[Operator Instructions]. our last question will come from the line of David Nierengarten with Wedbush Securities.

I just had one on -- when you look at your side effect profile and discontinuations, the actual discontinuations appear pretty comparable to Mero across trials. I mean is that what we should be looking at? Or should we be really looking at the actual grade 3 adverse events? And if so, several of them from mevro just seem to be lab values versus diarrhea or nausea. And maybe you can just walk us through like what's what are you looking at and prioritizing what the doctors are in your survey work?

Thanks, David. Yes, Pratik will cover that, including -- we get a lot of just qualitative guidance from doctors. Obviously, who are familiar with both drugs and to give us some color in terms of what are the more problematic AEs for Mero. So Pasi can kind of highlight all of that.

Yes. I mean I think there's a range of treatment modifications. And you're right that the discontinuation rate is not terribly distinct. But I think where you also have to focus is treatment interruptions and dose reductions. Dose reductions because of toxicity often almost inevitably lead to some treatment interruption, you may be able to keep the patient on drug, but you're now lowering the dose, and I'm not sure if you have to lower from the mevro 875, how much coverage you're going to get. And so that patient is going to be either underdosed or uncovered if you're going to do a dose interruption for a period of time, yet they're not going to technically have a treatment discontinuation. And so that's where I think the safety profile distinction in terms of adverse events, the grade 3s, maybe they can get patients through grade 3 toxicity, but they've got to hold the dose or lower the dose and they haven't discontinued, but they're on a lower drug and have had meaningful treatment gaps. Whereas we have the potential with the safety profile to have a continuous dosing for a given patient because they don't incur toxicity that requires those kinds of modifications.

Thank you. This does conclude today's question-and-answer session. Ladies and gentlemen, this does conclude today's conference call. Thank you for participating, and you may now disconnect. Everyone, have a great day.

All right. Welcome back, everyone, to the next session of the first day of Citi's 2026 Virtual Oncology Leadership Summit. I'm Yigal Nochomovitz, Biotech Analyst here at Citi in New York. The next session is with ORIC. It's great to have the CEO and CFO here, Jacob Chacko, CEO; and Dominic Piscitelli, CFO.

Welcome to both of you. Thank you very much for doing this. For those listening, if you have questions for the company, just e-mail me, and I will relay over to Jacob and Dominic.

So welcome, gentlemen. It's been a busy year, obviously, for you and for us. Maybe to start out, Jacob, if you could just kind of give us the very high level, highest level overview of the company, and then we can move directly into some of the key questions related to your prostate cancer program.

Yes. Happy to do that. Thanks for having us here, Yigal. So ORIC stands for Overcoming Resistance In Cancer. In a nutshell, that's the mission of the company. So we're focused on small molecule drug development in primarily solid tumors, but most specifically, prostate cancer and lung cancer. That's obviously where our 2 lead programs are currently being developed. Both of those programs are in dose optimization right now. Both of those are headed towards Phase III studies with a lot of data that's been presented over the last 12 months, showing the best-in-class potential of both programs.

The most imminent Phase III is for our prostate program, which ORIC-944 now has a name, rinzimetostat. And so we anticipate starting a Phase III study with that program in the first half of this year. We're awaiting some more data from our lung program in the second half of this year, after which we would potentially start the first Phase III for our lung program, ORIC-114, which is known as enozertinib, probably in the first half next year.

So a lot on our plate, but really excited about where the company is at, both in terms of data and cash runway to execute on our Phase III aspirations.

Okay. Great. Well, obviously, you've got a pretty significant competitor in the race here with Pfizer, and you have a very important and different molecule, too. So maybe if you could just start by talking about what we've seen from Pfizer so far and how that sets you up for how you're going to play out your data this year and beyond.

Yes. We like to refer that fluky young upstart, Pfizer, a lot like ourselves. They've done a lot for the field in terms of derisking this mechanism, Yigal. So as we're talking specifically about PRC2 inhibition within prostate cancer, it's an area that's been studied a lot over the years. And the first-gen PRC2 inhibitors really ran suboptimal clinical experiments. The reason being that those drugs were suboptimal. They had very short half-lives on the order of 1 or 2 hours. They had -- a lot of them had what's known as SIP auto induction, where they would rev up the SIP enzymes that would then metabolize the drug. So in some of those cases, they would get dose-dependent decreases in exposure.

So in other words, there was a lot of reasons why those drugs did not work in the clinic despite a really wide swath of preclinical evidence that suggested that if you combine a PRC2 inhibitor with an AR inhibitor, you ought to get longer, more durable outcomes by virtue of keeping those prostate tumors in an AR-dependent state, which is where those AR inhibitors work best. So we're really thankful that Pfizer has really derisked the mechanism quite a bit. You referenced their randomized data set that they presented almost exactly a year ago this time at ASCO GU last year. And in that data set, what they showed was that in a CRPC population where all the patients were post abiraterone, so they had already been experienced with abiraterone and where one prior line of chemotherapy was allowed, those patients achieved a 14.3-month radiographic PFS, median radiographic PFS. And that's in the context of a control arm of enzalutamide alone, so an AR inhibitor alone that achieved exactly what you would expect in that population, which was about 6 months of radiographic PFS.

And so that 8-plus month benefit on PFS was profound. It's longer than any other mechanism that you have seen studied in that patient population. Obviously, people talk about how -- what good Pluvicto has done for patients across the prostate treatment paradigm. Pluvicto has been studied in very analogous populations and doesn't come close to the PFS that Pfizer was able to show. And so it explains why Pfizer was investing so heavily in their PRC2 program Mevrometostat, in combination with their AR inhibitor, enzalutamide. They've now got 3 different Phase III studies enrolling and underway with MEVPRO-1, their first study in that post-abiraterone population having finished enrollment, and we're going to get to see a readout from them later this year.

But it's really could be game changing if their Phase III results replicate what they were able to show in Phase II. And obviously, we think we've got a better drug than they do.

Okay. So tell us more about that. What are the properties of your molecule that may be differentiated that would give you optimism that you have at least a good profile, perhaps a better one as you start to do your Phase III work?

Yes. I mean if you go through and do the analysis of the drug side by side, and again, if you look at all the ways that the first-gen PRC2 inhibitors sort of fell short of an optimal target candidate profile, it was really in all different ways that they fell short. So they didn't have enough potency. They didn't have enough in vivo activity. They had poor half-life, as I mentioned earlier. A lot of them had these CYP autoinduction issues where essentially they got very bad PK properties. didn't even get to the right exposures that they needed to, to test the clinical experiment.

Now Pfizer seems to have solved a lot of it. Their drug, Mevrometostat has very good potency, very good in vivo activity. It looks like it's got a half-life of roughly 5 hours, so better than the first-gen compounds, but clearly something that can be approved upon and doesn't look like it's got CYP autoinduction. And so by virtue of those things, it seems to be getting enough exposure in these patients that they're able to get the kind of profound outcomes that I mentioned earlier.

Now in the case of rinzimetostat, our drug, which we acquired from Mirati back in 2020, the chemist of Mirati, they went about this in a very empirical fashion, Yigal. So they just -- they looked at the space. They decided none of the drugs in the space were achieving the right target candidate profile, and they set out trying to make a drug that was every bit as potent and had as good in vivo activity as what you've seen from Pfizer, but importantly, a much better half-life. And in this case, they developed a drug that has a 20-hour clinical half-life, does not have CYP autoinduction. And what that means is that it's consistent with once-a-day QD dosing, but the benefit we're talking about here is not just simply a convenience benefit of QD dosing versus BID dosing.

Really, what it is, is the ability to cover target for 24 hours with your Cmin without pushing Cmax high to get -- or too high to get Cmax-driven toxicity. And that's where our drug really seems to differentiate. So if you look at the data we presented last year, we had a couple of different data readouts from our dose exploration work. As folks know, we're working with the other 2 big AR inhibitors. So Pfizer's got their own AR inhibitor, enzalutamide, but the other 2 multi-blockbuster AR inhibitors are apalutamide from J&J and darolutamide from Bayer. We're supported by both companies in our dose exploration and dose optimization work in combo with both of those AR inhibitors.

And in the data that we showed last year, we showed PSA50s and PSA90s that were numerically better than Pfizer's. And obviously, we showed some pretty profound ctDNA. We don't know what Pfizer's clearance rate on ctDNA is. They haven't shown it, but we showed about a 59% clearance rate on ctDNA which as you benchmark that across various Phase III data sets, again, is a very profound number.

And then finally, on the safety side of things, which is where you really see the differentiation is clearly a differentiated profile for rinzimetostat in combination with either apalutamide or darolutamide as compared to what Pfizer showed you with their drug -- with their combo. And with the PRC2 inhibitor, you should really see 2 major classes of toxicity. You should see heme tox in the form of various penias and you should see GI Tox in the form of diarrhea, nausea, vomiting and sort of that general constellation of GI symptoms.

Now clearly, the name of the game here is to try to minimize how much of the frequency and the intensity of those types of toxicities that you see. And in what you saw from us last year, you saw a safety profile that while we see those classes of tox like Pfizer does, we see a lower frequency and a lower intensity of those things while also having, like I said, numerically better PSA50s and PSA90s. Now we don't yet have our own mature PFS number to quote, but really, the way this should work is that if you've got better activity in those early proxy forms of PSA50s and 90s and ctDNA and you have a better safety profile that ought to long term translate to a better PFS profile.

Okay. That is a very, very comprehensive description of the situation. So now you're going to have an update soon, I believe, in the first quarter. You've talked about it a bit, but maybe we can just review and maybe Dom can jump in and comment. What will we -- what are we going to be seeing there? I know you mentioned the PFS is not quite ready for prime time, but what would you show us in this update coming up?

Yes. So big picture, as you know, we wrapped up the dose escalation portion of the study in the latter part of last year and we selected the doses for the dose optimization. So the data that we'll get in Q1 will be from the dose optimization portion of the study.

What we're saying is going to be 20 to 25 patients worth of data. Now as you know, we're studying 2 different patient populations. We're testing the post-abi patients, but we're also testing the post-AR inhibitor patient population. So it will be from 1 of those 2 patient populations. And then as Jacob articulated, we're also doing 2 different combinations. We're doing combination with apalutamide from J&J and with darolutamide from Bayer. So it will be from 1 of those 2 patient populations, and it will be from 1 of those 2 combinations.

Now this is very intentional. The patient population and the regimen that we disclosed, that's kind of a preface for the Phase III study that we anticipate starting in the first half of 2026. And what we want to show here is, again, PSA50, PSA90, we want that to be consistent to what we've shown you guys previously in 2025. We want to show obviously the ctDNA data that Jacob referred to. Safety and tolerability, we want to be at least as good as what we've shown you previously as well. And the new piece of information will be an early look on durability. And as you said, we will not have a mature PFS, but we'll have an early look and durability. So think of a landmark analysis at 3 months or 4 months, that's what we'll kind of show to kind of make sure there's nothing -- no surprises in the data and that things are trending in the right direction from a durability standpoint.

Okay. So just so everyone is clear. So we're going to see either it's going to be a post-abi group or it's going to be a post-AR. And then within that, you're going to show us -- if you do the post-AR, it will be either apa or daro.

Yes. Whichever patient population we'll show you, we'll show you one of the AR inhibitors. So you do apa or daro. That's correct.

Okay. And then -- so it's -- but it's not going to be both post-abi and post-AR. It's what you're going to pick.

That's correct.

Yes. It will basically, Yigal be a -- it will essentially be a laying the groundwork for the first Phase III study that we intend to start in the first half of this year.

Right. Okay. No, it makes sense. I just want to make sure everyone understands that. And then what -- tell us without revealing what it is because I mean, I guess you're close to the decision, but what are the factors that go into the decision in terms of what you want to see like apa versus daro, as you pointed out, is 2 different pharma partners so presumably that obviously has relevance, but there's also the drug-drug interaction aspects, there's dosing and so forth. So just tell us in broad terms like how you think about the decision.

Yes. In broad terms, I think it's -- we're very lucky to be in a position where both AR inhibitor drugs and both partners are great. And so what we talked about in the data last year was that we don't see any differences in the efficacy or the safety profile of the 2 drug -- the 2 combinations in our hand.

Look, there's differences, obviously, on the nuances of each drug and the way they're dosed. One is dosed twice a day, the other one is dosed once a day. One has a food effect, the other one doesn't have a food effect. There's some tolerability differences between the 2 regimens. If you really force rank kind of which of the 2 drugs -- which of the 3 AR inhibitors are the most tolerable, I think the good news is most physicians would tell you that darolutamide and apalutamide are both better tolerated than enzalutamide. And so in a lot of ways, Yigal, it really comes down to we'd be fine with either one of those as our go-forward combo partner for the first Phase III study.

And one thing we've emphasized throughout the course of our development of this program is the first Phase III study will choose one of those drugs to be our combo partner of choice. We'll keep an open mind as to whether we stick with that drug for future Phase III studies or whether we choose the other one to get experience with both of them. So there's reasons why we might choose one or the other. I think more fundamentally on just the dosing of 944, I think really the only difference is we use a lower dose of 944 when we dose with darolutamide than we do when we dose with apalutamide. And the reason for that is pretty self-explanatory for folks that have been following us for a while, which is that apalutamide and for that matter, enzalutamide, Pfizer's drug are both well-known CYP inducers. And what that means is that they will push down the exposure of many drugs you combine with them because so many drugs are metabolized by the CYP enzymes. And that's the case for 944. That's the case for Pfizer's drug, Mevrometostat.

And so we are testing higher doses of 944 in our dose optimization with apalutamide than we are with darolutamide. So that's the only really meaningful difference between the 2 regimens right now in terms of which one we -- in terms of the experience with the 2 drugs. We have our own choice internally that we've made. Obviously, we'll make that clear when we do the Q1 update.

Okay. But regardless, as you pointed out at the beginning, with the longer half-life and ability to have a better target coverage over the 24 hours and lower Cmax, even if you did go with like an apa for just hypothetically, you would -- you're in a good place because you've got that benefit on the PK.

That's right. There's -- the beauty here, Yigal, is with the combination regimen, we actually have the ability to double down on the differentiation versus Pfizer. And what I mean by that is for all the reasons I articulated earlier, we believe that our PRC2 inhibitor has a better profile and is a better PRC2 inhibitor than Pfizer's. And at the same time, we think that we have the option between darolutamide and apalutamide, either one of those is a better AR inhibitor than enzalutamide, Pfizer's AR inhibitor. And that's not to take anything away from enzalutamide. That was the first to market. It's done phenomenally for patients. But again, if you ask clinicians to rank order the efficacy of those 3 AR inhibitors as single agents, they'll tell you they're all the same efficacy. If you ask them to rank order the tolerability of those 3 AR inhibitors, every clinician is going to tell you it's darolutamide, then apalutamide and then third being enzalutamide.

So we actually have a chance to have a differentiated 2 aspects of the combo regimen here versus what Pfizer has got because obviously, Pfizer has chosen to go with enzalutamide, which is their own AR inhibitor.

Okay. I remember covering Medivation back in the day. Okay. So as far as assuming you'll tell us what you're going to -- plans, I guess, in the next 6 weeks, when would you be ready to start the study? When would you actually kick off this Phase III? What else has to happen before you can actually go?

Yes. So we've said that we want to start this first Phase III study first half of this year. That means that, obviously, there was a lot of work that went into that Phase III study planning and execution as early as last year, actually Yigal, so quite a bit has been done. And between now or between the data update and then when we actually kick off the study, it's really just about closing that last little bit of trial execution.

But a lot of the heavy lifting has already been completed at this point. We'll obviously -- once we've got data in hand from dose optimization, we want to finalize our end of Phase I conversations with FDA to get sign off on the dose that's going to be taken into that first Phase III and other aspects of the protocol. But those are really the major aspects of what's remaining at this point.

And then obviously, since the partner AR drug is coming from a pharma entity, just can you comment at all in terms of funding of the study? And would it be -- would you do this yourself? Would you partner it? Would you just purchase the drug? Like can you talk to any of that aspect in terms of the funding of the study or the study conduct at this point?

Yes. We raised a lot of money last year on the back of the good data that we presented. We were able to raise close to $250 million last year. And so really, that has put us in a good funding position. So we are fully funded and then quite a bit for this first Phase III study in prostate. We're also fully funded for our first lung study that would be coming as well. And so the cash runway is into the second half of 2028, Yigal, and that's including these 2 different Phase III studies.

The reason to do that, of course, was because, look, we recognize the strategic value of this program, both to ORIC as well as just the broader prostate landscape. And so we did not want any aspect of this first Phase III study being beholden to having to do a partnership or having to go find further funding, and that's why we were so aggressive on the capital raising side last year. We have cash runway into the second half of 2028. The study is fast. So if we start first half of this year, we will have our answer by second half 2027. So call it by the end of next year, have the answer from that first Phase III study in hand, and we've got cash runway in the second half of '28, so well beyond the first readout here for our first Phase III study.

We obviously have ambitions that will go beyond that first Phase III study to unlock all those full set of ambitions for multiple Phase IIIs across prostate and even getting into areas outside of prostate, we're going to eventually want to bring a pharma partner on board for a more meaningful BD collaboration. But at this point, look, we're going to get free drug from our -- one of those companies of choice just to extend the existing free drug arrangements so that they'll also cover that first Phase III study. But no other cash needs at this point in terms of us going about that first Phase III trial execution.

Okay. So then is there a situation or a scenario where you could start the second Phase III like in a staggered fashion? Or as you point out, since the time lines to get to top line PFS are pretty soon, relatively speaking, you would just kind of wait, level set, see what that looks like and then decide whether you even need to do anything else.

No. We're going to be full on the accelerator, Yigal. So we'll start this first Phase III first half of this year, but we're simultaneously evaluating doing a lot of internal diligence, both in terms of internal data generation, but also kind of talking to external stakeholders to figure out where the next Phase III study would be within prostate so that we can get that up and running in a staggered fashion, as you referenced, as quickly as possible here because the name of the game is going to be to cover the prostate landscape quite quickly in terms of all the different lines or areas that we might want to elucidate this mechanism.

And then like I said, even studying the drug outside of prostate. So there's -- we have a lot of ambitions to develop this drug more fully even beyond this first Phase III study. I think the thing that people need to appreciate here is people might be stuck in some of the old paradigms of some of the much older prostate studies, even dating back to like you said, Medivation days, if you look at these recent studies, if you look at the Pfizer study, the primary endpoint is radiographic PFS, it's not OS, which means that for a relatively small-sized study and a relatively quick to enroll study and most importantly, a relatively cost economical study, you can get a Phase III readout.

And so as you think about -- look at Pfizer's first Phase III study, it's MEVPRO-1 is 600 patients in total that are enrolled in 15 months with a radiographic PFS primary -- sole primary endpoint. And what that means is that you can get the answer for not that expensive pool of dollars in terms of a Phase III population that is pretty substantial in terms of commercial opportunity. And so the ability to go do that in a second population is absolutely in our -- within our purview here at a small biotech to be able to do that. And so that's where I think that the longer that -- the more aggressively we can evaluate this program in different indications, both in prostate and outside, the better.

Okay. I've gotten a lot of questions about this program update, which I know you've been left to sort of go a little bit loose as far as what you might discuss in the second half of the year. But any clues that you could provide? Obviously, there are a lot of hypotheses about what you might show there.

And then related to that, since the Pfizer data are coming later in the year, I mean, obviously, you pointed out the benefits in terms of the tolerability on the heme and the diarrhea. So if you -- essentially, if you can meet -- at least meet what Pfizer showed on a PFS basis, I guess that's going to be a good place for you.

Yes, I'll ask Dominic to cover both of those.

Yes. I think on the first question on what the program update will entail, I think I'm going to tell you the same thing I told you on the e-mail exchange we had when we first put out the guidance. So we haven't said specifically what that is, Yigal. That could just be a general program update on where we are with the first study, how we're thinking about the second study to your earlier question or it could be some additional data that we think is relevant depending on the mature of that data set. So a little bit of TBD on that from your perspective.

With regards to the commercial opportunity here, this is prostate cancer. I know we spent a lot of time at Medivation talking about this. But if you look at the AR inhibitors today, it's really the backbone of treatment for prostate cancer patients. I think back in 2024, the 3 big AR inhibitors did $11 billion in sales. And that really only represents half of the ARPI market because there's still abiraterone, which is about 40% to 50% of the market, and it's still widely used.

So when we look at this opportunity, we think this is obviously a huge commercial opportunity. The 2 patient populations that we're currently studying are post-abi and post-AR inhibitors. Each one of those, if you just run the numbers, there's 17,000 to 20,000 patients in the U.S. alone. We just did some back of the envelope math that gets you to each of those about a $3.5 billion TAM, Treatable Addressable Market for each of those in the U.S. alone. And if you look at any standard analog for prostate cancer, the ex-U.S. market is almost as big as the U.S. market. So we think it's a huge market.

The beauty of this is we're combining with the standard of care, right? Both urologists, oncologists, they're very, very comfortable prescribing drugs like enzalutamide, apalutamide and darolutamide, and we're just kind of piggybacking off their coattails and not -- and providing a great, great benefit with not much more adverse events. So we think this is a huge commercial opportunity from our standpoint.

Now do you have to be differentiated, right? And the short answer is, no. And the perfect analog for this is actually the AR inhibitors. Enzalutamide, [indiscernible] innovation, we launched that in 2012. In 2024, that did $6 billion in sales. Apalutamide came 6 years later and is not really differentiated, and that did $3 billion in sales. So 6 years later, and it's basically doing half the number of sales. We're about 18 to 24 months behind Pfizer. So even with an undifferentiated profile, we think this is a blockbuster opportunity.

Now there are reasons why we think we have a differentiated profile, and that then obviously would increase that potential market opportunity for us as well.

I mean is there a scenario where because you get the better tolerability that, that will drive your PFS better because you're not going to get the earlier dropout. Maybe the potency side is the same, but you just have a better tolerability, so that will boost PFS. Is that a scenario that's...

Yes, it's an excellent question, Yigal. And I hesitate to kind of hypothesize too much about it right now, at least in the CRPC setting, mainly because if you look at the Pfizer profile that they showed you for their combination regimen at ASCO GU last year, I think most folks would agree that the tolerability profile was okay, but left room for improvement. But they clearly still got a pretty profound PFS at 14.3 months PFS. So they -- my point is they managed to keep those patients on in the CRPC setting despite the tolerability they were seeing.

I think certainly, if you go earlier in earlier lines, so let's take castration-sensitive prostate cancer, CSPC I absolutely think that what you mentioned is going to become a factor there where a safer profile could also lead to a more efficacious profile because you're, by definition, going to be able to keep patients on for longer. And the bar for safety is just going to be that much higher in those earlier lines. In other words, people aren't going to put up with a tox signal that they don't have to. And so that actually might lead to a longer PFS, certainly in the earlier line settings. We'll see if that plays out in CRPC as well.

Okay. I mean -- so I mean, you mentioned getting into a lot of other studies, and you just mentioned the castration-sensitive. That's sort of a part of the long-range thinking at some point, too, for this asset?

It is. Yes.

All right. Let's switch over because we spent 30 minutes on prostate. We want to make sure we give due time to the other half of your company. So enozertinib. So let's just talk about that one for a bit. You had the ESMO Asia data recently, which you showed the exon 20 and the PACC data. Can you just -- let's just summarize that, please, and just kind of highlight where you think it's differentiated. As we all know, this is not an uncrowded space for these particular variants.

Correct. Correct. We've heard for many years how crowded these spaces are, and we continue to see dropouts along the way in terms of the drugs not meeting the TPP profiles that you're looking for here. And so the way I would characterize it, Yigal, is we have 3 different populations that we presented on at ESMO Asia last year. So there was EGFR exon 20, EGFR PACC mutations and then finally, HER2 exon 20 mutations. We are nothing if not a data-driven company. We -- in the data we presented in HER2 exon 20, it was not competitive relative to the benchmarks that have been put out there. And so we've stopped further development in HER2 exon 20. We're totally focused on those first 2 populations in the frontline setting. And the reason is, if you looked at the data that we presented, while early and small end, it's developing nicely.

And so if you look at the frontline EGFR exon 20 and the frontline EGFR PACC data that we presented at the end of last year, the response rates in terms of ORR response rates was as good as the best of our competition out there in both of those areas. The tolerability profile was as good as the best in terms of both of those areas, in both of those target populations. And what stood out relative to all the competition by head and shoulders was the CNS activity of the drug.

So we have always talked about the differentiation of enozertinib is the fact that not only is it exquisitely clean for these targets of interest without the off-target toxicities that all these other drugs suffer from, but it also has profound or should have profound CNS activity based on all the preclinical characteristics of the program. You've now seen that evidence in spades. And so in 100% of the patients with measurable lesions across those 2 populations I just mentioned, we had CNS responses, 100% intracranial response rate in the patients with measurable lesions. Even in patients with what are known as non-measurable lesions, meaning multiple lesions that are below 1 centimeter in size, we have multiple examples of patients with complete responses where every single one of the brain lesions went away.

And as you and others know who follow the targeted therapy space for a while, Yigal, the issue in this space, whether it's EGFR exon 20, EGFR PACC or some of the other mutations that people have been following for years with multiple approved drugs is you have this dearth of drugs that are CNS active. And the reason that matters, and you referenced the crowded landscape, the landscape is not crowded when you start to focus on drugs that are CNS active. The reason it matters is because 1/3 of patients in the frontline at initial presentation have CNS metastases at baseline. Many more patients will actually progress in the brain.

And then you also have this third category of patients who have the brain metastases present in what are known as micro metastases where the metastases are there, they just don't show up on imaging yet. And where this plays out is in the long-term PFS of these drugs. And so you can look at amivantamab in the EGFR exon 20 space. You can look at mobocertinib. You will see the same dynamic that you've seen play out in multiple other of these target therapy spaces, which is drugs that are not brain-penetrant end up with very different PFS profiles for their patients with versus those without brain mets at initial presentation.

Drugs that are CNS penetrant don't have dramatically different PFS profiles in those 2 different patient populations. And so that's where we think the ultimate differentiation for enozertinib is going to shake out is in the PFS because with a well-tolerated profile, with profound CNS activity, you should end up with better durability than for these drugs that don't have CNS activity.

And just tell us a little bit more about the design of the molecule that allows for this CNS activity, the properties that allow for blood-brain barrier penetration, what is happening there that's achieving this?

Yes. Well, I mean, we've got 8 minutes left in the conversation. I could talk -- I can use all 8 minutes to tell you about the specifics of how the drug was designed that way. But I'll maybe simplify it, Yigal, by saying the drug was designed by the company from whom we licensed the drug, Voronoi, which is a South Korean company. They looked at the space and they said, look, all these other drugs are not getting into the brain, and it's a big issue. And so you have to have a molecule that's from a chemical property point of view and from a molecular weight point of view is small enough and can get into the brain, can stay in the brain without getting pumped out and be highly potent for these targets of interest.

And so all of that translates into the CNS activity that you're seeing today with the drug, which is all the preclinical profiling showed that, like I said, it gets in the brain, it stays in the brain. It gets into the CNS. And actually, we even mentioned during the Q&A of at ESMO Asia that we have multiple examples of patients. It's very rare actually in clinical trials to be able to draw CSF from these patients. But in the very few patients that we were able to do that in, every one of them had the drug in sufficient quantities of enozertinib in their CSF. So that's the proof in the pudding that the drug is in the CSF, and that's what's giving you the brain activity.

Okay. So then sort of cutting to the chase in terms of where you're going with this. You mentioned HER2 is out of the picture. I think Dom has mentioned many times, the second line is not something you're going to focus on. So you're basically going to focus on 1L EGFR exon 20 and 1L EGFR PACC. So what do you need to show there relative to the benchmarks to be competitive? And where are you leaning in terms of how you would do a registrational study? We've seen some examples of registrational studies already, as you know, from some of the competitors, and that's probably giving you some insight into what you may want to do.

Yes. Dominic, do you want to take that?

Yes. Maybe we'll start off with the data update in the second half of the year, Yigal, because it is a pretty comprehensive data update. So just to kind of rehash that. So we'll have 3 kind of cohorts of patient data that we'll have. And for each of those, it will be 20 to 25 patients. So in total, 60 to 75 patients. It will be first-line EGFR exon 20 as a monotherapy, that's one. EGFR exon 20 in combination with Ami, that's the second. And then we'll have first-line EGFR PACC as a monotherapy as well. So what we're going to show here again, we want to obviously see systemic responses. We want to show CNS activity. And here, we want to get a good look at durability as well. As Jacob said, durability is kind of where you expect to see the benefit from a CNS active agent.

With regards to benchmark, I think, generally speaking, from a response rate, you want to be 60% or better in each of those general cohorts. Now obviously, we'll have some data from competitors in the first half of this year. We'll obviously look at those and see how those translate as well. But again, the key thing for us is the differentiation on the CNS activity. I think that's where we -- initially, based on preclinical data, that was the hypothesis that kind of continue to show that in the clinic, both in the dose escalation and then on the dose optimization we shared with [indiscernible] as well.

With regards to are we leaning towards one or the other, again, Jacob said, we're a data-driven company. We're going to look at our data, compare it to the competitive landscape and see if it makes sense for us to pursue first-line lung in exon 20 or PACC or both or neither. Obviously, the data will drive that decision. But again, if we continue to show the differentiated profile that we've shown to date, we think we could be potential best-in-class here.

Okay. And just sort of at a higher level, speaking about cash and runway and prioritization, when you think about the R&D budget for the company and kind of roughly, like how much is going to enozertinib versus the prostate work roughly?

Yes. Yes, it's a good question. I think the obvious thing is prostate is a much larger patient Phase III study that you'd have to run just as a hypothetical analog would be for prostate, it could be a 600-patient study. I think for lung, for 1 of those 2 indications, it could be significantly less, call it, 50% of that. So that study obviously would be less as well. But again, I think they're both great opportunities, and we'll have to make that assessment on lung later the part of this year when we have the data in hand.

I'll put it this way, Yigal. The entirety of a Phase III experience in the front line for 2 lung populations is going to be less than or the same as one prostate study. And so from a -- we -- look, we recognize that where investor mentality these days is on targeted therapies, which is investors tend to run hot and cold on targeted therapies. So we know our cost of capital for lung is a lot higher in the minds of investors than it is for prostate and the company is mindful of that as we allocate our resources to these various opportunities.

Okay. And just in the last few minutes here, you talked in a bit of detail about the prostate market. But if you could just very, very quickly just kind of enumerate what the market sizes are for some of these indications like the EGFR exon 20 and the EGFR PACC. I know it's still an evolving calculation, especially for the PACC as some of these are -- there's a long tail of mutations there, which are still being identified.

Yes. I think if you look at the EGFR exon 20, let's call it about -- it's about 2% and look at PACC mutation, it's higher than maybe closer to 2.5%, 3%. So I think if you do the simple math on this, right, 4,000 patients in the U.S. for EGFR exon 20 and call it 5,000 for PACC mutations. It's a sizable patient population or opportunity across the board in the U.S. I'd say that the exon 20 is close to $1 billion plus TAM, whereas the PACC mutation being a little bit higher there, that could be closer to $2 billion as well.

So we do think people are under calling it the commercial opportunity here. And again, being the best-in-class here with the CNS activity could position us nicely if we continue to show that.

All right. Well, awesome. Well, we appreciate the discussion. Super interesting. And of course, looking forward to your sort of biggest reveal in a few weeks when we learn more about which way you're going to pivot on the Phase III for prostate. So we'll be -- we're watching our e-mail for that. So great to talk to you.

Sounds good, Yigal. Thank you for having us.

Thank you.

All right. Let's go ahead and get started. Welcome, everyone, to the 44th Annual JPMorgan Healthcare Conference. My name is Anupam Rama. I'm one of the senior biotech analysts here at JPMorgan. I'm joined by my Squad, [ Rati Pinhe ], Priyanka Grover and Joyce Zhou. So, our next presenting company is ORIC and presenting on behalf of the company, we have CEO, Jacob Chacko.

Thank you, Anupam. It's my pleasure to speak to you today about ORIC Pharmaceuticals and the important work that we are doing within the oncology space. As always, I'll be making some forward-looking statements. I encourage you to look at our SEC disclosures.

So starting on Slide 3, ORIC stands for overcoming resistance in cancer, which in a nutshell is the mission of the company. We've assembled a talented group of drug hunters and drug developers that have worked together for many years at prior leading oncology companies and have developed many successful and commercialized products to come together to work on a pipeline of exciting therapies for patients.

So we have two late-stage pipeline assets, one focused on prostate cancer. That drug is called rinzimetostat and a second program called enozertinib, which is for lung cancer. Both of those drugs have presented -- we've presented a substantial amount of data on both of those drugs in the prior years, especially 2025. We look forward to presenting a lot more data this year, as you can see in the upcoming anticipated milestones.

The company is incredibly well funded such that we've got cash runway into the second half of 2028. The importance of that runway is not really the second half of '28 part, but the fact that you're going to get your first Phase III data readout for rinzimetostat, our prostate program in the second half of 2027. And so we are well funded for that first Phase III program, and we are also funded for our lung program, which is also going into Phase III studies.

So I mentioned the management team. We've been together for years. We've been together at ORIC. I've had the privilege of working with most of this team for 7 years at this point. I recruited this entire team into ORIC. We've had the privilege of working together previously and knowing each other for many, many years, even prior to ORIC, and that makes all the difference in small biotech in terms of the ability to weather the storms of biotech as we're all aware of.

Slide 5 highlights the pipeline that we're working on. So I mentioned there are two late-stage development programs, rinzimetostat, which is a PRC2 inhibitor. Both of these are small molecule oral inhibitors. Rinzimetostat, formerly known as ORIC-944 is a PRC2 inhibitor, which is being developed in prostate cancer in combination with two of the biggest drugs in prostate cancer today, apalutamide from J&J and darolutamide from Bayer. And enozertinib, which was formerly known as ORIC-114 is a selective and importantly, brain-penetrant TKI that is going after two different targeted therapy populations within non-small cell lung cancer, EGFR exon 20 and a group of mutations known as the atypical mutations, but more specifically PACC mutations.

Now in -- within lung cancer, we're obviously testing enozertinib in combinations with chemotherapy and also with subcutaneous amivantamab, which is an approved therapy from Johnson & Johnson for this indication, and we're also obviously testing monotherapy. The important piece here you can see and you can even see it from the clinical collaborations is the strategic importance of these populations of these targets, namely that these are high unmet need patient populations where there exists a dramatic area for improvement in both of these populations.

And you can see that the commercial relevance of these populations is pretty much self-evident. As you look at prostate cancer, even our initial indications within prostate cancer, which are focused within the castration-resistant setting and eventually the castration-sensitive setting you could see our blockbuster opportunities many times over. And within lung cancer, these targeted therapy populations while relatively small and smaller than the prostate cancer populations are again individually blockbuster opportunities.

Now on Slide 7, you can see what summarizes a very busy and transformative 2025. So starting with rinzimetostat. Rinzimetostat again is our PRC2 inhibitor being developed in prostate cancer. We reported a substantial amount of data last year that confirmed the potential best-in-class data and profile within metastatic CRPC.

Now as many of you know, we have one main competitor. It's a small company called Pfizer, which is working on the same mechanism, and they have demonstrated quite a bit of derisking data of this mechanism of action, in other words, a PRC2 inhibitor in combination with an AR inhibitor. Adviser is studying their drug in -- their PRC2 inhibitor in combination with their AR inhibitor, enzalutamide. We are studying our PRC2 inhibitor rinzimetostat in combination with the other two big AR inhibitors, apalutamide and darolutamide.

Now in all of these cases, we've been able to show in combination with apa and in combination with daro confirmed PSA response rates that compare quite favorably to Pfizer's response rates. We've shown really profound ctDNA clearance and I'll give you some snippets of those data later in the presentation. And most importantly, we've shown a clearly differentiated safety profile. The name of the game here in this space and with this target is going to be the safety profile.

And we are very encouraged by the fact that even with the early dose exploration data that we presented last year, we already see definitive evidence that, that safety profile is emerging. In other words, the benefit of our drug and its long half-life and its strong drug properties is emerging in the form of a strong, differentiated safety profile. That's important because it's going to be compatible with long-term dosing.

And as I said, the name of the game here in prostate cancer is certainly in CRPC, but especially as you go earlier line into CSPC, castration-sensitive prostate cancer, is going to be to have that clean tolerated -- well-tolerated profile. Importantly, last year, we selected the provisional recommended Phase II doses of our drug rinzimetostat in combination with both apalutamide and darolutamide. We initiated -- we presented a substantial amount of data related to that, which I will give you some highlights of that later today.

And importantly, we initiated dose optimization in combination with both of those drugs, and we look forward to presenting some of those dose optimization data later this year. We were also busy -- equally busy on the other program, enozertinib. So within lung cancer, we presented a substantial amount of data actually just 2 months ago at ESMO Asia and two different oral presentations of our drug and enozertinib as a monotherapy in EGFR exon 20 and separately in EGFR PACC mutations, both within non-small cell lung cancer.

I mentioned to you earlier that brain penetrance is the key differentiator for this program so importantly, while we're thrilled that we showed systemic ORRs that are as good or better than the competition in the space, the most important thing for us to show in that data update was the intracranial activity of the drug, and that's because of the high prevalence of CNS metastases within this population. And in that data set that we presented, we saw a 100% rate intracranial ORRs in patients with measurable disease.

That is an incredibly high number and it is one that is not often seen in this space, even across other targets within targeted therapy non-small cell lung cancer. So we're quite proud of that, and it continues to help differentiate the program relative to what is otherwise a fairly competitive landscape. We also had a well-tolerated safety profile. And importantly, we picked our -- we selected our Phase III dose at that time.

So on the corporate side, we were equally busy. We raised a lot of cash, as you can see from the slide. And importantly -- the importance of that cash was extending the cash runway into the second half of 2028, which, like I said, is well beyond the Phase III data readout for rinzimetostat, which we expect to occur in second half of 2027. So with that, let's dive into the programs. So rinzimetostat, as I mentioned, formerly known as ORIC-944 is a PRC2 inhibitor. For folks that have followed the prostate space, you know that PRC2 inhibitors have been studied by multiple companies with multiple drugs previously.

The issue has been, what you see here, this is what I like to call the problem statement. So the key limitations at the top of Slide 9 show you what has really plagued the field and the clinical experiments with PRC2 inhibitors previously, which is namely the -- running the gamut of things that you don't want to see in optimal drug profiles. So, in other words, poor in vitro potency -- poor in vivo potency as if that wasn't bad enough, inadequate clinical drug exposures related to things like CYP autoinduction and importantly, short half-lives. And then all of those drugs have also been plagued with suboptimal tolerability, which really comes back to the poor PK properties and the poor drug properties.

Now I mentioned the competitor compound from Pfizer, mevrometostat seems to have solved some of these issues, though not all of the issues. And importantly, by solving some of the issues, they have been able to show derisking clinical data that really has helped validate the promise of the synergy of a PRC2 inhibitor in combination with an AR inhibitor in prostate cancer. With rinzimetostat, we think that we have similarly solved actually all of these challenges.

And in that, I mean that we are selectively targeting the PRC2 complex. We go at it through the EED subunit of PRC2. We have an excellent in vitro and in vivo activity. We have synergistic activity with AR inhibitors that at this point, we've showed both preclinically as well as in the clinic. And most importantly, we have demonstrated many times over now the strong drug properties and the well-tolerated aspects of the drug both as a single agent, but also in combination with both of the AR inhibitors that we are studying it in combo with.

So I mentioned that we're conducting dose optimization right now. We're doing that in collaboration with J&J, with apalutamide and separately with Bayer, with darolutamide, and we expect to report more of those dose optimization data later this year. The big, big thing that's happening in the background, the team has been running very hard at actually for the bulk of 2025 and obviously, even now into early 2026 is standing up our first Phase III study. So for rinzimetostat, we expect that we will not initiate our first Phase III study in the first half of this year. As I mentioned, these are quick studies. There's a profound signal effect that is expected to be seen. And so we expect the primary data readout to come in second half 2027, not too far from now.

Now Slide 10 is one slide that summarizes a lot of complicated biology. So I'm going to -- I won't do it justice, but I will try to summarize for you essentially very complicated biology around the PRC2 complex. So PRC2 is an epigenetic modifier. As you think about the big AR inhibitors, the androgen receptor inhibitors in prostate cancer, they have done profoundly well in terms of treating patients.

But eventually, those AR inhibitors or the broader class of what are known as ARPIs, including abiraterone, eventually, those patients as well as they respond to the ARPIs eventually become resistant. So what happens is that the tumors mutate, they essentially become AR-independent and at that point, it doesn't matter if you were shutting down the AR signaling access. And so the promise of the PRC2 inhibitor that -- is that a PRC2 inhibitor is an epigenetic modifier and through the modifications with a PRC2 inhibitor, you should be able to -- the theory has been, you should be able to push the tumor to stay in an AR dependent state and in other words, allow the AR inhibitors to do what they're supposed to do, which is shut down that AR signaling and really should lead to more durable benefit of those AR inhibitors.

And as I mentioned, we have now seen that clinical evidence both in a single arm setting as well as a randomized setting from our competitor compound that Pfizer is developing. Now taking a big step back on Slide 11, why does this matter? Why are we talking about combining a PRC2 inhibitor with AR inhibitors. For folks that have followed the prostate space, you know that the AR inhibitors, the three big ones being Nubeqa, darolutamide from Bayer, Erleada, which is apalutamide from J&J and then Xtandi, which is enzalutamide from Pfizer, those three inhibitors in comp as well as abiraterone, which is now generic, the broader class called ARPIs have transformed the standard of care in prostate cancer.

You will be hard-pressed to find a physician or patient in prostate cancer that is not heard of or is treated by these drugs. And the commercial numbers obviously validate the statement I just made, which is that the three big AR inhibitors collectively sell $11 billion of revenue globally. The issue has been, if you talk to the prostate cancer physicians or the patients what you will hear is that these drugs eventually stopped working.

And when they stop working, there's not a good option for patients or what you'll hear is that the options that are there for patients are ones that the patients don't want to take. So in other words, things like chemotherapy or other modalities that are actually much more complicated to deliver, come with much more toxicity are administered by a different position altogether. And so the holy grail has been, can you come up with a drug that would make these AR inhibitors better?

And so the pitch is quite simple here, which is that if you have a small molecule oral inhibitor that is well tolerated, that you can add on to an AR inhibitor to extend the durability of that AR inhibitor, either after the patient has already progressed on another ARPI or even before they've ever progressed on the ARPI, that pitch is self-evident as to why that appeals so much to the physicians and patients.

Now I mentioned to you that this PRC2 target has been studied in prostate cancer before, in fact, studied by multiple companies with multiple drugs and the clinical data haven't generally panned out. Now why is that? So if you look at the first-gen compounds, and you see a couple of them profiled here as representatives, but really all the first 10 compounds seem to have the same general properties is what's displayed here on Slide 12, which is that you see that they really suffer from liabilities on a number of different fronts.

So they've had poor potency, they've had poor in vivo activity. Importantly, several of them have had what's known as CYP autoinduction. What that means is that those drugs will rev up the CYP enzymes and those drugs are also metabolized by the CYP enzymes. So that in this case of some of those drugs, the more drug that was given to the patients, the lower exposure of the drug, the patient actually saw biologically.

Clearly, that's not going to lead to a well -- a clinical experiment that's going to do justice to the mechanism of action. Now mevrometostat, which is Pfizer's drug, seems to have solved a lot of these properties. They have a drug that is very potent as good in vivo activity has held some of the drug property issues. It does not look like it has CYP autoinduction has a somewhat better half-life. So in contrast to the 1- or 2-hour half-life of the first 10 compounds, the Pfizer compound appears to have about a 5-hour half-life or so.

Obviously, that is still a profile with some room for improvement. But with that profile alone, they've been able to show some pretty profound activity in combination with their AR inhibitor where they have more than doubled the progression-free survival that you would expect from an AR inhibitor alone. With rinzimetostat, you see the representation on the right-hand side of Slide 12, which shows that we've got excellent cellular potency and in vivo activity clinical half-life of 20 hours, which is compatible with once a day dosing obviously leads to a well-behaved PK profile.

The toxicity that you expect to see here would be Cmax-driven toxicity, so that's why it's so important to have a long half-life with a well-behaved PK profile, and it does seem to be validating in the clinic. Now Slide 13 is a schematic of the study as it exists today. The left-hand slide is what has been completed, which is dose exploration. As I mentioned to you, we did dose -- we did both single-agent dosing with rinzimetostat, but, of course, dose exploration in combination with the two big AR inhibitors that I talked about, apalutamide, which is J&J's drug and darolutamide, which is Bayer's drug.

Having done a significant amount of that dose exploration last year, we identified that the drug works -- rinzimetostat works equally well with both of those AR inhibitors. It works at least as well as Pfizer's combination has been able to show, and it's been able to do that with a safety profile that at this point looks better than what Pfizer has been able to show. And we've shown that at multiple different doses.

So we selected doses for dose optimization, obviously, for Project Optimus purposes. And the right-hand side of Slide 13 is really what's going on right now, which is dose optimization in combination with both of those AR inhibitors. We're setting two different populations right now. So within the metastatic CRPC setting, we're looking at one population that is post abiraterone. So in other words, they've already progressed on abiraterone and they are now receiving an AR inhibitor, either apalutamide or darolutamide in combination with our drug rinzimetostat.

We are also separately studying a second population of interest within metastatic CRPC that is actually equally large, which is a population that has previously had an AR inhibitor, so either enza, apa or daro and is now being dosed with rinzimetostat in combination with either apa or daro. So all of that dosing work is ongoing right now. And as I mentioned, we expect to report some data from that dose optimization in the first quarter of this year.

Now to quickly review on Slide 14 and a few of the subsequent slides, just some of the key highlights from the dose exploration data that we presented last year. Slide 14 shows you a PSA waterfall plot. So why did PSA matter -- PSA responses mattered? These are generally thought of as early proxies of long-term durability within prostate cancer, obviously, the gold standard for an approvable endpoint remains radiographic PFS. We're not there yet. We're in the earlier stages. And so we look at PSA50s and PSA90s as one metric of the activity of the drug and another way to benchmark against, obviously, the competition.

Now first question you ought to ask when you look at a PSA waterfall plot like this of a combination regimen is what would you expect from an AR inhibitor alone in this setting. So in other words, if patients -- all these patients are in the metastatic CRPC setting, they've all progressed previously -- 100% of them have progressed previously on abiraterone up to one prior line of chemotherapy was allowed in this population. And in that setting, it is a very well documented population that with an AR inhibitor alone, you would expect to see roughly a 15% rate of PSA50s and roughly a 5% rate of PSA90s.

You obviously see a far higher rate here, a confirmed PSA50 rate of 40% as opposed to the 15% I mentioned. And you see a confirmed PSA90 rate of 20% as opposed to the 5% that I mentioned. So that is in line, actually higher than the numbers that you see from Pfizer and the randomized data that they presented. And importantly, you're seeing that regardless of the combo agent. So in other words, we see that same activity, whether it's apalutamide or darolutamide that we're combining with. We see that same activity at all the different doses that we tested. And so obviously, we're taking a few of those doses forward for dose optimization.

Now Slide 15, if you'll allow me to nerd out for a little bit is ctDNA data. And the question you should ask here is why does ctDNA doesn't matter in light of what I just showed you on the PSA activity. And the reason is there's now a literature that says that even more than the linkage between PSA responses, PSA activities to long-term durability measures like PFS, ctDNA actually tracks even better for a long-term durability -- for a proxy of long-term durability within prostate cancer. And this is why all the recent prostate Phase III studies have used ctDNA as an exploratory endpoint as well.

What you can see on the left-hand side of Slide 15 is that we have a 59% rate of taking ctDNA patients from detected to not detected. The right side of Slide 15 helps you contextualize whether that 59% is good or not. And so what I'll show you the first two bars on the right-hand side of Slide 15 are active standards of care that otherwise get used in this population.

You can see that enzalutamide -- and these are Phase III studies that looked at these agents. You can see enzalutamide achieved about a 12% rate of ctDNA going from detected to not detected, whereas chemotherapy, which would be another active standard of care in this setting has about a 32% rate of ctDNA going from detected to not detected in the case of rinzimetostat, we saw a 59% rate of going from detected to not detected, which also bodes well for the activity of this combination and the synergy of the combination.

So Slide 16 tries to summarize a lot of data from both ourselves and obviously, the competitor. The first two columns on Slide 16 are showing you a highly summarized version of the randomized data that Pfizer showed last year with mevrometostat, which, like I said, those data were profound full stop. You saw greater than a 2x extension of the PFS that you would expect with enzalutamide alone and that was in a controlled setting. The controlled -- the controlled arm performed exactly as you'd expect, which is a 6-month -- 6.2-month PFS and their treatment arm got a 14.3-month PFS.

And you can see the corresponding statistics that go with that. So as you look at PSA50s and PSA90s, Pfizer more than doubled, the PSA50 and the PSA90s that you would otherwise expect. But you can see it comes with a fair bit of toxicity. So as you look at the middle column, you can see a decent amount of toxicity. You would obviously expect to see two big classes of toxicity with the PRC2 inhibitor, which would be namely -- so hematological toxicity as well as GI toxicity, and you see both of those things.

You also see alopecia. You see obviously a high frequency of these things and also a high intensity. Now in the case of rinzimetostat plus the two AR inhibitors we looked at, you can see in the far right column. I won't go through everyone of these AEs, but you can visually see it's quite evident that you see less toxicity, both a less frequency and less intensity of that toxicity. And that's going to be at the end of the day, what wins the game here.

I won't spend too much on Slide 17 because I think you all know that the prostate market is large. And as good as the therapies have been thus far, there is need for better therapies, there's a need to kind of improve the standards of care that exist today. And you can see with any one of these potential Phase III studies for us, it's a multibillion-dollar opportunity just in the U.S. alone.

I don't have nearly enough time in this presentation to talk to you about the biological evidence for PRC2 inhibitors outside of prostate cancer, but really the right-hand side of Slide 17, attempts to show you to summarize for you several areas that we would intend to eventually develop our PRC2 inhibitor as well, which is there's ample evidence at least preclinically that PRC2 have the same epigenic synergistic effect in combination with KRAS inhibitors in lung and in colorectal cancer, and importantly, in combination with estrogen receptor inhibitors in breast cancer.

So these areas that we also look forward to developing a proof-of-concept in the clinic in the time to come. So with the time remaining, I do want to make sure we talk about our lung program as well. So enozertinib, formerly known as ORIC-114, is a brain penetrant inhibitor of EGFR. Slide 19 shows you the problem statement here, which is that as you look at this space for those that follow, the lung cancer space, you will instantly recognize that within targeted therapies for lung cancer, we have had a lot of good development of drugs for various targets within non-small cell lung cancer, but EGFR exon 20 and EGFR PACC mutations remain two classes or two slices of that non-small cell lung cancer pie that are still incredibly underserved today.

So there is one approved agent for EGFR exon 20, that is amivantamab from J&J. That drug is obviously not brain-penetrant. There's a lot of agents in development for EGFR exon 20 and others that are in development for EGFR PACC, none have shown profound CNS activity. With the exception, I would argue, of enozertinib. The CNS activity matters because of 50% of these patients will eventually develop brain metastases where you see the impact the durability of these drugs that are not brain-penetrant is because the patients eventually progress in the brain. That is the flaw in the armor of all of these drugs that are not brain-penetrant.

Previously, I and many of our team members worked at a company called Ignyta. We developed a targeted therapy for non-small cell lung cancer there and we saw the benefit of having a brain penetrating compound and what that leads to in terms of increased durability. And that's exactly what is missing from both of these spaces, EGFR exon 20 and EGFR PACC mutations. The other thing that has plagued the field historically with some of the first 10 compounds here were tolerability issues related to either GI tox or skin tox. A lot of that has been solved by us and by others in the field. And I think at this point, the remaining piece of the puzzle to solve is really the lack of CNS activity.

Now we presented a lot of data here just a couple of months ago. And the summary of that data, I'll show you some of the highlights and the slides to come. But the really high-level takeaway is that the data had response rates that were at least as good as competitors, if not better, in terms of systemic responses, but importantly, as I highlighted in my opening commentary, we had 100% intracranial ORR in patients with measurable disease. That is an incredibly high level of activity in terms of CNS activity.

And that was in the context of enrolling patients. So in contrast to the competition in the space, we enroll patients with active untreated disease into the study. In other words, they're allowed into the study. Almost all the other programs, certainly in the early stage, all of the programs excluded those patients and in later stages, most of the programs still exclude those patients. And what I mean by that is they require that if a patient has CNS metastases, those metastases need to have been treated with surgery or radiation prior to coming on the study.

That's obviously not a good way to detect whether your drug is CNS penetrant and able to treat CNS metastases, we allow patients with active untreated mets onto the study and in fact, enroll a substantial number of those patients and see that profound CNS activity in those patients as well. Now we've selected 80 milligrams once daily as the go-forward Phase III dose. And as mentioned, we're prioritizing first-line development in EGFR exon 20 and in EGFR PACC mutations in some cases, as a monotherapy and in other cases as combinations, and we expect a substantial amount of new data to be presented in the second half of 2026.

Slide 20 is a stylistic depiction of why that CNS activity matters. So the top half of Slide 20 just shows you some of the facts that I mentioned before, which is that at initial presentation, approximately 1/3 of patients have brain metastases at initial presentation. The important part, if you talk to a radiologist or you talk to a medical oncologist, what you're going to hear is that that's the 1/3 of patients that you know have brain metastasis because you can see it on imaging.

There is another group that obviously we don't know the size of that group that have what are known as micro metastases, meaning that the mets are there. You just can't pick them up on standard imaging these days. And so the number is certainly higher than 30% or 33% at initial presentation that have these CNS metastases. And then what happens is that eventually, as you go to later lines of treatment, up to half of these patients will present with CNS metastases.

But the biggest issue is really what you see at the bottom half of Slide 20, which is that for drugs that are not brain penetrant no matter how good they might be systemically. Eventually, patients will progress and for non-brain penetrant drugs, they will often progress in the brain. And so these CNS metastases will occur, that will be the site of progression. And at that point, the patient is really out of options. They have to go to something that's a lot more invasive in terms of treatment.

Where this comes out in the data. So as you can -- we're students of the targeted therapy lung space -- because, as I mentioned, some of us worked together previously at Ignyta. And what you can see time and time again, whether it's ALK, ROS, EGFR, any of the big targets in non-small cell lung cancer, is that for drugs that are not brain penetrant versus drugs that are brain penetrant, you will achieve generally the same systemic response rates, where you tend to have a big difference is progression-free survival. For the drugs that are brain penetrant, you end up getting longer progression-free survival.

The bottom half of Slide 20 essentially explains why that is. As you look at these drugs, both of which were developed in EGFR exon 20, both of which are not brain-penetrant, you can see there's a profound difference in the PFS, the durability of these drugs in patients with versus without brain metastases. And so for a drug that is brain penetrant, if you can close that gap and in other words, have both populations perform more like the good bars, in other words, the patients without brain metastases, you'll essentially end up getting a longer progression-free survival.

So Slide 21 shows you what we've done and what we are doing right now. So like I mentioned, we're focused on EGFR exon 20, both monotherapy of enozertinib as well as combos with J&J's drug, which is subcutaneous amivantamab as well as a combination with chemotherapy. And then separately, we're studying the drug in EGFR PACC mutations as a monotherapy. Now we presented a lot of data in two different oral presentations 2 months ago at ESMO Asia.

Slide 22 is essentially a one-slide summary of the key snapshot of those data. And what you can see in the top half of Slide 22 is that relative to competitor benchmarks in the pretreated population, the reason we're -- even though we're not focused on pretreated for later line development, the reason to spend a second here is because these are the most well-studied data sets, both from ourselves and from the competition.

You can see that enozertinib just delivers a response rate that's at least as good as the competitor benchmarks, if not better. And then importantly, on the bottom half of Slide 22, as you can see, obviously, as you move to the front line, you see even better response rates and then the 100% integral ORR that I mentioned earlier.

Slide 23 is just a little bit of a double-click on that activity that I mentioned to you. The waterfall plot speaks for itself in terms of the activity of the drug. So you see very good activity in frontline EGFR exon 20 in this waterfall plot. And like I mentioned, the asterisks at the top of the waterfall plot are showing you the patients that have CNS metastases at initial presentation. You can see even a greater percentage of those patients had CNS metastases at initial presentation than the 33% that I quoted to you earlier.

There is some sense of physicians and patients voting with their feet here. In other words, we do tend to enroll a higher percentage of our patients that end up having CNS metastases at baseline because the physicians know that the drug is brain penetrant. And you can see that regardless of whether the patient has mets at baseline or not, you see that good systemic activity.

And importantly, Slide 24 is, I'll call it, the triple click of those patients with CNS mets at initial presentation. And you can see with all the complicated annotations on the slide, the point of that is that we enroll patients -- several patients with measurable disease. We enrolled several patients who had active untreated disease before they came under the study it doesn't matter which of those categories they fall in, you see profound activity of the drug, including two complete responses.

And those complete responses, it's worth noting are in patients with what are known as non-target lesions. The reason why that's important is in patients with what are called non-target lesions in the brain. The only way to get an official response, so to speak, is to completely clear all the lesions. So in other words, if the patient has 5 lesions and you clear 4, that does not count as a response. The way the criteria work in patients with non-measurable lesions, you can see we completely clear the lesions in all those patients.

And here's one example on Slide 25. All the data, all the waterfalls, none of it -- all of it pales in comparison, I would say, to the actual patient stories. And this is where I spend a lot of my time is understanding the activity of these drugs and why it matters. So this is a 60-year-old female who presented with frontline EGFR exon 20 who had 5 lesions in her brain at initial presentation had no prior surgery or radiation for those lesions. And you can see after one cycle, she had a partial response, 47% reduction systemically and importantly after 1 cycle disappearance of all 5 CNS lesions.

So that is profound CNS activity. You can see that the drug safety profile that she experienced, which was well tolerated and a duration of therapy that at the time was 6 cycles and ongoing. Similarly, in the PACC population, you can see we have very good systemic activity here as demonstrated by the waterfall on Slide 26. And then similarly, as I showed you for EGFR exon 20, Slide 27 is the double click on the CNS -- the patients with CNS lesions who have these PACC mutations.

Again, you see profound activity, including complete responses in this population and that includes most of these patients actually having active untreated disease before study enrollment. Again, here, the patient stories are with -- speak volumes more than any other slide of data that I can show you. Slide 28 shows you a patient, a 67-year-old male, who came in with the PACC mutation -- frontline PACC mutation and had a systemic response of 43% after the first cycle. After the first cycle in the brain, he had a 66% reduction of his measurable lesions. But after cycle 4, that had moved on to a deeper response, in fact, a complete response and was at cycle 5 and ongoing.

So we get a lot of questions from investors around the market opportunity for lung, as some of you probably know, I think the investor enthusiasm waxes and wanes around targeted therapies over the course of time. It seems to be tied to what was the latest acquisition in the targeted therapy lung space. But you can see that these populations are sizable populations or populations that matter. These populations, any one of them, whether it's EGFR exon 20 or EGFR PACC is larger than ROS, larger than RET, there's a substantial commercial opportunity here. More importantly, there is a substantial patient need here in these populations for drugs that are truly active, well-tolerated and brain penetrant.

And so with that, in summary, you can see here on Slide 31, again, the active pipeline that we've got going in both prostate cancer and lung cancer, as I hope you've heard in my commentary today, we think that these drugs are substantially differentiated from the competition. There's a lot of milestones to come, a lot of activity going on at the company. And important thing we're about to embark on, one if not to two Phase III studies for these programs within the year to come.

So with that, I'll turn it over to Anupam for any questions.

Thank you, Jacob. We're coming up on time here. So I just first wanted to see if there's any questions in the audience. Yes. Go ahead.

If you -- bilateral glioma -- pediatric glioma is characterized by 85% of -- bilateral pediatric glioma are characterized by exon 20 EGFR mutant's main driver event, do you have any plans to make your inhibitor available for compassionate use or investigator-initiated trials in that setting?

Yes. We're aware of the data in that -- the clinical rationale in that space. We have not -- thus far not studied the drug in glioma. That's not to say that we're closing the door on that. So we'd certainly be open to a conversation around that.

On the dose optimized data that's expected in 1Q, can you give us any sense of more granular time lines? Is this going to be, I think, ASCO GU is coming up. There's also your press release webcast scenario that we could consider? Like how should we think about that?

So the data will be coming sometime between today and March 31 and this is probably how I'd characterize that.

Yes, solid guidance. Yes, all right. Okay. So in the next ...

Within this quarter.

Within this quarter?

Yes.

Next 75 days or so, yes? All right. So maybe then you could talk to us a little bit about the size and scope of the data that we're going to be getting and what you would really focus on given what you already know and what Pfizer has shown?

Yes, I'd be pleased to expand on that question. So we expect to see about 20 to 25 patients' worth of data. And what we've said is that, obviously, we're studying the drug in two different populations within metastatic CRPC. We're going to focus that Q1 disclosure on one of those populations of interest. Presumably, it will be the population that we intend to start that Phase III study in, in the first half of this year.

And then we intend to focus that disclosure on one of our AR inhibitor combo partners of interest. Again, presumably, that's the one that we intend to take into the first Phase III study. The 20 to 25 patients' worth of data, what we're going to present is like you've seen from us before, obviously, PSA50s, PSA90s, ctDNA data in terms of efficacy. We will have whatever is available in terms of durability because obviously, that's a key question here.

So we'll be looking for signs of durability that we are tracking towards what mevrometostat was able to show and certainly that we're hopefully tracking definitively better than an AR inhibitor alone in that space, so some type of landmark analysis on the durability side, and then most importantly, safety. As I mentioned, we're going to want to see that the safety profile is clearly differentiated from that of the competitor combination because that is what's ultimately going to lead to the long-term radiographic PFS and win the day.

I noted that in your comments, you noted at least 3 times that your first pivotals trial would read out in the second half of 2027, which would put you how far behind Pfizer in terms of timelines?

Yes. I mean it's exciting as I think our pipeline is, I think we get probably more questions about Pfizer and their time lines. So what they have said is that, in fact, Albert reiterated yesterday in his presentation that they're going to have their first Phase III readout for April 1 this year -- 2026. And so I guess it depends if that readout happens tomorrow or in December 31, but the point is, I think we're roughly, call it, 18 to 24 months behind them. We intend to run as hard as we possibly can to keep that gap or close that gap, but the race is on.

Thank you, Jacob.

Thank you.

Good day, and thank you for standing by. Welcome to the ORIC Enozertinib Program Update Conference Call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your first speaker, Dominic Piscitelli, Chief Financial Officer. Please go ahead.

Good morning from Singapore, and welcome to the ORIC Pharmaceuticals Enozertinib Program Update Conference Call. Earlier this week, we issued multiple press releases highlighting updated data from our ongoing Phase Ib study of Enozertinib in non-small cell lung cancer patients. You may find the press release is posted on the investor page of oricpharma.com. We have prerecorded our prepared remarks, after which we will host a live Q&A session. .

Before we begin, during this call, we will be making forward-looking statements, including forward-looking statements based on our current expectations and projections about future events. Our actual results may differ materially from those indicated by such forward-looking statements. For a description of risk factors, please refer to our recent filings with the SEC. ORIC specifically disclaims any obligation to update any forward-looking statements.

This presentation contains interim results based on data from Enozertinib trials as of the cutoff date set forth on applicable slide. During this presentation, we will not be speaking to any additional data subsequent to such date.

Now turning to Slide 3. During today's call, we'll discuss Enozertinib's preclinical differentiation Phase Ib clinical highlights from ESMO Asia, new preliminary first-line data in EGFR pack mutations and next steps followed by Q&A.

Joining me on the call today, we have Jacob Chacko, CEO; Lori Friedman, CSO; Pratik Multani, CMO; Matt Panuwat, CBO; and [ Keith Louis ], Senior Vice President of Commercial and Medical Affairs. Now let me turn the call over to Jacob.

Thank you, Dominic. Turning to Slide 5. We've obviously been busy at ESMO Asia with two oral presentations and one poster presentation that collectively summarize an enormous amount of Enozertinib data generated over the past 1.5 years in three different targeted therapy lung cancer population. This slide is a summary of the key takeaways from our Enozertinib experience, which we believe has established its potential best-in-class profile for patients with EGFR-mutated non-small cell lung cancer.

First, we've observed highly competitive response rates in both pretreated and frontline EGFR Exon 20 and EGFR PACC mutations, the two populations that we have prioritized for ongoing development.

Second, we've continued to demonstrate two key aspects that highlight Enozertinib's differentiation versus a crowded field of competitors, namely its profound CNS activity, which is critical because of the high prevalence of brain metastases in these populations, and its lack of significant off-target toxicities like cardiac, hepatic and hematological liabilities that are found with competitor inhibitors.

Finally, our substantial experience with Enozertinib points us to 80 milligrams once daily as the preferred dose for future development. We will continue enrollment and long-term durability follow-up in the first-line EGFR Exon 20 and first-line EGFR PACC population with the next planned update in mid-2026, ahead of the potential start of one or more Phase III registrational trials.

Slide 6 highlights why we are so passionate about developing Enozertinib as rapidly as possible for patients. EGFR Exon 20 and EGFR PACC mutation collectively occur annually in approximately 9,000 patients in the U.S. alone. There is one FDA-approved therapy for first-line EGFR Exon 20 and none for EGFR PACC mutation. And there is a complete lack of brain-penetrant compounds approved or in late-stage development to serve these patients. Either of these populations on its own represents a blockbuster opportunity in the U.S. alone, and both are among the largest, if not the largest, underserved targeted therapy populations that exist in lung cancer today.

Slide 7 summarizes the key aspects of an ideal target product profile that has yet to emerge to serve these populations, although we believe Enozertinib is well on its way to doing so. While the next-generation inhibitors, and Enozertinib included, have done a nice job of managing on-target toxicity, off-target toxicities continue to challenge the field.

Additionally, the prevalence of brain metastases and the brain often being the site of first progression mean that robust CNS activity is an absolute must for a best-in-class inhibitor. Ultimately, strong efficacy, both systemically and intracranially, combined with the manageable safety profile should result in the differentiated long-term durability.

Now I've already mentioned the importance of brain penetrants in effectively treating this cancer, and Slide 8 helps explain the rationale. 30% of patients have known brain metastases at initial presentation, and that number does not include the portion of patients who have brain metastases that are not yet detectable on conventional imaging. Over time, half of patients will develop brain metastases and the brain is often the first site of progression, especially for drugs that are not brain-penetrant.

The bottom half of Page 8 explains why this is such a problem. You can see that non-brain penetrant drugs have dramatically different outcomes for patients with or without brain metastases. There are countless examples in the targeted therapy space of best-in-class drugs that are brain penetrant and thus address this discrepancy.

Turning to Slide 9. You can clearly see that not only is Enozertinib demonstrating a response profile that is as good or better than competitor compounds, but you also see the preliminary evidence that for Enozertinib, the presence or absence of brain metastases does not make a difference. The drug delivers profound results for patients regardless of brain metastases.

In fact, we felt so strongly about this aspect of our drug that unlike every other competing drug in the space, from day 1, we never excluded patients from the study if their brain metastases were untreated before study entry. As Pratik will cover shortly, we've enrolled numerous patients with active untreated brain metastases and have achieved strong systemic and intracranial response rates.

With that, let me hand it over to Lori to remind you of the strong preclinical profile for Enozertinib before Pratik covers the Phase Ib clinical trial results and next steps for the program.

Thank you, Jacob. Slide 11 highlights our key aims in identifying a clinical candidate that would support a best-in-class profile for EGFR Exon 20 and atypical mutations.

Enozertinib was designed to have multiple areas of differentiation. First, Enozertinib has strong cell potency against a wide variety of EGFR Exon 20 and atypical mutations and demonstrate tumor regression in vivo. Second, Enozertinib is notable for its selectivity towards EGFR and while sparing all other kinases. Third, a crucial feature of Enozertinib is brain penetrant. This high brain exposure drives regressions in xenograft tumors grown in the brains of mice.

As shown on the right, these three areas of preclinical differentiation have all played out in the clinic with potency translating into clinical responses across the breadth of EGFR mutations, selectivity translating into minimizing off-target tox liabilities, and brain penetrants resulting in robust intracranial responses in patients.

Taking each area of preclinical differentiation in turn, starting first with potency on Slide 12. The A key differentiating feature of Enozertinib is strong cell potency across a variety of EGFR Exon 20 and atypical mutations. In this figure, potency is depicted on a color scale with dark teal blue being the most potent and gold being the least potent. When Enozertinib is compared to competitors in head-to-head in vitro studies, you can see that Enozertinib stands out with excellent potency across the spectrum of mutations.

Moving to Slide 13. A second differentiating feature of Enozertinib is selectivity. Off-target selectivity is one of the most important aspects for designing best-in-class compounds. In these data profiling multiple compounds across the kinome, Enozertinib is exquisitely selective, a key differentiation versus competitors. The table at the bottom of the slide summarizes the off-target data. Enozertinib has 0 off-target kinases inhibited, while other EDFR compounds inhibited multiple off targets, which can lead to adverse events not related to EGFR such as hematologic, cardiac or liver toxicities.

Finally, turning to Brain Penetrants on Slide 14. Brain penetrant stands out as one of the most distinguishing features of Enozertinib especially given the inability of approved and late-stage EGFR Exon 20 and PACC agents to tackle brain metastases.

On the left, in head-to-head studies in rodents, Enozertinib has a high free brain-to-plasma ratio comparable to Osimertinib and far higher than competitors that have minimal exposure in the brain. Shown on the right are results of an in vivo study measuring antitumor activity in the brain. This EGFR mutant lung cancer model was inoculated into the brain of mice and tumor shrinkage was measured by imaging. The Log scale on the Y axis shows Enozertinib achieving orders of magnitude deeper regressions in tumors grown in the brain compared to the competitor compound.

Next, I'll hand it over to Pratik who will discuss the clinical dose optimization results that show that these preclinical best-in-class properties are translating to patients.

Thank you, Lori. Before I get into the data, I'd like to provide an overview of the Enozertinib development program. All the data presented here at the ESMO Asia conference come from our global Phase Ib trial that is being conducted at 39 major academic centers in 10 countries in North America, Europe and Asia Pacific. Over 300 patients have been enrolled across the dose finding, dose optimization and dose expansion cohorts. .

Also, one key aspect of our program, which Jacob already raised is that unlike every one of our competitors, we allowed enrollment of patients with active brain metastases from the very beginning of our trial starting in dose escalation because we feel so strongly that CNS activity is necessary for a best-in-class molecule in lung cancer.

Now turning to Slide 16. We'll begin with our experience in non-small cell lung cancer with EGFR Exon 20 insertion mutations. We enrolled two populations of patients harboring these mutations. The first cohort to start enrolling with second-line post platinum-based chemotherapy in which patients were randomized 1:1 to receive either of the two provisional recommended Phase II doses we selected for dose optimization, namely 80 milligrams or 120 milligrams of Enozertinib once daily.

The second cohort, which started later, consists of first-line treatment-naive patients, and here, we enrolled the two dose levels sequentially one after the other. The first 15 patients received 120 milligrams of Enozertinib after which the remaining 18 patients up to the data cutoff received 80 milligrams. This shift was based upon safety observations we made at the 120-milligram dose in the second-line cohorts, which I'll discuss shortly.

Turning to Slide 17. Here, we have the demographics and baseline characteristics for the second-line cohort, totaling 45 patients randomized to the two doses of 80 and 120. Notably, across both dose levels, 38% had brain metastases at baseline, including patients with active CNS disease.

Turning to Slide 18. We have the safety profile for the second line post chemotherapy population by dose level. In general, treatment-related adverse events were predominantly Grade 1 or 2 and Grade 3 events occurred in roughly 1/3 of patients. Importantly, there were no significant off-target toxicities observed. For example, cardiac, hematologic and hepatic toxicity, all of which have been seen with other investigational agents. And finally, there was a low rate of discontinuations due to treatment-related events.

Dose reductions were significantly more frequent at the 120-milligram dose level with 57% of patients undergoing dose reduction down to 80 milligrams versus only 1/3 of the patients who started at 80. Looking at the table on the right, the most common treatment-related adverse events occurring in at least 20% of patients were diarrhea, followed by paronychia and stomatitis. These can all be attributed to on-target EGFR wild-type inhibition. Overall, the 120-milligram dose level had a higher rate of grade 3 toxicity, particularly diarrhea, which explains the high rate of dose reduction.

But that's not the full story. Besides more dose reductions at the 120-milligram dose level, there was also a higher frequency and duration of dose interruptions, which affected dose intensity. Thus, most patients assigned to receive 120 milligrams never truly saw that dose intensity and many fell well below even 80 milligrams. In contrast, the 80-milligram cohort was able to maintain this dose pointing towards 80 milligrams as our go-forward recommended Phase II dose.

Slide 19 depicts the reduction of ctDNA from baseline after the first 28-day cycle of therapy. You can see that there was a high and very similar rate of clearance at both dose levels with 69% clearance at 80 milligrams and 67% at 120. Thus, there seems to be little to no advantage to the higher 120-milligram dose.

On Slide 20, we'll turn to efficacy. Given what I just noted above that the 120-milligram dose level compromised dose intensity, I'll focus my discussion on the 80-milligram dose level. Here, we are looking at the efficacy evaluable population, which consists of patients who have received at least one dose of Enozertinib have at least one measurable lesion at baseline and have had the opportunity for at least three post baseline scans. The best objective response rate was 45%, all confirmed partial responses. And from the waterfall on the right, you can see that many of the PRs are deep with more than 50%, 60% regressions, and the disease control rate was 100%.

For the 40% of patients with CNS disease at baseline, looking at the table and the bars labeled with asterisks on the waterfall, you can see that there is no appreciable difference in response in these patients, which is the hallmark of a CNS active drug. Thus, Enozertinib, 80 milligrams once daily, appears to achieve a balance between an acceptable safety profile while providing strong clinical activity.

The next slide depicts the swimmer plot for the 80-milligram dose level in the second-line patient population. You can see that responses on Enozertinib generally occurred by 4 weeks which is the first on-study scan time point, but there are multiple examples of later responses occurring up to 4 or more months on treatment, demonstrating continued tumor regression with time. While progression-free survival and duration of response data are still immature, we can say that with a median follow-up of about 30 weeks, 2/3 of the responders remain on treatment.

On Slide 22, a we'll now turn to the treatment naive or first-line EGFR Exon 20 cohort, which is one of our main opportunities for future development. As I stated earlier, we initially dosed these patients at 120 milligrams but then shifted to 80 milligrams.

Turning to Slide 23. Our first-line experience to date consists of 15 patients who received 120 milligrams of Enozertinib followed by 18 patients who received 80 milligrams. In aggregate, 39% of patients had brain metastases at baseline similar to our second line population and higher than the literature average of 30%.

On Slide 24, we have the safety profile for the first-line cohort broken out by dose level. As we saw with the second-line data, here, there was also a higher rate of Grade 3 or greater adverse events at the 120-milligram dose level with 80% of patients undergoing a dose reduction, whereas there was only a 22% rate of Grade 3 or greater events at 80 milligrams with a 17% of patients undergoing dose reduction. Again, there were no significant off-target toxicities and a low rate of discontinuation. And as with the second-line cohort, the most common treatment-related adverse events were diarrhea, paronychia and stomatitis.

Note that of the dose reductions at 120 milligrams, approximately 60% of them occurred within the first couple of cycles. So these patients were more quickly dose reduced than in the second-line cohort and therefore, almost all we're receiving an average 80-milligram dose for their time on treatment. It was this observation that prompted us to shift from a 120-milligram dose and start a new cohort of first-line patients at the 80-milligram dose level.

On Slide 25, we have the available ctDNA results, which again show a high rate of clearance after one cycle occurring in 10 of 14 patients.

On Slide 26, we have the systemic objective response rate in the waterfall plot. We're looking at the efficacy evaluable population, those patients with the opportunity of at least three post baseline scans. Since in this cohort, we initially enrolled patients at 120 milligrams followed by a second cohort 80. As of the data cutoff, only the first group of patients are on long enough to read out for efficacy, follow-up is still in progress for the 80-milligram dose group.

Now based on my earlier comments on dose intensity, these patients, although they were assigned 120 milligrams because of the early and rapid dose reductions, they effectively received an 80-milligram dose. And so these data actually read more on the 80-milligram dose level. The best objective response rate here was 67% with a confirmed ORR of 60% and a disease control rate of 93%. On the right, you can see in the waterfall plot, multiple responses occurring in patients with brain metastases at baseline.

The next slide has the swimmer plot for the same 15 patients. And again, although many of the responses to Enozertinib occurred as early as 4 weeks, as in the second-line setting, we also see tumor regression over time with multiple late responses. At a median follow-up of 33 weeks, 80% of responders are still on treatment.

On Slide 28, we have the CNS-specific intracranial objective response rate using an independent radiological review employing the RANO criteria. On the right, you can see the responses in the waterfall. Seven patients had brain metastases at study entry. Three of these patients had measurable lesions, meaning that masses were 1 centimeter or larger, and all three had confirmed partial responses for an intracranial ORR of 100% for patients with measurable disease.

Four patients had what is termed nonmeasurable disease, meaning that the metastases in their brains were smaller than 1 centimeter, with nonmeasurable disease in the brain, anything short of 100% regression is termed non-CR, non-PD. So it's notable that two patients had total clearance of all their lesions thus achieving intracranial complete responses.

And finally, three of these five responders, including the two complete responses had active CNS disease, which means they received no prior treatment for their brain metastases. With the CNS ORR based on an independent third-party assessment using current CNS response criteria, we can confirm the CNS potency of Enozertinib it is able to achieve responses in the brain at the same rate as it does systemically, including in patients with untreated disease, which is a hallmark of a CNS active drug.

Turning to Slide 29. We have a vignette of one of the patients who had a complete CNS response. This is a 60-year-old woman with EGFR Exon 20 mutated non-small cell lung cancer and no prior therapy were presented with five nontarget lesions in the brain. These lesions had not been previously treated and therefore, would be considered active disease. She received 120 milligrams of Enozertinib and by cycle 1, she achieved a systemic partial response and an intracranial complete response which were later both confirmed. You can see the adverse events that she experienced with a Grade 3 event leading to a dose reduction. As of the data cutoff, she remains on treatment in response at cycle 6.

We highlight this case as another demonstration of Enozertinib's brain penetrant properties because these smaller nontarget lesions represent a setting where the blood-brain barrier would be largely intact. On the other hand, larger brain metastases can lead to a breakdown of the blood brain barrier, in which case even non-CNS penetrant agents can achieve some tumor regression. This distinction is important because one of the key properties of a brain-penetrant compound is not only causing regression of visible disease but also preventing the progression of currently clinically undetectable CNS disease. It's this property of decreasing the rate of relapse in the CNS that translates to the potential for a longer progression-free survival.

We saw evidence of this potent CNS activity during dose escalation and now have multiple examples here with our expanded EGFR Exon 20 experience. And as I'll discuss later, we saw intracranial CRs in our EGFR atypical population as well.

Turning to Slide 31, we'll shift to a discussion of the EGFR atypical patient data. Here, we enroll patients with non-small cell lung cancer including those with active brain metastases that harbor and EGFR atypical mutation, which includes PACC or PACC mutations, classical-like mutations and deletion 19 non-PACC mutations all as either Singleton or complex. In general, we were very permissive in terms of the range of EGFR A typical mutations we allowed into this dose optimization cohort. Although for future development, based upon the efficacy signals we've seen, we would focus on the first-line PACC population.

These patients were also allowed to have any prior therapy, including chemotherapy and EGFR tyrosine kinase inhibitors, such as Osimertinib and Afatinib. As a result, the median number of prior therapies for this patient population is two, meaning that on average, these patients are receiving their third line of therapy. A total of 47 patients were enrolled and randomized to receive either 80 milligrams or 120 milligrams of Enozertinib once daily. And because this is a later line population, there was a higher rate of CNS involvement at baseline. With 55% of patients having brain metastases at study entry.

On the next slide, we have a safety for these patients. As with the Exon 20 experience, the most common related adverse events were diarrhea, paronychia and stomatitis. Treatment-related adverse events were predominantly Grade 1 or 2 with no Grade 4 or 5 events and no significant off-target toxicities. There were no discontinuations due to treatment-related adverse events. However, as with the EGFR Exon 20 experience, there was a high rate of dose reductions at 120 milligrams with 68% of patients dose reducing. And 80% of those reductions occurred early in the first 8 weeks on treatment. This cohort was the last of the dose optimization cohorts to start enrolling. So by this time, investigators are quick to dose-reduce patients from the 120-milligram dose down to 80 milligrams, leading to a dose intensity in these patients of approximately 80 milligrams once daily. For this reason, they were analyzed by combining them with the 80-milligram assigned dose group.

Turning to Slide 33. We have the response data for the efficacy evaluable patient population, those patients with at least three post-baseline scans. In addition, this analysis is focused on those patients with PACC mutations, which is where we saw the strongest signal. As I stated earlier, we're combining all patients who were either assigned the 80-milligram dose or if they were assigned to 120, they actually received dose intensity of 80 milligrams. So of the 22 patients represented here, 12 patients started at 80, while 10 patients started at 120, but had an early dose reduction.

Focusing on these 22 patients, you'll see that the best ORR is 36%, all confirmed partial responses. With a disease control rate of 91%. And in the 59% of patients with CNS disease at baseline, looking at the table and waterfall plot, again, there's no meaningful difference in response. Overall, these results are all the more impressive given that this is a median third-line patient population, and they compare very favorably against efficacy benchmarks with other agents being developed in the same patient population.

Slide 34 shows the swimmer plot for these patients. And as before, we see many responses to Enozertinib occurring at the 4-week mark with additional examples of late responders, with a median follow-up of approximately 33 weeks, 35 responders remain on treatment.

Now before starting the next section, given that our initial treatment experience in the PACC population was so heavily skewed to later line patients, effectively median third-line patients. We felt it was important to provide a brief update here of our early experience in treatment-naive first-line PACC patients.

Turning to Slide 36. These are preliminary data from our ongoing first-line EGFR pack cohort who are all receiving the 80-milligram dose. These data were not available at the time of the abstract deadline for ESMO Asia but we are providing an early look here because it confirms our conclusion that 80 milligrams of Enozertinib once daily is a well-tolerated dose able to achieve significant clinical activity, including in the CNS.

Here, we have an early look at the first 10 patients with EGFR PACC mutations who have had at least one post-baseline scan on study. The safety profile we've seen in this cohort is in line with what we've seen to date at the 80-milligram dose level in other cohorts.

Turning to efficacy. Of these 10 patients, eight has a partial response giving an ORR of 80%. So far, three responses are confirmed and five are yet unconfirmed with still ongoing on treatment and pending confirmation. You can see the tumor regressions in the waterfall to the right.

Many of these patients also had CNS disease at baseline, indicated by the asterisks over the bars. We, of course, were interested to see if there was also evidence of intracranial response, and I'm happy to say there clearly was.

Turning to Slide 37. We have the CNS specific intracranial response rate here based upon investigator assessment using RECIST criteria. In this early look at our first-line EGFR PACC population, we had six patients with baseline CNS metastases at study entry, of which five had a post baseline scan. All these patients had active disease at baseline, meaning no prior treatment of their CNS mets.

On the right, you can see the responses in the waterfall. Of these five evaluable patients who have brain metastases of study entry four has measurable lesions and all responded with three partial responses and one complete response, resulting in an intracranial ORR of 100% for patients with measurable disease. The other patient has nonmeasurable disease, which right now is non-CR, non-PD.

While still early, we are very encouraged by these data and the potential of Enozertinib to be a best-in-class molecule in both the EGFR Exon 20 and EGFR PACC mutated patient population.

Finally, let me close with one more case vignette. This time of a 67-year-old man with non-small cell lung cancer and a PACC mutation. The patient had systemic disease as well as a target lesion in the frontal lobe of the brain, who received Enozertinib at 80 milligrams once daily and achieved a partial response in his systemic disease as well as a partial response in the brain, both confirmed.

He's only experienced Grade 1 skin toxicity and remains on study in response in cycle 5 as of the data cutoff. And hot off the press, we learned from the patient's position that the week before this conference that after the fourth cycle of treatment, the patient now has a complete response in the brain. How about that?

So this concludes the data I wanted to review today. I'll now pass it back to Jacob to put our results into perspective, but I think you'll agree that through this major update to the Enozertinib program, we have laid a strong foundation to support its best-in-class potential. Jacob?

Thanks, Pratik. Well, Pratik obviously covered an enormous amount of data. The most relevant which is summarized on Slide 40. You can clearly see that not only is Enozertinib demonstrating a response profile that is as good or better than competitor compounds, but you are already seeing the preliminary evidence that for Enozertinib, the presence or absence of brain metastases does not make a difference. The drug delivers profound results for patients regardless of their status of brain metastases. .

And while the data are too immature to comment definitively on durability, we obviously like what we've seen thus far and are looking forward to providing longer-term follow-up in future updates.

Turning to Slide 41. We have previously mentioned that our potential registrational development priorities for Enozertinib are focused on frontline populations in both EGFR Exon 20 and EGFR PACC mutations. We believe today's substantial update establishes Enozertinib's potential best-in-class profile for patients with EGFR-mutated non-small cell lung cancer. We've observed highly competitive response rates in both pretreated and frontline EGFR Exon 20 and EGFR PACC mutations, out two populations of interest. We have continued to demonstrate Enozertinib's two key differentiators profound CNS activity and a lack of significant off-target toxicities, two factors that we believe will be key to eventually establishing long-term differentiated durability.

Finally, we've selected a preferred dose of 80 milligrams once daily for future development, and we will continue enrollment and long-term durability follow-up in these two frontline populations with the next planned update in mid-2026, and ahead of the potential start of one or more Phase III registrational trials.

We'll wrap up our prepared remarks on Slide 42. We're very proud of the team and pipeline that we have assembled here at ORIC, and we're looking forward to providing additional updates for both Enozertinib and ORIC-944 over the coming quarters.

Before we open it up to Q&A, I'd like to thank our investigators as well as the entire ORIC team who worked diligently to tackle our mission on behalf of patients. And most importantly, I'd like to thank our patients and their families who we hope to help overcome resistance in cancer. With that, let's open it up for Q&A.

[Operator Instructions] and our first question comes from the line of Anupam Rama from JPMorgan.

Congrats on the data and go [ Buckeyes ]. So within the second-line EGFR Exon 20 data set, you guys talked about how your response rate was lower than at the 120 mg than the 80 mg. You alluded to this being driven by some safety. Can you dig into what exactly you're seeing in terms of the AEs impacting dose intensity.

And then a second question, just what gives you confidence in the 80 mg moving as your Phase III dose? And when do you think you might have FDA sign-off to move forward with the dose?

Anupam, thanks for the question. Go [ Trojan ], and I'll ask Pratik to address your questions.

I think I'd have to take the [ Buckeyes ] side of things. So thanks for the questions. I'll take them in order. So yes, you're right. We did see a lower response rate in the second-line EGFR Exon 20 cohort at the 120 versus the 80 there was a higher rate of Grade 3 diarrhea at the 120-milligram dose level, which largely explains the higher rate of dose reductions as well as some of the skin tox we saw again at the 120.

But beyond the higher rate of dose interruption, there were also more dose holes. And the issue with those holes is you have periods where you're not going to have enough drug on board. And so the patient may progress in this window or actually never have a chance to respond. So we saw this when we looked at the average daily dose of the patients in the 120-milligram dose group, with the dose reductions and interruptions, although they were assigned 120 milligrams, they actually had an average daily dose of 65 and some patients went below 50 as their average daily dose. So they just weren't getting continuous target coverage necessary to either achieve or maintain response.

That's in contrast to what we saw at the 80-milligram dose where patients had lower rated dose reductions and dose holds, and so most of those patients actually saw the effective dose of 80, which allows for continuous target coverage and the full efficacy of the drug. So that's kind of how the safety played off into efficacy in that second line cohort.

Now in terms of confidence that 80 milligrams are dose moving forward to Phase III and our sort of feeling about FDA's what there are will be as well. So I think at this point, we've generated a robust data set with Enozertinib at both the 120 and the 80-milligram dose levels across all the cohorts, we have over 170 patients treated. And so I think within any given cohort and across all the cohorts, they collectively support 80 milligrams being the go-forward dose. But let me go into a little more detail.

First, the second-line cohort data, which EGFR cohort data, which I just mentioned, the 80-milligram dose level, we saw a 45% confirmed ORR which compared to other benchmarks where it's good or better in that same patient population. Second, in our first line EGFR Exon 20 cohort Here, we did report on the patients who were signed 120-milligram dose level, but with the high number of early dose reductions and the key here they were early, these patients actually received an average daily dose just about 80 milligrams. So we feel those data also reinforce the clinical activity of Enozertinib at the 80-milligram dose level. But of course, we have an ongoing 80-milligram cohort in the first-line Exon 20. So we'll report on that next year.

And then finally, the sort of late-breaking data we disclosed on the call in the first-line EGFR PACC population these patients are all receiving 80 milligrams, and we saw an 80% ORR in the first 10 patients evaluable. And on top of that, four of these patients had active measurable brain mets at baseline at all four had an intracranial CNS response, 100%, including one CR.

So I think collectively, these data really support our choice of 80 milligrams at the RP2D. And importantly, this is a highly active dose, and we're not leaving any efficacy on the table.

So now in terms of FDA and Project Optimus, as they've said, the objective of this initiative is to determine whether or not a lower dose of a given drug may be equally efficacious, but better tolerated and trying to move away from the MTD paradigm. I think our data support that conclusion for Enozertinib that 80 milligrams has a better safety profile, while it's retaining clinical activity. And frankly, I think the clinical activity could be better than we saw at 120 because of the dose hold and interruption issues that I discussed. So we'll see how the cohorts play out. But I think we feel pretty confident about FDA's concurrence with our decision.

Our next question comes from the line of Prakhar Agarwal of Cantor Fitzgerald.

I have two, so maybe first one, can you help us put into context a CNS activity of Enozertinib relative to your competitors? And secondly, if you can just put more final details on how the overall profile of efficacy and safety you shared today compared to your competitors, especially for the first line setting in both EGFR 20 and PACC mutations.

Yes. Prakhar, thank you for the question. Overall, I'll ask Pratik to address your first question. Overall, we believe that Enozertinib data that we presented today specifically at the 80-milligram selected dose, which is what Pratik just highlighted in the last set of questions, are best-in-class for EGFR Exon 20 and PACC mutations full stop.

I'll ask Pratik to kind of elaborate that on the CNS side, and then I can address the other part of your question.

So we presented quite a bit of CNS data, but in particular, across the first-line patient populations, the first-line EGFR Exon 20 and the first-line EGFR PACC. Across those, we had 12 patients with CNS disease. Seven of those patients had measurable CNS disease and all responded. So the intracranial ORR was 100% and one of these was a CR. And then in the patients with nonmeasurable disease, we have five of them, and we had two more CRs in that group and nonmeasurable just for information's sake are tumor lesions that are less than 1 centimeter in size. And then on top of this, this is all these 12 patients, nine had active untreated brain mets. So these are patients who didn't have any other treatment to those brain mets apart from Enozertinib most of our competitors really don't claim to be CNS active and a few that do haven't really shown convincing intracranial data as convincing as what we've shown today.

And then one thing we didn't mention in the prepared remarks was we had the opportunity, which is very rare to collect CSF from several of our patients to see whether the drug can be definitively identified in the CSF and having crossed the blood brain barrier. And so I can report that with three samples of patients on Enozertinib, we're achieving therapeutic levels in the brain in every one of those patients. So yes, I think the CNS penetrant has been demonstrated in humans and the activity is clear.

And then Prakhar, on the overall profile, I mean, the systemic response rates that we've observed with as we profile today are generally on par with or they exceed the best competitor data sets from other multinational studies across these two EGFR populations that we reviewed. You have to keep in mind that our ability to equal or exceed those benchmarks is in the backdrop of the fact that our study enrolled more difficult patients to treat based on the higher percentages having baseline brain mets. And then keep in mind, even in that group, most of those patients had active untreated CNS disease. Those are patients that were literally not enrolled in the early data sets from any of our competitors.

On the tolerability front, clearly, at 120 mg, we're kind of beyond the tolerability threshold of what we view to be competitive but 80 mg, the treatment discontinuation rates are for are generally similar to, if not better than those from the competitor trials. And importantly, it has not been associated with significant off-target toxicities that you do see with the competitor compounds, and that comes in a variety of different combinations that include cardiovascular hepatic and hematological events, and we do not see those with Enozertinib. So that's on the tolerability side.

And then as Pratik did say on the CNS and is covered quite nicely, we've obviously demonstrated definitive and profound CNS activity with 100% intracranial response rates in first-line EGFR Exon 20 and first-line PACC mutations, which are our target populations moving forward. There's actually no benchmark to date on the EGFR Exon 20 side from any competitor. And our -- on the PACC side, our CNS is significantly higher than the top data sets in first-line pack.

So it's obviously the last piece of the puzzle here is durability. It's obviously too early to compare on durability at this point just given where our data sets are. But as you can see from the swimmer plots. And as you look at those early signs, even of durability, and we look forward to updating on that next year, we believe that the strengths of Enozertinib compelling systemic activity, the improved tolerability, the strong CNS activity all collectively should lead to better long-term clinical durability in the future.

Our next question comes from the line of Maurice Raycroft of Jefferies.

Congrats on the data update. Following up on the brain mets line of questioning. Your data set contains a higher proportion of brain mets at baseline versus comp data sets. And you said in the prepared remarks, you didn't exclude any patients with active brain mets at baseline. Can you talk more about how this factors into enrollment. Was there a concerted effort to do this? Or was there any enrichment for these patients?

Yes. Let me have Pratik take that. Thanks for the question Maurice.

Yes. So you're right. From the beginning, we've been confident about certain brain penetrant properties based upon how it was originally designed and all the subsequent preclinical profiling that we've done, which is why -- as you said, we have allowed enrollment of these patients with stable untreated brain mets from the very beginning of dose escalation, which is different from the more narrow enrollment criteria used by a lot of other agents that are in the same space.

And just as a reminder, I mean, our original Phase I dose escalation data that we presented at ESMO 2 years ago, 86% of patients had brain met at study entry a very high rate which set that study apart from all the other agents.

But to answer your question, the short answer is no. We haven't made any special effort to disproportionately enroll patients with brain met into our study. But I guess I'd just say investigators are voting with their feet or enrolling with their feet, so to speak, by enrolling these patients onto our trial. I think it goes to show the overall need for CNS penetrant drug. We've been enrolling these patients in the face of other competing trials that are enrolling the same patients. And so now that we have many examples of clear CNS activity including 100% intracranial response rate in our first-line patients with measurable disease, I'm sure we'll continue to get these patients.

Got it. That's helpful. And for patients with brain mets, you're breaking out if brain mets were active and untreated and whether the lesions are measurable for your naive patients. Are these specific parameters representative? And can you talk about why these distinctions matter relative to competitor programs?

Sure. Yes, I'll have Pratik continue on that one more.

Yes. No, that's a good question. I think we have been kind of explicit about breaking up active, as you said, and measurable. And that's because many members of our team have lived the importance of CNS activity. and how the FDA wants to see it demonstrated, both myself as well as many of -- as I said, members of our team worked on Entrectinib, where CNS activity was a key differentiating feature.

So with that program in our discussions with FDA, and they've since made sort of more formal guidances that captured those discussions that we had. There's a number of important considerations that they outlined in terms of how they like to see CNS activity demonstrated.

First of all, for them, CNS mets to be truly considered evaluable. They must be active. So either they haven't been treated or if they're treated and the mets have progressed since that last treatment or there's been a sufficient interval since there were latest treated, so something on the order of 12 weeks. So the met need to be active. And then they look at measurable disease looking RANO criteria, and that's the metric by which they judge CNS activity. So that's why we're focusing on active measurable brain mets, because it's the regulatory basis for ultimately getting a CNS efficacy claim.

And our next question comes from the line of Brad Canino from Guggenheim.

Great to see all these data really all at once here. I'm probably going to put the cart before the horse a bit here on this question because I know it's too early for any sort of median PFS or DOR, but what can you say about the durability you're seeing thus far? And you're really calling out two elements. It seems like dialing in the right dose for a safety profile around the 80 mg and the CNS responses. So when do you think you'll have a good sense for whether those properties are resulting in an improved PFS versus the benchmarks?

Sure. So yes, I mean, we don't right now have estimal medians that we can provide. We did provide the swimmer plots, and as you can see from the multiple swimmer plots, most of our responders are still on treatment. So at the second-line EGFR Exon 20 cohort at the 80-milligram dose, six of nine are still on treatment after immediate follow-up of 30 weeks, which is about 7 months in the first-line EGFR Exon 20, 8 of 10 are still on treatment, same follow-up about 7.5 months. And in the third line EGFR PACC, similar follow-up, 6 of 8 responders are still on treatment. So that's kind of what we have right now. But you're right, the CNS activity will play a key goal, given that we had anywhere from 40% to 55% of patients with brain mets at study entry. A non-brain penetrant drug would have a very different PFS in patients with brain mets versus those without. And we saw that with mobocertinib and with the any chemo combo. But with CNS active drug, which we believe certainly is the PFS shouldn't dramatically be different between those two patient populations. So we expect to do an update on next year, and we should have the mature data to confirm that.

Our next question comes from the line of Colleen Kusy from Baird.

Congrats on the data presentation. So you touched on this a little bit Jacob, but just on the treatment-related AE discontinuation rates, you said I think relative to competitors was low. But I was just curious, the discontinuation for the 80 mg dose appeared a little bit higher than the 120 mg dose, even though we saw higher tox at the 120 mg dose. So just any color on why you might be seeing that higher discontinuation rate?

Yes. Colleen, I want to clarify my comments should what it should have reflected is essentially the safety profile at 80 mg obviously, overall is better tolerated than at 120 mg. Some of the individual stats are actually turned around on 120, but I'll ask Pratik to kind of walk you through the reasons for why that is.

Sure. So that second-line EGFR exon 20 cohort was the first cohort we started enrollment with, and so there was sort of some investigator learning along the way. But if you look at the discontinuation rate at 80 milligrams across the entire patient experience that we presented at 6%. So that number is the sort of collective rate, and that's as good, if not better than the other agents in this class.

The reason for the low discontinuation rate in the 120, and it's kind of -- yes, it perplexed me as well when we first through, but it's really sort of safety and efficacy being two sides of the same coin. And so at the 120, we had the dose reductions. And as I said earlier, those dose reductions come with dose holds and those dose holds lead to impaired efficacy. And so instead of these patients coming off for safety events, they come off because they either don't respond and progress or they progress. And so what might have been a safety discontinuation ends up being a progression discontinuation at the 120-milligram dose. So that's sort of the explanation.

That as the investigators got more experience with the drug, especially at the 120 milligram, as I said in my remarks, they started to dose escalate very quickly and maintained dose intensity, but now it is at the 80-milligram dose level just because that's the dose reduction from 120 milligram.

Got you. That's super helpful. And then not sure how many members of the team are in Singapore for ESMO Asia this weekend, but just curious any color from the general feedback that you're hearing from investigators on the data update.

Yes, Colleen. There's four of us here in Singapore, but I'll ask Pratik, Pratik have obviously spoken to a lot of investigators here in Singapore.

Yes. So this conference, I encourage people to attend. And I came to this conference when it first started 10 years ago, and it's grown considerably. And so it's a good chance to see a lot of our Asian investigators from Korea, Taiwan, Hong Kong, Australia. So we were able to link up with both our investigators as well as just other KOLs here who are giving talks and such.

And I think the biggest flash was clearly the CNS data. I think people were impressed with the response rates with the fact that it was in patients with active disease. And now we're moving beyond anecdotal case vignettes but really sort of response rates with the safety profile is the 80-milligram dose level that people feel comfortable moving forward with. So that's the feedback we've gotten so far.

Our next question comes from Derek Archila from Wells Fargo.

So again, I wanted to get your thoughts on a potential Phase III design in the first-line EGFR Exon 20 patient population, particularly given that Ami Chemo is already approved there and just how you're thinking about maybe relative to some of the other Phase III trials?

And then just one follow-up, since you're already evaluating Eno and combo with Ami, I guess any color on the potential treatment are you might pursue in that trial?

Derek, thanks for the good questions. Yes, I mean, I'll ask Pratik to kind of cover off on the detail of your questions. But at a high level, we're obviously going to see -- we presented a huge amount of data here at the conference. We'll see a lot more of our own data in the two first-line settings, first-line EGFR pack and first-line EGFR Exon 20 over the next coming quarters. We'll also see a lot of competitor data over the coming quarters. And so all of that will have a bearing on the questions you asked. But we've been actively thinking about that Phase III trial design for both of those populations. So let me ask Pratik to hit that.

Yes. So you're right. So Ami Chemo has been approved in the frontline setting. But the approval of a new agent or in this case, a regimen doesn't automatically make it the standard of care that needs to be the sort of control arm of any future Phase III. Despite the fact that any chemo is approved for first line, we haven't had any trouble getting patients who are second line post chemotherapy only post -- without any Amivantamab, and that's in the U.S. So chemotherapy is still widely used in the first-line setting. It's still in the guidelines, not just in the U.S., but European and other guidelines.

I think just indirectly, you can get some read as well the Ami Chemo label was approved in March of' '24, just 6 months after the [ Thermo ] Phase III started. And FDA had the Ami Chemo NDA in their hands well before then. And I don't think [ Ervance ] has said that they ever had to consider changing the control arm or are concerned that their control arm of chemotherapy is going to be invalid. So as it stands right now, chemotherapy remains an acceptable standard of therapy for first-line EGFR Exon 20 and a big consideration is that any Phase III would be a global trial. So you have to consider global clinical practice where chemo remains an option on all the guidelines, as I said.

And then I think you asked about, yes, what regimen we might take into Phase III, given that we are also besides all of the single agent data generating any combo data Enozertinib plus Amivantamab is ongoing in a separate trial. We also have ongoing -- now a little dose -- exploration of Enozertinib plus platinum-based chemotherapy. So there's actually three options that we're looking at for a potential Phase III for the Enozertinib regimen, single agent, combo with chemo and combo with Ami. So we're going to let those data play out, especially the combo with Chemo and Ami to see what makes sense moving forward.

Our next question comes from the line of Yigal Nochomovitz of Citigroup.

Congrats on the data. I had two related commercial ones and then one on the data itself. In the past, you've talked about a commercial opportunity in the U.S. in the neighborhood of around $3 billion, $3.5 billion for [ Enzo ], I'm wondering if you could just walk us through a little bit how you get to that number. And then obviously, as you've already highlighted on the call, it is a competitive landscape, both for frontline Exon 20 and frontline PACC. So could you just kind of discuss in a little more detail your views as to what supports success commercially in both of those settings.

Yes, sure. [ Keith Louis ], who's heading up our commercial and our medical affairs efforts at ORIC, is here with us in Singapore. So I'll ask him to take both of those.

This is Keith. Thanks for the question. Regarding the EGFR Exon 20 population, that accounts for about 2% of non-small cell lung cancer and the EGFR pack atypicals are slightly higher, about 2.5% of NSCLC. And that's just based on the literature out there.

And then regarding our duration assumptions in Exon 20, we assume treatment duration of close to 1 year. And then in PACC, we assumed duration of about 16 months, and both of these numbers are premised on the current best data from the competition. And then obviously, there's upside to those duration numbers. If our CNS profile that we discussed on today's call, translates into a durability benefit.

And then regarding pricing, we take into account the current market pricing of various TKIs in non-small cell lung cancer.

And I think the second question you asked about was around why we think Enozertinib could be potentially successful commercially in these base populations, frontline Exon 20 and frontline PACC. And as we discussed, as Jacob and Pratik mentioned in their presentation, we think Enozertinib has the potential to be a best-in-class drug in this space, specifically addressing unmet medical needs of frontline patients with EGFR Exon 20 and PACC mutations. Given the 30% rate of brain mets at presentation for non-small cell lung cancer patients and the fact that about half of these patients will develop CNS mets over the course of their disease, we think a confirmed brain penetrant properties are going to be a key differentiator and really a game changer for treating oncologists and for non-small cell lung cancer patients.

I would also say adding to this ideal product profile is the convenience of an oral once-daily regimen. And then when you couple that with a manageable safety profile as a selected 80-milligram dose that we are going to take into potential Phase III with no significant off-target toxicity and low rate of discontinuation, I think this really sets us up to be an ideal product profile and particularly on the manageable safety profile, it's especially important because patients may achieve responses in later cycles, as we saw as late as the fourth or fifth cycle and they continue to respond on therapy for years.

And then Yigal, you mentioned you had a question on the data as well.

Yes. Thanks. Yes, it was just sort of a quick one. I was just curious, in the frontline PACC patients where you have the 10% response rate in those with the measurable CNS disease. I was just curious of those, how many also had the systemic responses.

So yes, I mean, by RECIST, they were also responders. All of them.

Our next question comes from the line of Matthew Biegler from [ OpCo ].

This is Tracy on for Matt. We just had a couple of questions. Are the responses seen in EGFR Exon 20 near loop or far loop mutations? And are the responses seen in the two most common PACC mutations or complex PACC mutations?

Yes. Thanks, Tracy. I'll ask Lori, our CSO, to take those.

Thanks for that question. So we use the Guardant ctDNA assay to really exhaustively characterize the EGFR mutations. And as expected, we enrolled patients with a broad spectrum of EGFR mutant. Specifically, in the EGFR Exon 20 cohorts, we do see responses in both the near loop and the far loop mutations which is consistent with our preclinical data.

And then in the EGFR PACC cohorts, we also had robust responses in Singletons, including the two most common mutations, the G719X and S768I as well as responses in a variety of complex mutations. So our response rates, for instance, in the first-line treatment right naive PAT cohort are comparable for the Singleton mutations at 75% for best ORR and the complex mutations at 83% best ORR. So we feel that the preclinical data has translated very nicely to the clinical responses.

Our next question comes from the line of Corinne Johnson of GS.

Maybe you could talk a little bit more about your registrational trial plans. And in particular, I'm curious how you plan to further build the case for differentiation against these CNS metastases. And how does that kind of feature as you think about patient selection and stratification in the registrational programs?

Yes, sir, I can answer that. I mean, I think -- as I said, there's a number of factors that we -- that still have to play out in terms of how we design our Phase III plan. First of all, which one are we going to prioritize first-line EGFR Exon 20 or first-line EGFR PACC. I think we have great activity, both systemically and in the CNS in both of those indications at the 80-milligram dose as a single agent. Then within the EGFR Exon 20, there is the -- as I mentioned earlier, the options of single-agent combo with chemo and combo with Amivantamab. So those are considerations. .

I think as we have already done, we're always going to lean heavy into the CNS activity. We feel that the 80-milligram dose is able to achieve that in so far in 100% of patients in the first-line setting with measurable disease. So I think there's a number of factors that you still need to sort of have to play out to make those decisions. And then obviously, the durability assessments in the various indications as well. So I think it's too early for us to kind of give you the actual sort of decision, but these are the variables that we are considering.

And Corinne, it's a good question. I'll just add on to a couple of things that -- add on a couple of things to what Pratik mentioned, which is one of the reasons we obviously went out of our way in the presentation to highlight and specify exactly which patients had measurable disease in the brain. And then which of those were active in untreated diseases because as Pratik mentioned in the prepared remarks, those are the two variables that matter to FDA. And so we have experience of this directly from developing Entrectinib, which is a brain-penetrant compound that several of us were involved in at Ignyta where if you want to get data into the label, the FDA wants to see patients with measurable disease in the brain, and they want to make sure that those patients have active in an untreated disease. And so that's why we made such a point to highlight those 2 aspects of the data.

And our last question comes from [ Johnny Fan ] from EVR.

It's [ John Afric ] from Evercore. I wanted to ask you guys had any more details you could share about the kinetics of the response and how they differ for patients on the 80 mg dose and versus those at the 120 mg dose that got dosed down?

Sure, John. Thanks for the question. I think it was cutting out a little bit, but I think you were asking about response kinetics in the patients. I'll ask Pratik take that.

Yes, it's the same. So in the 80-milligram dose level, we see the responses majority happen at the 4-week mark, which is the first time we check. We saw that in the second-line EGFR Exon 20. We're seeing that in the first-line PACC, EGFR PACC. So even with the lower dose. That's why, like I said earlier, we don't feel like we're leaving any efficacy on the table because the kinetics of the 80-milligram dose response are as quick as what we saw at the 120.

Thank you for your participation in today's conference. This does conclude the program. You may now disconnect.

Welcome back everyone. This is final session of the second day of the Biopharma Back to School Summit. So hopefully, everyone has sharpened pencils and is taking good notes. So I'm Yigal Nochomovitz, biotech analyst here at Citi. Next company is ORIC Pharmaceuticals. I've been covering them for many years following the progress. And I'm pleased to introduce Jacob Chacko, the CEO of the company and of course, Dominic Piscitelli, the CFO. So welcome, Jacob and Dom. Thank you both for participating.

So I guess maybe to start out, if you wouldn't mind, just giving just an overview of the pipeline and what are some of the key objectives of the company. And you recently bolstered the balance sheet, as I understand, so you got a little more runway. So tell us about just what are the key -- and the key readouts, which we'll, of course, get into a lot more detail.

Sure. I'm happy to jump in here, Yigal, and I'll keep it short because I know you have a lot of detailed questions In the pipeline. So ORIC is a clinical stage oncology company. ORIC stands for Overcoming Resistance in Cancer. In a nutshell, that's the mission of the company. We -- obviously, cancer is a very, very large area. So within oncology, we tend to specialize primarily in small molecule drug development in solid tumors, specifically prostate cancer and lung cancer.

So we have 2 clinical stage programs that are in dose optimization right now, getting prepped for the start of Phase III studies that would initiate potentially next year. And one of those is ORIC-944, which is a PRC2 inhibitor that's being studied in combination with 2 different AR inhibitors, apalutamide from Johnson and darolutamide from Bayer. And we can talk about the mechanism of action there and why we're so excited about that. But essentially, that's a target that has been derisked by competitor data that shows that when you combine a PRC2 inhibitor in combo with an AR inhibitor, you get dramatically longer durability, longer PFS outcomes than with an AR inhibitor alone.

So as I mentioned, that's in dose optimization right now with 2 different combo agents on the AR inhibitor side, and we plan to initiate the first Phase III study first half of next year that is joined in the pipeline by ORIC-114, which is a brain penetrant small molecule for lung cancer, specifically for 3 different targeted therapy populations of interest: EGFR exon 20, EGFR atypical mutations and HER2 exon 20.

As folks will know, all 3 of those are patient populations that have had a dearth of options, in fact, no options of drugs that are brain penetrant. The reason why that brain penetrant is so critical, of course, is because so many patients with non-small cell lung cancer, particularly with these mutations, end up developing brain metastases. And so -- that is also in dose optimization in cohorts across all 3 of those populations, again, with the goal to initiate the first Phase III study next year.

The company is super well funded. We've done quite a bit of capital raising this year to shore up the balance sheet. We'll talk about the specifics of that. But long story short, we're in the second half of 2028, which gives us cash runway importantly, past the Phase III primary data readouts for both programs. And in fact, it's over a year past the Phase III primary data readout from ORIC-944, the prostate cancer program. So quite a good position in terms of where we are from a stage of development perspective and appropriate funding for that.

All right. So maybe -- that's great. So maybe just a brief word about what's the current standard of care in the setting that you plan to pursue the Phase III programs in prostate cancer and a bit about the market opportunity there where you could improve?

Yes. So within prostate cancer, I mentioned that the target of interest here for ORIC-944 is called PRC2. That's an epigenetic modifier. The -- as people have been following the development of therapeutics within the prostate space, you'll be aware that the AR inhibitors, the androgen receptor inhibitors, of which there are 3, enzalutamide from Pfizer, apalutamide from Johnson and darolutamide from Bayer, those 3 drugs have transformed the treatment of prostate cancer. And that -- even that statement is an understatement. If you look at just what they've done for patients.

So those are all small molecules, they're pills that patients take. And they've treated tens of thousands of patients around the world, given them phenomenal outcomes across the whole gamut of the prostate cancer landscape. But those drugs, like most drugs, if not all drugs within oncology drug development, eventually, patients end up progressing even as good as those drugs are. And so what has really alluded the field within prostate cancer is what comes next. So as good as those androgen receptor inhibitors are, as good as abiraterone is. And collectively, those 4 drugs, those 3 AR inhibitors and abiraterone are what are called ARPIs, androgen receptor pathway inhibitors.

Those 4 drugs collectively do great for patients, but eventually, the patients progress. And at that point, when you talk to clinicians, when you talk to patients, the only real viable option today is chemotherapy. Of course, where we and where several companies are trying to develop therapeutics is really to come after those AR inhibitors and resensitize patients.

And the promise of a PRC2 inhibitor is that what it seems to be doing as an epigenic modifier is that when a PRC2 inhibitor is dosed in these patients, mechanistically, it looks like the tumors rather than mutating, evolving and essentially becoming androgen receptor independent, the PRC2 inhibitor on board is able to rewire the machinery such that the drug -- sorry, the tumor continues to stay AR dependent and therefore, an AR inhibitor can continue to work.

And so I referenced competitor data, clinical data that's already derisked this mechanism. Of course, as folks who have been following the story know, Pfizer has presented a lot of data, both Phase I as well as randomized Phase II data that shows that the combination of their PRC2 inhibitor along with their AR inhibitor, enzalutamide gets dramatically longer durability PFS outcomes than you'd otherwise expect.

So in 2 different settings where the drug was tested within metastatic CRPC, essentially, with their PRC2 inhibitor along with their AR inhibitor, they're able to get roughly 3x the PFS that you would otherwise expect with an AR inhibitor alone. They then ran a randomized Phase II study that replicated that magnitude of results. So essentially, in a post abiraterone-treated population within metastatic CRPC, the control arm was given enzalutamide and that control arm of roughly 40 patients achieved a median PFS exactly as you'd expect of approximately 6 months, whereas the treatment arm, which was given enzalutamide plus Pfizer's PRC2 inhibitor was able to achieve a PFS -- a median PFS of 14.3 months.

So more than doubling of the PFS in that setting and then all the other ancillary measures that you would look at as well. So things like PSA50s, PSA90s, RECIST responses, everything was more than double in the treatment arm as compared to the control arm. So clearly, derisking of the mechanism. It's been the real first proof of concept, at least in the clinic of that mechanism of action. Of course, for people that have followed the story for a while, you know that there are several PRC2 inhibitors that have been developed in the past and studied in that same population and not been able to show that same type of profound therapeutic benefit.

The main reason being that all of those drugs suffered from various degrees of really horrendous drug properties. And so if you look back at the field of failed PRC2 inhibitors within prostate cancer, what you will see is some common threads, which is short half-life. And when I say short, I mean very short. We're talking about a 1- or 2-hour half-life for a lot of those drugs. And as if that wasn't bad enough, they were also -- several of those drugs were plagued by things like CYP autoinduction. And so they would -- those drugs would rev up the CYP enzymes and they -- those drugs were also metabolized by the CYP enzymes.

So essentially, they would rev up the very same enzymes that are metabolizing the drug. And in several of those cases, you would get things like dose-dependent decreases in exposure. which again, is the opposite of what you want to do. So the more drug you give, the less exposure you are getting. And some of the drugs were so bad, they were given 3 times a day and in combo with a CYP modifier just to try to get to the right exposures.

Now it seems like Pfizer has solved quite a few of those issues because their drug appears to have about a 4- or 5-hour half-life, which obviously isn't amazing, but it's certainly far better than 1- to 2-hour half-life. They haven't said, but it doesn't look like the drug has CYP autoinduction if you look at the PK data that's been shared. And so it looks like they have been able to achieve exposures.

And clearly, from the clinical data, it seems to be implied that they're getting good exposures and an ability to actually test this mechanism in the clinic the proper way, and it's why you're seeing those results. Now in the case of ORIC-944, this is a drug that we acquired from Mirati back in 2020. The Mirati chemist did a phenomenal job. They looked at this field of PRC2 inhibitors and the poor drug properties and essentially sought to optimize on the drug properties and come up with a drug that had no CYP autoinduction and had a better half-life, good bioavailability, all the things you look for with good drug properties, and they seem to have been able to do that.

So with ORIC-944, we have a 20-hour clinical half-life. The drug is, therefore, dosed daily in contrast to several of these other drugs, Pfizer included that are dosed BID. And like I mentioned, some of them were even dosed TID. The importance of that is not just, by the way, convenience of daily dosing versus 2 times or 3 times a day dosing. The real issue is from a pharmaceutical property perspective, a PK/PD perspective, what you're essentially trying to achieve here with an epigenetic modifier is you want to cover C-min for 24 hours of the day so that you know you've got target coverage, but the toxicity is going to come from hitting C-max.

And so when you have a drug that's got a very short half-life where you're trying to brute force exposure by giving big boluses of the drug 2 times a day, you essentially run the issues by hitting C-max and therefore, seeing toxicity. And that's -- obviously, that risk is mitigated with the profile we have with ORIC-944 because you've got a 20-hour clinical half-life, the drug being dosed one time per day.

It just enables you to cover C-min in a more effective way without sort of tempting that C-max in the same way that a shorter half-life drug would do. And so that's sort of the theory of the case, and that's what we're testing right now, and I'm sure we'll get into some of the early clinical data that we've shared earlier this year.

So no, that was great. So you mentioned a lot of important points. So if you have better tolerability, as you're pointing out, that could potentially lead to a better ability to stay on the therapy and therefore, better PFS. I mean, are you making the argument that that's part of the value proposition or that would be above and beyond what's necessary to be competitive in the marketplace?

Yes, that's absolutely part of the value proposition. You started your questions by asking just around the state of play within prostate cancer drug development. And what I would suggest is that if you look at the course of those AR inhibitors and the drug development of those 3 big AR inhibitors that I mentioned to you, enzalutamide, apalutamide and darolutamide are almost indistinguishable on efficacy. If you look at any setting in which those 3 drugs have been studied, the efficacy looks the exact same.

From a toxicity point of view, all 3 are well-tolerated drugs. Apalutamide is perhaps slightly better tolerated than enzalutamide and darolutamide is perhaps better tolerated than the other 2 drugs. But it's really minor differences in the profiles of those 3 drugs. And the reason I sort of set the stage with that, Yigal, is this is such a large patient population that even with those 3 drugs having fairly indistinguishable profiles on the toxicity front and completely indistinguishable profiles on the efficacy front, all 3 of those drugs are blockbusters many times over, even though apalutamide was second to market by 6 years and darolutamide was third to market an additional year after that.

The point being that with as large as a population as this is, with as large of an unmet need as this is, a second player, a third player with a totally undifferentiated profile can have -- can be quite meaningful to patients clinically and obviously, the commercial success that comes with that. The reason I lay that groundwork is if the base case here is that we are just the second player to market with a PRC2 inhibitor that can be combined with an AR inhibitor and if we do it with a profile that ultimately is completely undifferentiated from the first mover Pfizer, this would obviously still be hugely valuable to patients and a commercial success.

That's not the base case for what we think the TPP is going to end up being for the reasons I mentioned to you earlier that with the better drug properties of the compound, who knows whether that will translate into longer efficacy outcomes like PFS and ultimately OS. But at a base case, if all we can do is have a better tolerated profile, which for all the reasons I just outlined earlier, we ought to end up with a better tolerated profile that would be a huge home run for this drug in terms of the overall profile within the broader competitive landscape.

Now there are 2 big forms of tox just from a class perspective that you'd expect with the PRC2 inhibitor. So you should expect to see GI tox in the form of diarrhea, nausea, vomiting and then heme tox various penias. And you can just look at the tazemetostat label, tazemetostat, a PRC2 inhibitor, and you can get a good sense of seeing those 2 major types of toxicities. Certainly, Pfizer sees those toxicities. Certainly, we see those toxicities. I would argue that we, even in our early clinical data show a lower incidence of those toxicities, both in terms of number and overall incidence rate and severity of those toxicities as compared to what Pfizer has shown. And I do think that, that is the drug properties in effect.

Okay. And then there's another aspect, too, which I wanted to ask about. Getting sort of delving into the Biochem a little bit. In the past, you've referenced not only PRC2, but the domains, the EED and the EZH2. Aren't there some differences there as well with respect to Mevro and your compound that are worth highlighting?

Sure. I figured we only have 40 minutes for today's fireside. So I was going to -- I can certainly highlight those and give a quick biology lesson. So PRC2, I mentioned is an epigenetic modifier. It has 3 different subunits to it. For companies that have attempted to develop drug candidates targeting the PRC2 complex, they have focused on 2 of those subunits, either EED, which is how you achieve allosteric inhibition of the PRC2 complex. That's what we're doing. That's what Novartis had done in the past with a compound called MAK683.

And then there's the catalytic subunit, which is called EZH2, and that's where Pfizer has been focused and some of the other competitors have been focused. There's no real -- short answer, Yigal, is there's no real difference in targeting one of those subunits or the other, at least in terms of initial ability to inhibit the PRC2 complex. So in other words, if you have 2 drugs, both have exactly the same drug properties, exactly the same potency, one is an EZH2 inhibitors, one is an EED inhibitor, they should be equally good at that initial inhibition of the PRC2 complex.

Where you would expect to see a difference biologically is potentially that things like long-term resistance from things like bypass resistance from EZH1 or acquired mutations to EZH2, those are mechanisms of resistance that would be relevant to an EZH2 inhibitor. In other words, diminish the long-term efficacy of an EZH2 inhibitor and would not be relevant to an EED inhibitor. So if anything, there ought to be an advantage to drugging EED rather than EZH2 from that perspective.

Okay. Well, let's get into some of the important clinical data then. So you had a pretty significant update, I believe it was the end of May of this -- just a few months ago. So maybe just kind of recap what the key learnings were out of that in terms of both what you saw on the key metrics, PSA50, PSA90, which obviously have important implications for translation to PFS and then into the future into OS as well as where you see dose. And of course, as you pointed out at the beginning, the combos with Apa and dara and how that -- those doses will intersect with your chosen dose or your planned dose for 944.

Yes. So at the end of May, we shared that update that you mentioned. It was an early dose exploration update, which -- what I glossed over at the beginning is we already had a substantial experience with ORIC-944 being dosed as a single agent, which is where we started to just establish the single-agent properties of 944 to understand what the half-life look like, what the safety profile look like, understand where from a PK and PD perspective, we ought to see efficacy once the drug was dosed in combination.

And so we basically got to start out of the gates in the combination dosing at therapeutic levels of the drug. And so we tested as part of that May update, we presented data that we had tested in patients at various dosing cohorts, which included 400 milligrams, 600 milligrams and 800 milligrams of 944 tested in combination with the labeled doses of darolutamide and separately with apalutamide and essentially looked for -- early on, we want to understand what the combination profiles were of 944 with darolutamide and separately of 944 with apalutamide, the short answer is that those profiles were nearly indistinguishable as you looked at things like PSA50s and PSA90s.

As you highlighted earlier, in prostate cancer drug development, you look at a hierarchy of clinical endpoints. So obviously, the long-term endpoint you need to see is OS and radiographic PFS. Pfizer is obviously more advanced than us with their program. So they've already been able to get those glimpses of radiographic PFS that I quoted earlier. But before that, it's kind of tried and true in prostate cancer drug development, you look at things like PSA activity, so PSA50s, the ability to reduce the patient's PSA levels by 50% and then also PSA90s, the ability to reduce those levels by 90% as early surrogate markers of what ought to translate into long-term durability measures.

The other thing that people have started to look at, of course, we're looking at as well, although it was not part of the May update, is looking at things like ctDNA as another measure of an endpoint that ought to translate to long-term durability. And then -- so those are things that we looked at. And we commented specifically around PSA50s and PSA90s as part of that May update on the efficacy side. Of course, you also want to look at safety. The name of the game here is going to be, as you alluded to earlier, drugs that are well tolerated in combination with the AR inhibitors because that's how you ultimately are going to get long-term PFS in these patients. It's not just the efficacy, but also a drug regimen that can be well tolerated by these patients.

And ultimately, beyond CRPC, which itself is a massive commercial market with high unmet need. You're also -- anyone developing a drug in this space in combination with an AR inhibitor is obviously going to want to look at CSPC as well, castration-sensitive prostate cancer. And that's a population in which this tolerability profile is going to be even more important just because the tolerance for a drug that's poorly tolerated there is low. And so you're going to really want to optimize around the toxicity profile of a regimen. And so we reported on all those measures as part of the May update.

And the short answer is even though it was a small end in the sense it was 17 patients, it still was able to replicate a very preliminary update with just 6 patients that we had presented earlier this year in January. And namely, what you saw there was in contrast to Pfizer's rate of confirmed PSA50s of 34% in their randomized data set that they presented, our rate of confirmed PSA50s was 47%. In contrast to their confirmed PSA90s of 12%, our rate of confirmed PSA90s was 24%.

And so already out of the gate, you're seeing an improvement in both the PSA50s and PSA90s, albeit small end, but I would argue a substantial enough end that you can start to gain some level of confidence on what the emerging profile of the drug is, at least with respect to things like PSA50 and PSA90, and it's comforting to see that there's some daylight where we're north of Pfizer's numbers on both of those metrics.

I think even more important than that, as I alluded to earlier, is if the ultimate end profile of this drug, when all is said and done, is a PFS and an OS that are indistinguishable from the competitor, but the toxicity profile is better that will be a home run scenario unto itself. And so that's where I took real comfort in looking at the toxicity profile that we were able to present, which, as I alluded to earlier, we did see the expected on-target tox of heme tox and GI tox just like Pfizer did. But again, we saw lower incidence and lower severity of all those kinds of toxicities and then in addition, Pfizer had a 40% rate of alopecia in their data set. To our knowledge, that's not an expected on-target toxicity of a PRC2 inhibitor, and we do not see any alopecia.

And so from an overall toxicity profile, the drug looked about as good as you could hope for at that early stage, even though it was dose exploration where we were clearly testing not only therapeutic doses, but we were doing dose finding. So we pushed the dose to try to find where we would see the level of toxicities. And so I would argue that as we get -- as we move forward in dose optimization and are honing in on the ultimate Phase III dose and regimen that will be used, if anything, that toxicity profile ought to even get incrementally cleaner than what you saw in the -- as part of the May update.

Now one thing that's worth noting, which is relevant here because I mentioned that the 3 drugs are nearly indistinguishable on all these different metrics -- the 3 AR inhibitors are nearly indistinguishable on all these different metrics. One area in which they are distinguishable is the fact that apalutamide and enzalutamide are both well known to be CYP inducers. And what that means is that because so many drugs are metabolized by the CYP enzymes, and this would be true of Pfizer's PRC2 inhibitor as well as ours ORIC-944, both are metabolized by the CYP enzymes. And therefore, when you combine with either enzalutamide or apalutamide, you do expect to see a DDI where apalutamide and enzalutamide push down the exposure of the combination drug that's being dosed with them.

So in other words, clearly, Pfizer has to, and we would also have to push for a higher dose of the PRC2 inhibitor than would otherwise be the case to kind of back solve for the right exposures, just given the impact of apalutamide and enzalutamide as CYP inducers. Darolutamide is well characterized as not being a CYP inducer. So you would not expect to see the same DDI with darolutamide.

So the implication of what I just mentioned just from a PK perspective is simple, which is that the final dose that we end up selecting of ORIC-944 that would go along with apalutamide would almost certainly be higher than the final dose of ORIC-944 that we would dose with darolutamide, and that's just because of this DDI.

So you said 400, 600, 800, and there was also some discussion of even higher dose, if I'm not mistaken. 1,200, is that still in the cards or that's...

Still in the -- yes so that's still in the cards. And so what people will remember back from that May update was essentially -- I think the way to think about it just conceptually is we got experience in dosing ORIC-944 at either 600 mg or 800 mg with each of apalutamide and darolutamide. And then, again, because of this expected DDI with apalutamide, for that matter, the same thing would be true with enza is that we always intended to then go higher in the dose exploration in the combo with apalutamide and to go lower in the dose exploration with darolutamide.

So conceptually, the way to think about it is that the 600 mg dose and the 800 mg dose of 944 will have experience with both apa and with daro. From there, the 400 mg dose of 944 will only -- will have experience with only darolutamide and the 1,200 mg dose of 944 will only have experience with apalutamide.

Okay. And when -- how much more work needs to happen and how many more patients before you settle on a regimen then for the Phase III to sort this out?

Yes. Not a whole lot more is the short answer. We do have an update that's coming in the second half of this year, and that will address your question very clearly in that update. So as part of that, our next ORIC-944 update, essentially, the point of that update is to lay out the rationale as to why we chose the provisional recommended Phase II doses that we chose for each of the combos for apalutamide combo and for the darolutamide combo to satisfy the Project Optimus requirements.

And so I would think of that update as probably fairly incremental in nature to the May update just because I think we have so clearly telegraphed where we're heading in terms of dose selection for the 2 combos. But as part of that update, we'll give you the specificity as to exactly what doses did we select for ORIC-944 in combo with apalutamide and separately, what doses did we select for ORIC-944 in combo with darolutamide and as part of making that case, we'll obviously add any new patients that we enrolled since the May update as part of that dose exploration, which, as we've said before, would be less than a handful of patients just given how far we already got in dose exploration as part of the prior update.

But more importantly, so as we lay out those rationale, that will include efficacy measures like PSA50s and PSA90s. Again, you've seen most of those already. But it will also include very likely ctDNA, which is, as I mentioned, another metric that people look at in terms of trying to triangulate to what might ultimately lead to long-term durability outcomes. We'll also potentially share PK or PD data and of course, safety data. And that will lay out the rationale for the Project Optimus doses that we ended up optimizing against and really more than anything, set the stage for the update, the data update in Q1 of next year, which is really where you'll see new data.

And that's really all about laying out the provisional recommended Phase II doses and which one are we going to select as the Phase III dose because the plan for this is for the first Phase III study to start first half next year.

Okay. And then as you pointed out at the beginning, you're going to do both of these combos essentially in parallel in 2 Phase III trials, the apa and the daro? Are they staggered? Or how is it going to work?

Yes. So that's one thing that's worth clarifying, which is we're certainly doing -- we certainly did dose exploration, and we certainly are and will be doing dose optimization of both AR inhibitor partners in parallel with one another. We will not be taking both of them forward into the first Phase III study only because we are a small biotech company, can't afford to do 2 mirrored Phase III studies with, like I said, indistinguishable AR inhibitors.

So the long story short, Yigal, is when we start that Phase III study first half of next year, we will have selected one of those AR inhibitor combo partners to be our combo partner of choice for that first Phase III study, and we'll only be running one of them in that first Phase III study. It doesn't mean we can't run a different one in a different Phase III study, but we'll pick one of them. And rather, there's just no point in doing 2 parallel Phase III studies with each of those drugs.

And what are the considerations in terms of which one you would go with first?

Yes. So that's probably the most common question we get is which drug would we pick for the Phase III study. I think I'm not being coy when I say it really is sort of indistinguishable on the profiles of the 2 compounds, and there's not a reason why we would preference one over the other. So as you look at the data we've already generated, again, aside from the DDI that is expected with apalutamide and is not expected with darolutamide related to the CYP induction of the AR inhibitor -- that the AR inhibitor causes, at least apa and enza cause.

Aside from that, one characteristic, there's no other difference in the efficacy or the toxicity profiles of those drugs, at least no meaningful differences. And so it comes down to other considerations ultimately, which will be as we think about long-term development partners and who can help us not only with this first Phase III study, but other Phase III studies, there's a lot of other considerations that would come into play that I would characterize more as strategic in nature than having to do with the drug themselves.

Now look, you can make an argument as to why apalutamide might be the better combo drug. You can make just the same number of arguments as to why darolutamide might be the better combo drug. Now apalutamide does have the DDI that I mentioned. So all things equal, you'd rather not have a DDI when you dose your drug with another drug because it means you don't have to do as much dose finding and dosing up to kind of back into the right exposures.

But on the other hand, darolutamide is dosed 2 times per day and with food and apalutamide is only dosed one time per day, and it doesn't matter if it's with or without food. And with 944, it's dosed one time per day, and it doesn't matter if it's with or without food. So there's reasons why you could say it ought to -- the combo partner ought to be apa. There's other reasons why it ought to be daro. And so what I love about that setup is it's actually not clear to anyone, ourselves included that one of those drugs is clearly the better partner for us than the other, which means we have 2 excellent amazing AR inhibitor combo agents we could think about and 2 excellent partners in Bayer and Johnson that we could think about moving forward with.

So at the current moment, the arrangement with Johnson and Bayer is what is the nature of that it's a supply agreement?

It's a supply agreement. So we get free drug from -- provided by both companies so that we can do our dose exploration, our dose optimization, and that's it. So there's no strings attached. There's no economic exchange, no rights exchanged. It's nothing more than a free drug agreement.

Right. And I'm assuming the fact that you would use less drug with dara is not a major consideration just from the perspective of COGS, given that's sort of the decimal point.

Yes. I mean it's always better to lower COGS. So when COGS are as low as they are, yes, that's not a major consideration.

Okay. All right. Well, let's -- we spent a lot of time on prostate cancer. Okay. Let's shift over then to 114, which has a name now, enozertinib, if I'm saying that right.

You said that exactly right or at least the way that half our team says it.

The other half says it.

I don't want to say because I don't agree with the way the other half says it.

Okay. So you mentioned a few things there in terms of the EGFR exon 20, the atypical cluster and then the HER2 exon 20. So maybe you can just walk us through what you've shown in each of those settings so far. It is quite a competitive space, as you know. So what is your strategy there to be to differentiate?

Yes. I'll take that one, Yigal. So yes, we don't disagree with you. It is somewhat of a crowded space. But at the same time, we think there's significant room for potential differentiation here. You look at some of the molecules, some of the data that we've seen to date, we still see some good response numbers on an ORR basis. But at the same time, you see a lot of both on and off-target toxicities. The 2 things that we really like about ORIC-114 is one is our safety profile. So based on the data that we've shown previously at ESMO we saw very little on-target toxicity and actually minimal off-target toxicity. And I think that's attributed to the clean kinome profile that we have when we kind of profile versus competitors.

And then probably more importantly, as Jacob kind of alluded to in the preamble was the CNS activity. 1/3 of these patients do present with baseline brain mets, and it is often the point of first progression. So having a CNS active agent here is potential differentiation here that should translate into better efficacy and longer duration as well. So -- those are the 2 things that we've seen both preclinically and in our early data set that keeps us excited about this. And we've got a number of data readouts, both in the second half of this year going into mid-2026 as well.

So in the second half of this year, we'll be reading out 3 patient populations in the second line or later setting. This is second-line EGFR exon 20, second line or later HER2 exon 20 and then second line or later or atypical EGFR as well. So we're expecting to show here is about 25 patients in each of these cohorts across the 2 provisional RP2Ds, as you remember, to satisfy Project Optimus, we brought forward 80 and 120 once a day for all 3 of those cohorts.

In addition to that, we'll give you guys an early look on first-line EGFR exon 20 in the first-line setting. Here, we'll have about 15 patients worth of data that we'll share. And then jumping to the data that we expect in 2026. We have 2 data readouts. One is, again, in the first-line EGFR exon 20. This is actually an interesting approach. We're the only one that are really combining with amivantamab. If you look at the competitive space, most people are taking 1 of 2 approaches here, either monotherapy against chemo or combining with chemo against chemo.

So given our profile, both on the CNS activity that we've shown and then on the safety profile, it does make an opportunity for us to kind of differentiate here and combine with amivantamab. So that's -- we're excited about that. And then we'll also share the first-line atypical EGFR data in mid-2026 as well. So we've got a number of data readouts in, call it, the next 9 to 12 months.

And correct me if I'm wrong, but you've made some strategic decisions recently about where to prioritize amongst the pretty large set of opportunities you highlighted in first and second line. So...

Yes, that's correct. That's correct. I think it was back in February this year, we have made the strategic decision to not pursue the second-line setting. And that's really driven by 2 things, right? Obviously, the second-line setting is smaller than the first line. So we wanted to focus our operational and capital on the first-line setting. And given the cost of capital, it just didn't make sense to kind of pursue that second-line setting. So we're really focused on -- for the second half readout, I think the major focus will be on the first-line setting. And then obviously, the readouts in mid-'26 will also be focused on that first-line data set.

And then for the front line, how are you thinking about this a typical setting? It's a very fast-moving space. It's been recently identified. There's a long list of mutations, as you know, a lot of players. What's your strategy there in order to carve out differentiation?

Yes. I think there, the data will drive our strategy in the first-line setting. You're absolutely right that people seem to be cutting that data a little differently. Some people are more strict definition of PAC mutation, while others are allowing more classical like mutations as well. We are enrolling a broader group for the current study. But for the Phase III, I think there's a little TBD, which will be driven by our data set, obviously.

And the differentiation there, Yigal, is going to be the same as the differentiation in other populations, which is it will come down to the CNS activity of the drug and the clean kinome profile of the drug. So those 2 means of differentiation, so in other words, the CNS activity and then the safety profile ought to translate across all 3 of these populations. And all 3 of these are populations that, like I said, are just woefully underserved in terms of the ability to have clean, well-tolerated drugs that importantly have CNS activity. So that applies to atypicals as well.

All right. One of the other companies in the space received FDA feedback, as you know, for their Phase III for atypical. And it was interesting because, I mean, some people thought this was a bit of a surprise from the FDA that they had the kind of dealer's choice of afatinib and OC, which obviously makes things more challenging because you kind of serve a lot of different needs there from the point of view of the different atypical mutations because as you know, they -- some of them are approved in some of them. So how are you thinking about that from a longer-term perspective, given that FDA feedback?

Yes, we certainly took note of that regulatory design for their Phase III study. We're not as advanced as they are certainly to have had those level of conversations with FDA. But all I can say at this point is we took note of that and had the same observation that you did. It was also interesting to note that chemotherapy was not one of the physician's choice regimens as part of the control arm. Chemo is generally in control arms in most oncology studies just because it is thought of as a standard of care, even if it's not the standard of care. So yes, we noted those same things that you did.

Very good. Thank you both, gentlemen. Appreciate it...

Thank you for having us. We appreciate it. Thank you.

Good morning, everyone. Thanks for joining us at the Goldman Sachs Annual Healthcare Conference. Thrilled to be joined today by the team from ORIC. And maybe you guys could start with a brief introduction and then give us an overview of the company and pipeline with a focus on near-term value drivers.

Sure. My name is Dominic Piscitelli. I'm the Chief Financial Officer, and I'm joined with Matt Panuwat, our Chief Business Officer. So for those of you that are not familiar with ORIC, we're a clinical stage oncology company. Our focus is small molecule, solid tumors given the team that we've assembled here at ORIC, the 3 areas of focus for us are prostate cancer, lung cancer and breast cancer. And we have 2 clinical programs that we'll talk about throughout the presentation today. The first 1 is ORIC-944. This is an allosteric PRC2 inhibitor that we actually in-licensed from Mirati back in 2020. And we're studying this in combination with AR inhibitors in prostate cancer. The second program is ORIC-114. This is a brain-penetrant EGFR HER2 Exon 20 program that we're studying in 3 distinct non-small cell lung cancer mutations, which include EGFR Exon 20, HER2 Exon 20 and EGFR atypical. Looking forward over the next 12 months or so, we've got a number of readouts across both programs. So I'll probably touch upon those throughout the presentation. And then the goal is to start 2 Phase III studies in 2026, one for ORIC-944 in the first half of the year. and then a second Phase III study for -- which will be our first Phase II for 114 as well in 2026. So a lot to cover and a busy next 12 to 15 months for us.

Perfect. Since we spoke last year, 944 has become kind of front and center to the pipeline. Maybe let's start with a high level, why are you so excited about the target in this asset?

Yes. So PRC2 inhibitors have been studied in prostate cancer for many years, dating back to GSK Constellation Epizyme. And the issue that's really plagued the first-generation PRC2 inhibitor has really been for drug properties, and what I mean by that is poor potency for -- in vitro potency for in vivo activity, short half-life, SYP autoinduction. So all these things have really kind of resulted in lackluster results when combining with AR inhibitors. But what kind of changed that was Pfizer. Pfizer back in the first half of 2023, they presented some really compelling data with their PRC2 inhibitor called mevrometostat, in combination with their AR inhibitor enzalutamide. Basically, what they showed in 2 different patient populations, both metastatic CRPC, they basically sold a 3 to 4x increase in radiographic PFS in what you'd expect to see there with enzalutamide alone. So that really kind of reinvigorated the interest on the programs. The 2 caveats there were was relatively small ends and it was single-arm data. But really, I guess, it was early this year in February of this year at ASCO GU, they presented their first randomized data set. These are patients that were required to see abiraterone and they could have seen up to 1 round of chemo. And what they showed here was a radiographic PFS of 14.3 months in the treatment arm versus a control arm of 6 months, which was enza alone, [ hazard ] ratio of 0.5. So really, really compelling data. In addition to that, they showed good PSA response. They had a PSA50 of 34% in the treatment arm and about 15% in the control arm as well. PSA90 was 12%, for the treatment arm at about 8%. So this really good overall data set, if you compare that to some of the recently approved agents, it's actually, the 14.3 months compares pretty favorable against that as well.

Okay. You mentioned this has been kind of a challenging target because the 4 drug properties. Can you talk about the specifics on 944? How have you guys overcome those challenges?

Matt, Do you want to take that one?

Sure. Yes. That was kind of the fundamental philosophy on sort of what we wanted in a molecule like that. There's been a number of early generation PRC2 inhibitor that went into the clinic with some success, not so much in prostate hander. None of the early generation molecules were optimized for prostate cancer. And so it's a much more difficult to treat cancer preclinically. Many of those were optimized for hematological malignancies and had some success there. But when they went into prostate cancer, have not had much activity, which is supported by the preclinical data. Again, not much in vitro potency, really limited in vivo potency. A lot of them are associated with SYP autoinduction, where you get lower exposures over time. Two, a lot of them have drug-drug interactions with a lot of drugs and things like that. So really just not optimized for something that you want in prostate cancer. And so knowing that we in-licensed this program several years ago, the molecule that we're working with now, 944, it seems to have solved all of those problems preclinically. And so what we saw preclinically is essentially on all of the pharmaceutical properties that you want in a molecule is essentially orders of magnitude better than kind of what came before, better solubility, better half-life, better metabolic profile, much higher potency. And so we were really excited by the preclinical data and so the program went into the clinic. Now we have a single-agent experience that we have seen with our profile. It looks great from a pharmacokinetics, from a pharmacodynamic aspect. What we've shown our molecule has about a 20-hour half-life. So easily once-daily, all of the early generation molecules are about 2 hours half-life. And so really, you can see kind of the dramatic difference in kind of PK properties. We have been very excited by that. Now we're in a combination study with AR inhibitors.

Okay. You kind of touched on this, and maybe we can be more specific. The mechanism is expected to be more of a combination approach. But in terms of single-agent activity, what have you shown?

In terms of single-agent activity, PRC2 inhibitors don't have a lot of single-agent activity in the clinic. What we have seen, and I think others have shown a stable disease in prostate cancer, and that is supported by the preclinical data, where you see the dramatic benefit preclinically, is obviously in combination with AR inhibitors. You see pretty dramatic synergy. And so many companies, including Pfizer, essentially just went straight into a combination study. They did a very quick dose escalation across all solid tumors, had a handful of prostate cancer patients, again, showed some stable disease in prostate cancer. So that's essentially what we've shared as well.

H

You reported data from a Phase Ib study about a week ago, I think. Can you just walk through the highlights of that -- those results?

Yes. So This was the initial data on the combination. And just to remind everybody, this is combination with combining both with apalutamide from J&J and with darolutamide from Bayer, we do have clinical supply agreements that Matt was able to secure for us for both those programs. And this is dose exploration. So we started at 600 to 800. And what we've showed last month is really 400, 600 and 800. What we did see here, again, being the caveat, this is only dose escalation data. We showed a PSA50 of 47%, and that excludes 1 patient that is still pending confirmation, and we showed a PSA90 of 24%. So that does compare Pfizer's -- compares favorable to Pfizer's 34% PSA50 and their 12% PSA90. So overall, it looks pretty good. Again, early data. Obviously, we need to show more durability at a later date, but we were absolutely pleased with this. And then what you'd expect to see with PRC2 inhibitors from a safety standpoint, it's a on-target tox really consists of both GI and heme tox. If you look at the Pfizer data they presented at ASCO GU, they had like an 80% rate of diarrhea, 60% rated dyskinesia, and about a 40% rate of alopecia. So we've seen much better safety standpoint. We see much lower diarrhea. I think our diarrhea rate, which is our most common tumor-related adverse events is about 50% or so, 53%, and we only had 1 Grade 3. So from a safety standpoint, we seem to look a little bit cleaner, but obviously, this is the end of [ 17 ] for the randomized study. But overall, both from a safety standpoint and an efficacy standpoint, we're starting to see good activity. And now what Pfizer really did show us is really important here. They showed us that with the PSA50 responsive of 34% compared to 15% in the control arm. They started doubling the PSA response, but they also show that, that translated into a nice PFS benefit. So obviously, that's the next step for us, but given that they've shown that, that obviously bodes well for us as well.

Okay. you've kind of described like a wide therapeutic index for the program. I guess talk to us about the doses that you're moving forward with if you've made those decisions? And what else do you need [indiscernible] there's still additional data that's necessary?

Yes. So we're still doing some more dose exploration with both programs. I think what we said on the call is that we're most likely move forward with the 400 and the 600 for the combination with daroluatamide, and then with apalutamide, even though the 600 and 800 looks good, we do want to kind of push the envelope a little bit and see what we can see with the 1,200 mg, so we have started in that cohort as well. One thing to keep in mind here is that both apalutamide and enzalutamide are inducers of certain SYPs and drugs like 944 and mevrometostat as well are metabolized via SYP -- the SYPs as well. So you have this kind of drug interaction with the 2 compounds. So basically, you have to increase the dose. So again, this is just hypothetical. But as we move forward in the 2 combination to the dose optimization, we're most likely have a higher dose for the 944 with apalutamide than we would with the 944 with darolutamide because darolutamide does not have the SYP interaction.

I see. That makes sense. In terms of patient baseline characteristics between your study and the Pfizer study, can you tell us anything that we should be aware of as we look to compare these 2 trials?

Yes. So both the Pfizer randomized data and the data that we presented last month, these are patients that had failed abiraterone and were allowed up to 1 round of chemo. So from that perspective, the patient population is the same. What is different is we actually allowed other therapies. So we -- as you look at our patient characteristics, you saw that we had immunotherapy, PARP inhibitors and other agents as well. So if you look at the prior therapies, we had a median of 3 lines. If you look at Pfizer's disclosure, it's -- they didn't give the specifics, but it's probably closer to 1 prior line. So based on that, it looks like our patients are more pretreated than the Pfizer patient populations. One thing that they did say is, they had about 40 -- about 40% of their patients had seen chemo, where about 30% of the patients in our study had seen chemo, so we had a smaller percentage of patients. But we did say that the responses that we saw were consistent both patients that had seen prior chemo and those that did not. So that wasn't different for us. Pfizer didn't provide any color on that on their disclosure.

Okay. As you think about [indiscernible] program and the development program maybe broadly, mevrometostat has set a precedent here. I guess what have you learned from that data and their execution that's informing the way you think about these trials?

You want to take that one Matt?

Sure. I think the first Pfizer Phase III study that they started last year is very similar to the randomized study, similar to the data that we've shown. And so this is in a post abiraterone setting. So patients have failed abiraterone, they're allowing chemotherapy. And so it's very consistent with the data they've already reported. So I think that is a very good place to start. And then from there, they're essentially moving in earlier lines of therapy. And so their second study will be in patients with metastatic CRPC that have not seen an androgen receptor pathway inhibitor. So that is their next study. And I think what they have said so far is that they will be starting their third Phase III this year, which will be in the castration-sensitive setting. So they're essentially taking kind of a middle early line metastatic CRPC setting and then going earlier from there. So I think that makes sense, both mechanistically, it makes sense from a commercial standpoint. It makes sense from an unmet need. And then just where you would go in prostate cancer if you have an oral therapy kind of in combination with standard of care.

As you look at mevrometostat, are there any limitations for that drug that you think you can overcome? And are you thinking about this as an attempt to be like a best-in-class profile? Or what will drive the competitive landscape there?

Yes. I think a couple of things. I think we're -- I think the bar is to really be as close to a profile as they are. I think that would be a very significant commercial success. I think we say that because prostate cancer is such a significant opportunity. And we have seen that with the androgen pathway inhibitors, where you have abiraterone, enzalutamide, darolutamide and apalutamide, all relatively indistinguishable. They all have very similar clinical efficacy. The safety profiles are slightly different, but all of them are significant blockbuster programs, even apalutamide and darolutamide that were approved 7 years after enzalutamide, they're all easily blockbuster status. So I think if we're in the range of mevrometostat, that is a very good opportunity for us. We are striving for a potential best in class. I think the data we've seen before, again, it's still very early, but our PSA responses are trending higher than Pfizer's. The confirmation of our PSA responses are higher than Pfizer's, the safety profile a little bit better than Pfizer. So I think we have confidence that there are ways to differentiate. We definitely have a once-daily therapy, which we think obviously makes a big difference, their drug in their randomized study was dosed twice daily at 1,250 BID, so 2.5 grams a day. They are plagued with a very short half-life, they are plagued with drug-drug interaction with enzalutamide and so to get exposures that they need, they have to dose very significantly much higher than we do. So I think our molecule seems to be differentiated from the data we can see so far.

Yes. And maybe just to add to that, like this is prostate cancer. This is huge. It's 40,000 to 50,000 patients in metastatic CRPC on an annual basis. And the perfect analogy is the AR inhibitors, right? The big 3 inhibitors are enzalutamide, apalutamide and darolutamide. And if you look at the sales of those programs, so enzalutamide -- and Matt and I were both at Medivation, enzalutamide was approved in 2012 and it's doing $6 billion in sales worldwide, apalutamide came 6 years later, and it's still doing closely -- It's run rate is probably $3 billion and then daralutamide came after that, it's in $2 billion. So the point being, this is prostate cancer. There's a lot of patients, and there's a lot of durability here. So even being as good as Pfizer being second to market potentially 2 years behind, that puts us in a great position, but to Matt's point, I think there is potential for us to differentiate, whether it's on safety or efficacy. Obviously, we need to run the study, but that potential is definitely there.

When should we anticipate an update on the Phase III program for Pfizer? And could that further like derisk the trials that you guys are running?

Do you want to take that one, Matt?

Yes. I think what just based on -- obviously, what Pfizer has said is that the primary completion date for the first Phase III is the end of this year. And so I think they're guiding to a data readout next year, 2026 and launch next year. And so that is their time line for their first Phase III study. Obviously, the second one will be after that. They said, and the third one hasn't started yet. But...

Are there any other programs in development that you think about when you consider the competitive landscape?

Yes, there's been a number of PRC2 inhibitors, I think now with the Pfizer randomized data, people are kind of relooking at those. We are aware of several that are being studied in prostate cancer. Novartis has 1 that they acquired with their acquisition of MorphoSys. And so that is in a study broad, solid tumors, prostate cancer is 1 of them. There is several out of China that are looking at prostate cancer. And so there are a number of them. Most of those molecules at least what we see from their profile, they're more similar to the first-generation molecules than they are mevrometostat or our molecule. And so they seem to have, again, kind of the short half-life, the poor pharmaceutical properties. It does not seem like they were optimized for prostate cancer, but there are a number that are starting to go into development.

You've been developing this in combination both with apalutamide and darolutamide thus far. Can you talk about how you pursue like pivotal development with either or both or how you make those choices on forward? And can you talk about the partnerships that you -- or the kind of agreements you currently have with J&J and Bayer?

Sure. So we do have a clinical supply agreement with each company, darolutamide from Bayer and apalutamide from Janssen. They're essentially just structured as they're giving us free drugs. We meet with them and we get advice and feedback and things like that. But for the most part, for us, we are running a study. We're paying for the study. We kind of control the data and everything like that, but we are getting free drug for the current studies. And those are the molecules we're focused on right now. Our protocol is written very broadly, so we could also study ORIC-944 with enzalutamide or abiraterone that also makes mechanistic sense, but we haven't done that yet. Our expectation is that we will select 1 of those to actually go into Phase III, it doesn't really make sense for us to do more than one in a Phase III. And so we will want to see the data kind of play out for both of the molecules, just to make sure to see if we can figure out which one is better from a clinical standpoint. Preclinically, there's no difference. They are the same mechanistically. And then I think strategically, which one might be more interesting. So far, the data we've shown, we seem to have equal efficacy with both molecules. Both are extremely great drugs for Janssen. I think Dominic said, is doing $3 billion. They're both growing significantly. Darolutamide is the last one that came to market, but it is growing the fastest. That seems to have some safety benefits. Apalutamide is once-daily, so you can kind of split hairs, both of them have their advantages I think it will depend. I think both are great drugs, I think, either would combine well with 944. But I think more data and more discussions with our partner, what might make it more clear which one we should select.

How much is like the dosing matter? You mentioned that you have to dose higher, I think, with darolutamide and you start to get to like a lot of drug. So how much does that matter in the calculus between the 2 programs?

Yes, I don't know if that's going to weigh too much in, but obviously, I need to figure out what that dose would be. But each -- to Matt's point, when you look at all 3 of the AR inhibitors from an efficacy standpoint, they're pretty much indistinguishable, even enzalutamide apalutamide, darolutamide, so we don't expect to see any difference there. Obviously, everyone has a slight benefit. To your point, darolutamide, the fact that it doesn't have the SYP interaction is a slight benefit for it, but darolutamide is twice a day where apalutamide is one a today. So each 1 has their own [ slight and ] cons, but we think they're both great drugs. We think both J&J and Bayer are great potential partners as we think about development in longer term, but as Matt said, I think at the end of the day, we'll look at the data set that we have later part of this year, and it's somewhat of a strategic discussion. Obviously, we'd look to get some -- hopefully, some free drug from 1 of the partners as well, around that as well. And kind of we're ready to run that first Phase III metastatic CRPC study ourselves.

Okay. So what should we look for in terms of the next update, how many patients, what kind of follow-up and what are the benchmarks there?

Yes. So for what we've said for the next update, we've got 2 more updates on ORIC-944. One is in the second half of this year. And what we've said there originally was 20 to 25 patients worth of data. Now we have exceeded our prior guidance for the first half. We are -- enrollment has picked up post ASCO GU, post the Pfizer data, so we'll probably be north of that 25 patient number. This is still from the dose escalation portion of the study. So the focus here again will be on PSA response, safety, tolerability. So similar to the first half update, just more patients. In addition to that now, we'll probably provide some color. So we do expect to start the dose optimization portion of the study in mid-2025, so pretty soon. So maybe we'll provide a little more color on the selection of the doses for the dose optimization portion of the study. We did say on call 2 weeks ago that we have started enrolling post AR inhibitor patients. So again, not promising anything that's something we could potentially share as well, depending on how many patients we have and that data as well.

Now the next update, which is either going to be in Q4 of this year or Q1 of next year, that will be from the dose optimization portion of the study. So that will be at the provisional RP2Ds for both the combination with darolutamide in the combination with apalutamide. So that's what I think is a more relevant data set. Obviously, we look at PSA responses. We want to continue to see good safety and tolerability. And that will be kind of our first look at what's called durability, maybe be a landmark [indiscernible] of a 4-month or a 6-month landmark analysis. And obviously, we want to see that patients are staying on the drug. And to be clear, if you look at the Pfizer data, we're not going to wait for a full mature PFS data. If we did for that -- if we did wait for that data, excuse me, we wouldn't be able to start this Phase III study until 2027. So that landmark analysis, and then we're looking to start that first Phase III study in the first half of 2026.

Okay. In terms of your like -- I think you said this, but you would look to do the pivotal on your own. Would there be any interest in exploring like an expanded partnership with either 1 of these potential partners?

Matt, the BD guy, let him answer.

Yes. I think we're committed to running the first Phase III. We just completed a financing. And so that gets us through the first Phase III. But I think in prostate cancer, there's a number of lines of therapies we want to consider, prostate cancer, if you have an active molecule, you really want to be running 3-plus type Phase III studies. So the other studies get longer and kind of bigger. So I think at some point, it would make sense to have a big pharmaceutical company on board. We don't need that for the first Phase III study. But as we think about Pfizer, for example, their study that they'll run this year is a castration-sensitive study. That is a study where the control arm is likely to be enzalutamide. That has about a 50-month PFS. So the combination of arm, you want to beat that. So that is definitely within kind of the big pharma territory, that is the real significant commercial opportunity. So I think for something like that, at some point would make sense for 944 most likely with a big pharmaceutical partnership.

Okay. Maybe we can turn to 114, [indiscernible] earlier, designed for potency against Exon 20 atypical mutations or HER2. Let's maybe just start with how the agent is differentiated versus the [ slew ] of other EGFR TKIs.

Sure. Yes. We -- there's another program we in-licensed a few years ago when we looked at the landscape. Mostly, it was designed for EGFR Exon 20. And so that's 1 area of differentiation. Most of the other molecules were repurposed for EGFR Exon 20. They were designed for sensitizing EGFR mutations and things like that. I think that's one. The second key differentiato is highly brain penetrant, and so it was prospectively designed to have that feature preclinically. We felt that, that was missing. That is definitely a distinguishing feature of almost all of the target therapies in lung cancer, as we think about osimertinib in the sensitizing mutations. If we think about alectinib and the ALK fusions and things like that, you really need a brain penetarant molecule in lung cancer because most patients progress CNS metastases. And so that was kind of the fundamental differentiating feature of what our molecule can do preclinical, now that we put it into the clinic, we have shared data that it actually does, in fact, do that. So it is a very highly potent and selective molecule. I think we've looked at that preclinically. From the clinical data, there's no off-target toxicities, that we've seen so far. So it's all primarily rash and GI is kind of what you would expect in certain doses. And then two, we are -- our clinical trial design is also different from everybody else. We essentially allow patients to enroll in our study, having any prior therapy is, one. And then two, they're actually if we're able to come into our study with active metastases. And again, those were the actual, that's kind of how we want to see proof of concept. Essentially, every other study out there excludes those patients. And so they have very stringent inclusion/exclusion criteria, sort of what patients -- most patients cannot enroll in these studies. And so we have seen patients. Again, we've shown a really interesting case study that we saw early in our study, but a patient had progressed on chemotherapy had progressed on amivantamab, which is the approved therapy for EGFR Exon 20, came into our study with untreated brain metastases, and essentially, after the first cycle, we saw 100% complete response in the lung. After the next cycle, we saw 100% shrinkage in tumor -- target tumor, nontarget CNS lesions. So essentially 100% complete response in the brain, 100% complete response systemically. And so that's something that nobody else has shown to date. So we think that kind of bodes well for the long term. And so that's kind of the update. We'll see more patients. We'll see longer follow-up. And so really, when we put out that data, there's been a lot of interest from investigators. One of those interests was looking at our molecule in atypical mutations, which was not something that was designed with our molecule. We did go back and profile our molecule against a number of atypical mutations. Serendipitously, it's actually much more potent in a typical mutation than it is even in EGFR Exon 20, which I believe we are the most potent molecule out there for Exon 20. And so we're obviously excited by that potential path as well. So we're kind of looking forward to seeing that data. And basically, everybody else's data as well will come out this year. So I think we'll really know if we have a best-in-class molecule or not.

Okay. You talked about this, you'll have data in the second half. I guess what is -- what should we expect in terms of number of patients, in terms of follow-up. I think there's a couple of different cohorts here. So how should we be thinking about those results?

Yes. So for 114 program, second half update, 4 readouts there. So in the second line or later setting, we'll have 3 different cohorts, the EGFR Exon 20, HER2 Exon 20 and the atypical. So again, this is the second line or later. And one thing Matt pointed out, we do allow patients with and without brain mets and including active brain mets where a lot of others have kind of excluded those patients. So across those 3 cohorts, what we've said is we expect 30 to 35 patients worth of data for each one of those, a total, call it, of 90-plus patients. Obviously, those would be across the 2 provisional RP2Ds that we've selected. If you guys remember back in 2024, we did decide to go forward with the 80 mg and 120 mg once a day dose. So that will be that readout as well. And then early this year, we did bring in due to higher better-than-anticipated enrollment, we did bring in one of our readouts for the first line EGFR Exon 20 setting as well. And there, what we've said is we expect 20 to 25 patients worth of data in that data set as well. This will be kind of the first look. This will be more focused on top line ORR, won't be durability data. Durability data will probably come more in 2026 standpoint. And we've put some kind of benchmarks for each of these out there in the second line or later setting for EGFR Exon 20 and atypical, the bar there is probably 35% or better. HER2 is somewhere north of that, probably 50% or better. And for the first line EGFR Exon 20 as a monotherapy, the bar there is about 55% or better for us to kind of think about moving that forward. And then jumping to 2026. We've got 2 more readouts with that program as well. One is in the first-line EGFR atypical, and that's monotherapy. And then we also have the combination with amivantamab in the EGFR Exon 20 first line as well. So a lot of data, a lot of cards to flip in the next, call it, 12 months. And as Matt said, there's a lot of competitive data sets that we are kind of reading out from now until then as well, so we can compare and contrast our profile and hopefully have that continue to show that differentiation both on safety and the CNS angle.

Okay. Maybe talk a little bit about the combination with amavantimab. Are you anticipating those will be additive or synergistic. And where do you think that kind of combination fits best in the EGFR landscape?

Yes, sure. So this is another collaboration we have with Johnson & Johnson. So we are combining ORIC-114 with amivantamab. Interestingly, this will be the subcu formulation of amivantamab, it's still pending approval, but that is kind of the next-generation molecule from them. So we do view that this potentially could be synergistic. The combination, I think, scientifically makes a lot of sense. Amivantamab, I think as some people might know, it's a bispecific antibody. Half of it is EGFR, the other half in cMET. And so kind of the 2 on-target restresistance mechanisms that you often see with EGFR inhibitors is cMET. And so they -- that would be covered by amivantamab, that wouldn't be covered with 114. Also C797S, so mutation in the cystine, where ORIC-114 binds that would be covered by amivantamab as well. We bring the brain penetrance, we are inhibiting EGFR from a different -- on the target differently. And so there are a lot of potential benefits on combining the 2. What we've seen with amivantamab in the EGFR-sensitizing mutations they are combining with lazertinib. They see dramatic benefits in combination. They've also reported some data in atypical mutations, significant PFS and OS benefit is what they can see with the combination. So we are hoping that should play out with ORIC-114 in the Exon 20 space. Lazertinib is not -- it does not have activity in Exon 20. And so this kind of essentially would be replacing lazertinib in this type of mutations. So we're obviously very excited about to see that combination data as well.

Okay. And would that -- as synergy play out in terms of duration? Or would it be visible even in response rate data?

Potentially both. I think duration is what you really want to see. Right now, amivantamab is approved in frontline in combination with chemotherapy. It has pretty high response rates in general. But the PFS, we haven't seen a very significant PFS benefit yet in the EGFR Exon 20 space, both with amivantamab or the other therapies as well. And so if the combination of amivantamab, ORIC-114 can approach anything kind of close to the lazertinib data in the other EGFR mutations, that would be dramatically better. So I think that's where you'll see the real benefit.

Okay. Great. Maybe we can spend our last minute or so talking about cash runway and how you think about sources of capital. What kind of clinical activities are embedded in the cash runway while you're at it?

Yes. So concurrent with the ORIC-944 update, we did do a concurrent financing, we raised $125 million in a pipe, so with that pro forma cash at the end of March is $349 million. So with that, we've extended our cash runway into the second half of 2027.

And your second question is a good one, what's included in that? We don't risk adjust our cash runway. So that's a fully burdened number that does assume we're kind of maintaining control of both assets, no strategic partnerships of any sorts. That also assumes you're starting the 2 Phase III studies I alluded to before, both the 944 and the first half of this year -- I'm sorry, first half of 2026 and then it's also starting the Phase III study for ORIC-114 in the second half of 2026. So that's a fully burdened number, includes all the CMC and everything associated with it.

Okay. Great. Well, I think that brings us basically to time. Thanks so much for joining us today, guys. Thanks, everyone, who joined us here in online.

Thanks.

Good day, and thank you for standing by. Welcome to the ORIC-944 program update call. [Operator Instructions] Please be advised that today's conference is being recorded. I would now like to hand the conference over to your host today, Dominic Piscitelli, Chief Financial Officer. Please go ahead.

Good afternoon, and welcome to the ORIC Pharmaceuticals' ORIC-944 Program Update Conference Call. My name is Dominic Piscitelli, CFO. Earlier today, we issued a press release highlighting updated data from our ongoing Phase Ib study of ORIC-944 in combination with apalutamide and with darolutamide in patients with metastatic CRPC. You may find the press release posted on the Investor page of oricpharma.com. We have prerecorded our prepared remarks, after which we will host a live Q&A session.

Before we begin, starting on Slide 2. During this conference call, we'll be making forward-looking statements, including forward-looking statements based on our current expectations and projections about future events and trends that may affect our business utilizing data available to us as of May 28, 2025. ORIC's actual results may differ materially from those expressed in or indicated by such forward-looking statements. For a description of risk factors associated with investing in ORIC, please refer to our recent filings with the SEC. ORIC specifically disclaims any obligation to update any forward-looking statements, except as required by law.

This presentation contains interim results based on the data from ORIC-944 clinical trials as of the cutoff date set forth on the applicable slide. During this presentation, we will not be speaking to any additional data subsequent to such date.

Now turning to Slide 3. During today's call, we'll discuss the preclinical rationale, Phase Ib clinical data and next steps. And finally, the prostate cancer market opportunity and potential expansion opportunities for the program, followed by Q&A.

Joining me on the call today, we have Jacob Chacko, CEO; Lori Friedman, CSO; Pratik Multani, CMO; and Matt Panuwat, CBO. Now let me turn over the call to Jacob.

Thank you, Dominic. Turning to Slide 4. At ORIC Pharmaceuticals, our clinical pipeline is focused on the advancement of 2 potentially best-in-class programs, both of which have multiple data readouts expected in 2025 and the first half of 2026 and are on a path to initiation of Phase III registrational trials in 2026. The subject of today's presentation will be the first substantial readout of combination data for ORIC-944, a potential best-in-class PRC2 inhibitor, which is being studied in metastatic castration-resistant prostate cancer in combination with 2 different androgen receptor inhibitors, ERLEADA or apalutamide and NUBEQA or darolutamide.

Turning to Slide 5. There is compelling biological rationale for combining a PRC2 inhibitor with an androgen receptor inhibitor to delay or overcome resistance that results in prostate cancers becoming AR independent. Unfortunately, the first-generation PRC2 inhibitor suffered from numerous limitations related to interior potency, drug properties and tolerability. And so we're unable to demonstrate a meaningful treatment effect. ORIC-944 was rationally designed with the goal of addressing each of these limitations.

Having completed single-agent dosing last year, we then initiated combination dose exploration with the support of our partners at Johnson & Johnson and Bayer to explore the activity and safety of ORIC-944 in combination with each of their AR inhibitors.

Turning to Slide 6. The purpose of today's update is to provide an initial data set that establishes a safety and activity profile of ORIC-944 at multiple doses and with each of our combination partners that is comparable to or better than that of our competitors with a particular eye towards another next-generation PRC2 inhibitor that has recently demonstrated meaningful clinical outcomes substantiating this therapeutic combination. In the second half of this year, we look forward to providing additional data to support our selected project optimist doses.

And by the end of this year or early next year, we intend to provide dose optimization data that establishes the safety, activity and most importantly, durability underlying our selection of a final dose for ORIC-944 with our AR inhibitor of choice to take into our initial Phase III trial in metastatic CRPC, which is slated to initiate in the first half of next year.

Turning to Slide 7. I previously referenced a competitor next-generation PRC2 inhibitor that is being developed by Pfizer in multiple Phase III studies in a randomized controlled trial, that PRC2 inhibitor in combination with an AR inhibitor, demonstrated substantially better PSA activity and ultimately, median radiographic PFS in comparison to enzalutamide monotherapy.

As we will discuss in more detail later in this presentation, our initial experience with ORIC-944 in combination with either apalutamide or with darolutamide has yielded strong results with the safety profile and activity as measured by PSA 50 and PSA 90 response rates that compare quite favorably to the mevrometostat plus enzalutamide combination data.

With that, let me now hand the call over to Lori to provide an overview of the preclinical rationale underlying PRC2 inhibition before Pratik walks us through the early clinical combination data. Lori?

Thanks, Jacob. It's my pleasure to talk about PRC2 and our excitement for developing ORIC-944 in prostate cancer. Turning to Slide 9. I'll take a deep dive into the function of PRC2. As shown in the diagram on the left, the PRC2 complex functions as a transcriptional repressor by modifying histones to regulate gene expression. ORIC-944 is an allosteric inhibitor of EED and blocks the function of the entire PRC2 complex. PRC2 is dysregulated in several cancers with data implicating its role in sulfate and differentiation.

In patients with prostate cancer, the expression of PRC2 target genes is associated with poor prognosis. Recent randomized clinical data in metastatic castration-resistant prostate cancer demonstrated a significant progression-free survival improvement for the combination of a PRC2 inhibitor with an AR inhibitor versus standard of care.

Now turning to Slide 10. With this strong biology behind it, PRC2 has been a target of interest for many years. However, the first-generation inhibitors such as CPI-1205 and tazemetostat had multiple shortcomings as shown in the left half of the table. Mevrometostat, a second-generation inhibitor, addressed some of these issues, including cell potency and CYP autoinduction. Yet falls short in other drug properties such as solubility and half-life. ORIC-944 shows improved drug properties in all categories. Thus has potential as a best-in-class PRC2 inhibitor that addresses all the limitations of earlier generation inhibitors.

On Slide 11, are 2 examples of preclinical in vitro data demonstrating the superior potency of ORIC-944 to first-generation PRC2 inhibitors. In these dose-ranging studies, AR-positive prostate cancer cell lines were treated head-to-head with 4 different drugs and assay for effects on cell growth and viability. The cell potency for the first-generation inhibitors shown in black and dark blue curves are right shifted due to their weaker potencies. ORIC-944 demonstrates comparable potency to mevrometostat in prostate cancer cell lines and ORIC-944 is superior to the first-generation inhibitors.

The graphic on Slide 12 summarizes how therapeutically targeting PRC2 reverses the natural evolution of prostate cancer. As prostate cancers are treated with hormone blockade or with AR-targeted therapy, they evolve to evade these therapies. Going from left to right, the graphic shows prostate tumors progressing from castration sensitive to insensitive and from AR dependent to AR independent. Epigenetic reprogramming is the mechanism by which prostate cancer cells transition to change their cell state evolving away from a differentiated cell state in primary prostate tissue. PRC2 inhibition can delay or reverse this process so that prostate cancer cells regain the luminal cell state that reflects the tissue of origin and thus, regain their AR dependency. This mechanistic rationale supports the combination of PRC2 inhibitors with AR inhibitors and suggest that the therapeutic potential of ORIC-944 in prostate cancer will be maximized in combination with AR inhibition.

On Slide 13 is an example of preclinical data supporting this mechanism of ORIC-944 sensitizing prostate cancer to AR inhibition. In the experiment shown on the left, prostate cancer xenografts were treated with either ORIC-944 or the vehicle control and tumors were then assessed for transcriptional changes using RNA sequencing. Two consistent changes were observed. A significant increase in AR signaling and a significant increase in luminal cell state markers. These transcriptional shifts result in the prostate tumors having an increased dependency on the androgen receptor.

To confirm this mechanism of ORIC-944 treatment restoring a cell state that has enhanced sensitivity to AR inhibition, we assess synergy for this combination as shown on the right. Prostate cancer cells were treated with dose ranging concentrations of enzalutamide and a PRC2 inhibitor alone and in combination. The impact on cell viability was then analyzed for synergy potential and the thermometer summarizes the results. A synergy score of 10 or higher denote strong synergy of 2 drugs. The combination of enzalutamide with ORIC-944 demonstrated a strong synergy score of 15.8. Head-to-head experiments for the enzalutamide combination with mevrometostat produced a similar result to ORIC-944.

Carrying this combination forward into in vivo prostate cancer model, on Slide 14 is an example of a study where we treated AR inhibitor resistant prostate cancer xenograft with darolutamide with and without PRC2 inhibitors. The combination of ORIC-944 with darolutamide impressively improved progression-free survival in this castration-resistant prostate cancer setting. Thus ORIC-944 has been shown to reverse AR inhibitor resistance in prostate cancer to improve PFS and importantly, with ORIC-944's improved drug properties, it sends out as a best-in-class PRC2 inhibitor. We're excited to assess these AR inhibitor combinations in the clinic, as Pratik will tell you about.

Thank you, Lori. Turning to Slide 16. I will now provide a comprehensive update of our ongoing Phase Ib trial of ORIC-944 in patients with metastatic castration-resistant prostate cancer, or MCRPC. This first study explored ORIC-944 as a single agent in patients with MCRPC who have progressed after at least 1 AR inhibitor and had received up to 2 prior chemotherapy regimens. Through an i3+3 design, we demonstrated the strong pharmaceutical properties of ORIC-944, specifically, its long clinical half-life with dose proportional exposure and no evidence of CYP autoinduction, which supports once-daily administration.

We also demonstrated robust target engagement through measurement of H3K27 methylation status in peripheral blood cells. And finally, ORIC-944 as a single agent exhibited an overall well-tolerated safety profile, making it highly suitable for drug combinations. Collectively, these properties differentiate ORIC-944 from other PRC2 inhibitors and position it as a potential best-in-class molecule.

Turning to Slide 17. You can see the PK curves from the single-agent dose escalation ranging from 100 milligrams up to 900 milligrams once daily. You see nice dose proportionality as we went up in dose and can derive the approximately 20 hour half-life, which is compatible with once daily dosing. Comparing the ORIC-944 PK curves to target efficacy thresholds, you can see that doses as low as 200 milligrams achieved concentrations associated with efficacy in preclinical models of prostate cancer, which affords us a broad, potentially efficacious dosing range for ORIC-944 in the clinic.

Slide 18 shows the safety profile of single-agent ORIC-944 across our dose escalation experience. ORIC-944 was generally well tolerated at doses up to 900 milligrams, well above the efficacious dose projections I described on the previous slide. The main classes of toxicity expected with a PRC2 inhibitor are hematologic and GI, and the ORIC-944 adverse event profile is consistent with that. Almost all events were grade 1 or 2 and as expected, we did see a few Grade 3 hematologic adverse events at the highest dose levels tested. We saw no grade 3 diarrhea and no grade 4 or 5 events.

Taking the PK curves from the previous slide and the safety from this slide, we have a wide therapeutic window in which to study ORIC-944 and optimize its performance. In general, doses between 400 and 800 milligrams once daily reach exposures compatible with potential efficacy while still having a favorable safety profile.

Slide 19 highlights the key differences in pharmaceutical properties of ORIC-944 compared with other PRC2 inhibitors. In particular, 944 stands apart even from mevrometostat with its long clinical half-life of approximately 20 hours compared to 4 hours or shorter for other PRC2 inhibitors.

Turning to Slide 20. With the completion of single-agent dose escalation, we proceeded to dose exploration in combination with apalutamide and with darolutamide. In this ongoing part of the study, patients are eligible if they have received prior treatment with an androgen receptor pathway inhibitor. Patients are also allowed but not required to have up to 1 prior chemotherapy. We started initially with post abiraterone patients. More recently, we've just started enrolling post AR inhibitor patients, that is patients post enza, apa or daro. Today, we'll focus on the post abiraterone-treated patients.

The combination dose exploration is being carried out in 2 distinct cohorts. One with various doses of ORIC-944 in combination with the standard dose of apalutamide and the other with various doses of 944 in combination with the standard dose of darolutamide. Once dose exploration is completed for each of these combinations, 2 candidate RP2D would then be carried forward for each combination to satisfy project Optimus requirements. This optimization for each combination would be conducted in the 2 distinct patient populations I outlined earlier, one with only prior abiraterone exposure and the other with only one prior AR inhibitor exposure.

Based on the results of these dose optimization cohorts, we would then select the appropriate combination dose of ORIC-944 for each of the 2 potential AR inhibitors of interest, apalutamide and darolutamide. We would then carry one of these combinations forward into our first Phase III trial.

Turning to Slide 21. Let me present the initial data we've generated. We have compiled safety and initial efficacy data from 17 patients with MCRPC after prior abiraterone treatment enrolled into our dose exploration of ORIC-944 with either APA or Darrow. On this slide, we have the baseline characteristics of the 17 patients. Of note, these patients had a median of 3 prior lines of therapy, excluding ADT therapy, which is not counted in this median. Since these patients are all post abiraterone, which accounts for 1 prior line, you can see that patients had also received a variety of other approved and investigational prostate cancer therapies including immunotherapy in 41% and chemotherapy and 29%.

Slide 22 depicts a waterfall plot of the best percent change in PSA from baseline in these 17 patients as of a data cutoff of May 9. The bars represent individual patients and are color coded by ORIC-944 dose, 400, 600 or 800 milligrams once daily. Overall, there was a 59% rate of PSA 50 response. Nearly all patients with a PSA 50 were confirmed 1 month later for a confirmed PSA 50 rate of 47%, which does not include 1 additional PSA response pending confirmation. There was also a 24% rate of PSA 90 response, all of which confirmed one month later. Of note, PSA responses were observed across all ORIC-944 dose levels and were also observed at comparable rates with both apalutamide and with darolutamide. The majority of these patients are still ongoing with multiple approaching one year or beyond. Further dose exploration remains ongoing in both combination cohorts. But even with this preliminary look at efficacy, there appears to be a strong clinical effect with doses of ORIC-944 as low as 400 milligrams once daily, confirming the broad therapeutic window we had expected from our single agent work.

With that in mind, let's turn to Slide 23, which depicts the safety profile of the 17 patients who received combination therapy with either apalutamide or darolutamide. Here, we have the treatment emergent adverse events attributed to either ORIC-944 or the AR inhibitor that we're seeing in 15% or more of patients. You can see that almost all events are Grade 1 or 2 in severity. In fact, most were grade 1 and consists largely of mild GI-related toxicity with very little grade 3 toxicity and no related Grade 4 or 5 events. Diarrhea was the most common treatment-related event occurring in 53% of patients across all dose levels with only one instance that was grade 3.

Coupled with the PSA efficacy data on the previous slide, the safety data show that we have a wide therapeutic window as we continue dose exploration to identify the optimal doses of ORIC-944 for each of our combinations with an AR inhibitor.

Turning to Slide 24. You can see our PSA 50 and PSA 90 response rates as well as our safety profile to date for the combination of ORIC-944 with either apalutamide or darolutamide, alongside the same reported outcomes from the mevrometostat randomized data, both for the combination arm with enzalutamide as well as a single-agent enzalutamide control arm. Although all patients on this slide are post abiraterone, as I described earlier, the ORIC-944 patient population had a median of 2 additional prior therapies, while for the mevrometostat population, the only additional prior therapy was chemotherapy in about 45% of patients.

With that said, you can see that single agent enzalutamide gives you the expected low PSA 50 rate with just single-digit PSA 90. When combined with mevrometostat, this rate approximately doubles which translated into a more than doubling of the radiographic progression-free survival from 6.2 months to 14.3 months. Although our data are too early to report on PFS, the PSA response rates we've seen so far, both PSA 50 and PSA 90 with the combination of ORIC-944 with AR inhibitor compares favorably with the mevrometostat combination data. Looking at safety, you can see that enzalutamide alone has a modest but measurable rate of adverse events with fatigue in about half of patients and nausea, anemia, diarrhea and decreased appetite occurring in approximately 20% to 25% of patients all grade 1 or 2.

With the addition of mevrometostat, these adverse events increase in rate and severity with now almost 80% experiencing diarrhea, Grade 3 in 18%. Similarly, decreased appetite and fatigue along with dysgeusia now occur in almost 60% of patients. Anemia is seen in about half of patients, and we don't know the mevrometostat adverse events that occur at rates below 30% since they were not disclosed. The combination of ORIC-944 with an AR inhibitor does lead to the expected adverse event of diarrhea but in about half of patients, of which 6% have reported Grade 3. Fatigue and nausea come in at about 35% to 40% and other AEs are below 30% incidents, so we can't make a comparison to the mevrometostat data, but we haven't seen comparable rates of anemia and certainly no alopecia.

Overall, we feel we are in a strong position with these initial ORIC-944 combination data, both in terms of early measures of efficacy through PSA 50 and PSA 90 rates and with a safety profile compatible with long-term dosing and a convenient once-daily regimen. These data position ORIC-944 as a potential best-in-class PRC2 inhibitor that could benefit a broad range of patients with prostate cancer.

Finally, on Slide 25, we've outlined our next steps to Phase III. First and foremost is completion of dose exploration with both apalutamide and with darolutamide to identify the candidate RP2D for each combination. We expect to complete this in the first half of this year. Following that, in the second half of this year, we would proceed to dose optimization to identify the final RP2D for each combination. We will then also determine which combination we take forward into our first Phase III trial.

Finally, in the first half of 2026, we expect to finalize the Phase III trial design, get the necessary input from multiple regulatory authorities and initiate our first global Phase III study. Now I'll turn it over to Matt to provide an overview of the commercial opportunity for ORIC-944 in various settings of prostate cancer, in which we may choose to focus our future Phase III development plans. Matt?

Thank you, Pratik. As a quick reminder, starting with Slide 27, ARPI's have become the foundational class of therapy in prostate cancer and are widely used across the treatment continuum. Although initially approved for patients with metastatic castration-resistant prostate cancer, ARPIs have gained multiple approvals and are recommended by NCCN guidelines for use in earlier lines of therapy in disease states including in non-metastatic and hormone-sensitive disease. This therapeutic class has transformed the standard of care across the spectrum of prostate cancer. The widespread use of ARPIs represents a significant commercial opportunity for PRC2 inhibitors, given the potential to reverse or delay resistance to ARPIs and further improve outcomes for patients with prostate cancer.

Turning to Slide 28. Widespread usage of ARPIs has created a substantial therapeutic class that could become even larger through extended durability enabled by combinations with PRC2 inhibitors. Last year, worldwide sales of AR inhibitors reached approximately $11 billion, while Xtandi was first approved in 2012 and is the market-leading AR inhibitor, the subsequent ERLEADA launch in 2018 and NUBEQA launch in 2019 have helped expand the ARPI market with each product easily reaching blockbuster status.

Even with the success of these 3 blockbuster therapies totaling $11 billion in annual sales, this only accounts for approximately half of the global prostate cancer market for ARPIs since branded and generic abiraterone still represents approximately 50% of the market by patient share, further illustrating the commercial potential for therapies like PRC2 inhibitors that can easily combine with ARPI to extend their durability.

Turning to Slide 29. Beyond the opportunity to combine PRC2 inhibitors, wherever AR inhibitors are used de novo, PRC2 inhibitor can also be combined with AR inhibitors to enable more meaningful clinical outcomes from the already common practice of ARPI switching. Unfortunately, for patients who progress on ARPIs, there are limited therapeutic options that provide good efficacy with tolerability that physicians and patients find acceptable. As a result, ARPIs are frequently sequenced one after another despite limited clinical benefit.

U.S. real-world data shows that ARPI use has grown to about 70% in metastatic castration-sensitive disease, and about half of that ARPI use is abiraterone, and the other half is comprised of the 3 branded AR inhibitors. Upon progression to metastatic castration-resistant disease, up to 50% of these ARPI treated patients will receive a different sequential ARPI rather than other therapeutic interventions like chemotherapy. This ARPI sequencing decision is often driven by factors like patient tolerability, treatment access and a preference for convenient and well-tolerated oral regimens despite the suboptimal efficacy, which ranges from between 3 to 6 months of radiographic PFS. The PRC2 inhibitors enable ARPI switching to achieve extended durability, this already common practice could become even more widespread.

Finally, on Slide 30, this is a summary of the U.S. prostate cancer market landscape, detailing the various treatable patient populations and current approved therapy efficacy parameters across disease states. In metastatic CRPC, we estimate about 37,000 patients will have been treated with either abiraterone or an AR inhibitor. And based on available PRC2 and AR inhibitor combination data to date, we believe this regimen could significantly improve radiographic progression-free survival meaningfully from 3 to 6 months to 12 to 14 months, and this is where we initially intend to develop and commercialize ORIC-944.

This ARPI treated MCRPC patient population alone represents an addressable market opportunity of over $7 billion in the U.S. annually. Given ORIC-944 synergy with AR inhibitors, we may have the opportunity to target ARPI naive MCRPC or earlier disease stages that have even larger patient populations with the potential of establishing a new all-oral, well-tolerated PRC2 inhibitor combination standard of care regimen and improve patient outcomes across the disease landscape. Now let me turn it over to Lori to discuss potential expansion opportunities for the development of ORIC-944.

Thank you, Matt. We have shown mechanistic data in castration-resistant prostate cancer model, that epigenetic changes drive evasion from AR-directed therapeutics, and this resistance can be reversed with a PRC2 inhibitor combination. As highlighted on Slide 32, it's notable that additional research has shown that linear change occurs in a spectrum of different cancers, opening the potential for ORIC-944 in additional indications and combinations. Recent studies have demonstrated that there's a shared reliance on the PRC2 mechanism in cancer evolution, which stimulated interest to explore the combination of PRC2 inhibitors, with oncogene directed therapies across prostate, breast, lung and colon cancers.

We've now begun experiments to investigate these indications for their future potential, and I'll share a few highlights with you today. First, on Slide 33, we assessed castration-sensitive prostate cancer to confirm that ORIC-944 had the same mechanism and synergy that we've previously seen in the castration-resistant setting. Importantly, we found that ORIC-944 effects in castration-sensitive cells were comparable to the studies in castration-resistant prostate cancer cells. On the left, ORIC-944 increases AR signaling in luminal markers in castration-sensitive prostate cancer cells, to then produce synergy when combined with an AR inhibitor. On the right, the strong synergistic effect on cell growth was observed for enzalutamide combined with either ORIC-944 or mevrometostat in these castration-sensitive prostate cancer cell models.

We then proceeded to in vivo assessment shown on Slide 34. This castration-sensitive prostate cancer model responds to the AR inhibitor, darolutamide, but importantly, the ORIC-944 combination prolonged progression-free survival in the CSPC xenograft, providing proof of concept in supportive development in earlier prostate cancer setting.

On Slide 35, we expanded the prostate cancer combination synergy into hormone positive breast cancer, which has parallel biology to AR-positive prostate cancer with hormone signaling being a key tumor dependency in both cancers. In ER-positive breast cancer, ER antagonists or degraders such as fulvestrant are standard of care and are efficacious. The addition of ORIC-944 to fulvestrant improves the progression-free survival in ER-positive breast cancer xenograft, supporting development in this indication.

And finally, on Slide 36, recent literature published in the Journal of Cancer Discovery noted the role of PRC2 lineages change in colorectal cancer driving combination benefit for PRC2 inhibition with KRAS inhibition. We assess this possibility for ORIC-944 in KRAS G12C mutant xenograft in both colon cancer and lung cancer models, and found that ORIC-944 drives tumor regression when combined with the KRAS G12C inhibitor at aggressive, supporting development in these indications. Thus, there are multiple potential indications supported by strong preclinical results. And Jacob will now summarize expansion opportunities and next steps.

Thank you, Lori. Turning to Slide 38. We've outlined the next steps for ORIC-944 beyond its initial development in metastatic CRPC. Building on these data, we intend to evaluate earlier stages of the disease, including in the ARPI naive setting and the castration sensitive setting. There is also the potential to study ORIC-944 in combination after prior AR inhibitor therapy, which, as you saw, represents a substantial opportunity. Based upon our analysis and additional preclinical data, we intend to design and launch a second Phase III trial in one of these prostate cancer indications. But as you heard from Lori, the potential for the biology of PRC2 inhibition and for ORIC-944 in particular, extends into multiple other common solid tumor types, such as breast, non-small cell lung and colorectal cancer. Therefore, alongside our prostate cancer Phase III program, we intend to design and initiate proof-of-concept clinical development in one or more of these additional solid tumor indications to fully demonstrate the potential of ORIC-944 in cancer.

We'll wrap up our prepared remarks on Slide 39. We continue to be excited about the development prospects for both our clinical programs with numerous upcoming data readouts that should set the stage for the initiation of Phase III registrational trials in 2026. Within prostate cancer, we believe the initial combination data presented today helped build a strong case for the potential best-in-class profile of ORIC-944 in combination with apalutamide and with darolutamide.

Concurrent with the data readout today, we also announced the successful completion of a $125 million pipe financing by health care specialist investors, which has extended our cash runway into the second half of 2027 and importantly, beyond the projected mid-2027 data readout from our first Phase III metastatic CRPC study. Before we begin Q&A, I'd like to thank our investigators as well as the entire ORIC team who worked diligently to tackle our mission on behalf of patients. And most importantly, I want to thank our patients and their families who we hope to help overcome resistance in cancer.

With that, let's open it up for Q&A.

[Operator Instructions] Our first question comes from the line of Maurice Raycroft with Jefferies.

Congrats on the data update. Wondering if you can talk more about how these patients in your study compared to Pfizer's mevrometostat Phase II population. And it looks like you have fewer chemo or docetaxel treated patients in your study at 29% versus Pfizer's 45%. Wondering if you saw a higher PSA response in the chemo-naive patients. Or if you could talk more about that. Can you hear me or...

Yes, we can hear you, Maurice. Can you hear us?

No, we can't hear you.

Can you hear us now?

Yes. Yes, I can hear you now.

Sorry, I don't know what happened there. So I'm not sure which part you cut, Maurice. This is Jacob. Again, thanks for your questions. Pratik, our CMO, is going to restart answering your questions since apparently we cut out. Go ahead, Pratik.

Sure. So I'll answer your 2 questions sequentially. So in terms of the overall comparison of the patient populations, based on the information that Pfizer disclosed at ASCO GU. The patients in our study were more heavily pretreated. The MEVRO study required prior abiraterone as do we. They also required -- or they also permitted up to one prior chemotherapy as do we, but the MEVRO study did not allow any other prior treatments, whereas we did. So we had a median of 3 prior therapies in our patients. And so many of our patients on top of prior AbbVie and possibly chemotherapy also got immunotherapy, PARP inhibitors and other agents.

And you can see that in the baseline characteristics slide in the presentation. Pfizer didn't disclose the median number of prior therapies for their population, but you can basically calculate it from their inclusion and exclusion criteria. They all had prior AbbVie and 45% of patients had prior chemo. So technically, actually, their median prior therapies is one. In terms of the chemotherapy, yes, we had 49% of our patients have prior chemotherapy in this cut versus Pfizer's 44%. But if we look at the PSA 50 response rates in the chemo pretreated and the chemo-naive patients in our data set, they were identical. So we don't see prior chemo as having an impact on ability to achieve a clinical effect in our study.

Got it. Okay. That's helpful. And maybe another question, just for the 4 PSA 90 patients, what is deepening from PSA 50 to PSA 90 look like? And do you anticipate that a proportion of the PSA 50 patients will convert to PSA 90? Or is this a relatively mature snapshot of PSA responses.

It's -- for the PSA 50 and the PSA 90s, the PSA 50 certainly could evolve over time. We are -- we have many patients still on trial. The majority of our patients are still on study. So I can't comment on sort of the pace or the frequency of 50s going to 90s, could still evolve, certainly.

Our next question comes from Anupam Rama with JPMorgan.

Congrats on the data. Just 2 quick ones for me. Look, I know it's super early right now, but any qualitative commentary on durability here or how we should think about durability. And then second question, have you -- or do you plan on looking at any other correlative responses like RECIST responses or ctDNA.

Thanks, Anupam. Pratik will take those as well.

Okay. So we're still in combination dose exploration. So as Jacob said at the front of the call, our objectives with disclosure more to give an initial read on combination safety and clinical activity across multiple doses and with both apa and daro. And so I think we were able to achieve that today. Given that we're in a dose exploration data set, we have cohorts of patients on apa and daro with widely different start dates. We have some cohorts where patients have been on study, as I said, close to a year or more and other cohorts that are very fresh with much less follow-up. So here's what I can say about durability at this point.

Nearly every observed PSA 50 response that we saw confirmed one month later and every PSA 90 response that we've seen confirmed one month later. This is in contrast with what Pfizer's recent data set showed where they had a drop off from 54% to 34% on PSA 50s from unconfirmed or confirmed and 17% to 12% on PSA 90s unconfirmed or confirmed from their mevro data set. A majority of our patients, as I said a little while ago, are still on drug. And we have a patient with a PSA 90 out past a year in multiple patients approaching a year or greater.

So that's what I can give you right now. But for a more detailed read on durability, we're going to use our dose optimization data set. Here, we'll have a good robust set of patients at just 2 dose levels. And the expectation is that we'll have a readout on durability as well as safety and such in the fourth quarter of this year, first quarter of next year.

And then your second question was correlative measures like RECIST or ctDNA. So most patients with advanced prostate cancer have bone-only disease and most of the soft tissue disease that they have are nontarget. So the majority of patients that -- with prostate cancer and on our study are not evaluable for RECIST response. So for us, we just need to have a larger end to get some of these patients to get any kind of true read on RECIST response rate. So we did look at ctDNA and measure it in all our patients. And happy to say it's not in the main presentation, but the vast majority of patients had a substantial decrease in ctDNA with complete molecular clearance in many of these patients. So this gives us really another read and assurance on our clinical activity, and we'll probably share these data in a future update.

Our next question comes from Prakhar Agrawal with Cantor Fitzgerald.

Congratulations on data as well. So maybe firstly, what do you expect will be our RP2D for ORIC-944 with apalutamide and darolutamide. There seems to be some signs of dose response on PSA 50 confirmed, but 800-milligram dose also had 80% Grade 1, 2 diarrhea. Also can you confirm the rates of cytopenias? And then finally, how would you decide which AR inhibitor to combine for Phase III trials?

Sure. So in terms of the RP2D for the apa and daro combination. So first, you have to sort of keep in mind that enza and apa are both CYP inducers. So they will push down the exposure of mevrometostat in the Pfizer combination with enza and ORIC-944 for our combination with apalutamide. Darolutamide doesn't have this CYP induction effect, so you wouldn't expect a drug-drug interaction. So we have to take into account these potential interactions or lack thereof when we think about the appropriate dose for daro and apa. In terms of what we think the RP2D will be for, say, first darolutamide, most certainly, I think we're going to be optimizing 400 of ORIC-944 versus 600, as you saw from the single-agent presentation -- part of the presentation, we see great target coverage at 200 milligrams -- as low as 200 milligrams. So we have great safety at 400. We're seeing clinical activity.

So 4 and 6 with daro seems like the path forward for us, and we'll then suss out, which is the one we take as the nominated as the RP2D. For apalutamide, we have to go with higher doses to account for the CYP induction. So right now, it's looking like maybe 600 versus 800. But the safety with apa looks really good. And so we are actually looking now at 1,200 milligrams of ORIC-944 with apalutamide. That needs to read out. So that could be a contender for one of the dose optimization cohorts. So that has yet to be determined.

Another question was around cytopenias. So you saw we don't see cytopenias at a high rate. Our cutoff for adverse events in this presentation was 15% or higher. And so you saw that no cytopenias made on that list. We only had one event of anemia and one event of neutropenia. So it's very low in the population across the dose levels that we've tested. I would contrast that with close to the 50% anemia rate that Pfizer saw in their experience. So we're not seeing high rates of cytopenia at all at the dose levels we're looking despite the fact that we're seeing good clinical activity.

And then Prakhar, I'll take your last question. Just in terms of how we decide which AR inhibitor we're going to take forward into Phase III or at least the initial Phase III study, I mean, obviously, apalutamide and darolutamide are both great drugs. We've been well supported by both of our partners at J&J and Bayer. And those 2 drugs have done phenomenally well for patients with fantastic efficacy that's really indistinguishable from that of enzalutamide as monotherapies, but clearly, safety profiles for both apa and daro that do distinguish from enzalutamide.

So we see really compelling efficacy as Pratik walked through with you today and also good safety with both apalutamide and darolutamide in combination with 944. So from a clinical perspective, there has been no reason thus far that we would prefer one over the other. As folks know, we are imminently going to kick off dose optimization of 944 with both combination regimens. So that will give us additional insight into safety, efficacy and importantly, durability of each combo regimen in larger numbers of patients at provisional RP2D doses. But again, to reiterate, we have not seen differences in our clinical experience thus far, and there's no reason mechanistically why the 2 drugs would behave differently. The 2 combo agents would be named differently from one another.

So ultimately, the decision on which AR inhibitor we select for the first Phase III study is going to be based on the overall data, but probably just as important, if not more important, it will be based on a variety of strategic considerations.

Our next question comes from Colleen Kusy with Baird.

Congrats on the data today. So your competitor's combo uses enzalutamide. Your data is obviously in combo with darolutamide or apalutamide. We have some monotherapy data for enza alone. Are there any good apa and daro single agents in this patient population? Just trying to figure out the better PSA responses that you're seeing, whether that could be attributable to the better combination partner.

Sure. Pratik can take that, Colleen.

Sure. So all 3 of these agents, enza, apa and daro, have been studied in bunch of different indications. And when you look at an indication where they all have run trials and you line up the outcome in those studies, PSA response, radiographic PFS, overall survival, the results are nearly identical. So there's really no evidence that they would behave any differently from each other in the post AbbVie MCRPC population. Now enza has a label in that indication, so you can look at their Phase III study. But the other 2 have done studies in that indication as well. And again, the outcomes are identical. So we don't think there's really any meaningful effect coming from sort of a difference in the AR inhibitor we're using.

Great. That's helpful. And then from a higher level, obviously, Pfizer is roughly 2 years ahead of you. How do you think about how this profile will shake out relative to mevro. Do you think you need to be better than them to be competitive or as good given the delay in time lines?

Yes, Colleen, thanks for the question. It's Jacob. I can take that. The short answer is we do not think that we need to be better than them. But obviously, you've seen today some hints of why we may, in fact, end up being better than them. Maybe the longer answer, if I could expound on it would be if you -- the perfect analogy, I think, is staring folks in the face, which is if you look at the androgen receptor inhibitor.

So obviously, the 3 big AR inhibitors, as we review today, are enzalutamide, apalutamide and darolutamide as we've said today on the call and as folks know from empirical experience, those 3 drugs are indistinguishable in terms of efficacy in all the populations in which the 3 drugs have been studied where there is some slight difference is that while enza is not a particularly poorly tolerated drug, certainly apalutamide is better tolerated than enza and darolutamide is also better tolerated than enza by patients. And so there's some slight benefit there for apa and for daro. But the reason I give you that background context is as we review today, enzalutamide does over $6 billion of sales globally each year, still growing double digits and was approved in 2012.

Six years later, apalutamide came to market as the second entrant and darolutamide even after that as a third entrant, obviously, both of those drugs are blockbuster drugs, many times over, growing significantly. Point being that in a population as large as prostate cancer, really even the second or third entrant that is fairly indistinguishable from the first still lands itself in blockbuster status. So that's why I say that for us, if the base case here is that we end up with as good as Pfizer in terms of the combo regimen, both in terms of efficacy and safety and just keep that time line gap as short as possible.

We feel quite comfortable with that profile being extremely competitive and obviously, commercially attractive. But as we touched on today from a early read on efficacy as measured by the PSA activity, PSA 50s, PSA 90s, just the overall rate of how much of those -- how much of that PSA activity ends up confirming. And then obviously, the safety profile, we think there's several reasons why we may, in fact, end up better with our combination agent, whether that's a combo with apa or daro may end up better than mevro combo.

Our next question comes from Matthew Biegler with Oppenheimer.

Congrats as well. I wanted to first ask about the GI side effects, nausea, diarrhea, et cetera, seems to be on target. I think Pfizer is arguing that with food, the side effects were more manageable. Have you guys studied food effect? And can you comment on how you stack up so far? And then I just had a question on broader strategy. I think you mentioned expanding into castration sensitive. So I was just curious how supportive you think these data today are in terms of translating from castration resistant to castration sensitive?

Thanks, Matt. I'll take -- I'll ask Pratik to take the first one, and then Lori, our CFO, can take the second one.

Sure. So we don't have an appreciable food effect. Pfizer did their food effect study to look whether food improve the safety profile. We're not in a position yet that we need to ask that question of our molecule and our combination. As you saw, these are doses that are clinically active. So we're not like still at low doses where the safety profile is sort of not informative. This safety profile is informative because we are seeing PSA response rates. And so we are seeing low rates of GI tox. And so if we need to, we would, but we don't right now feel the need to look at a food effect to try to ameliorate safety.

Yes. And then, Matt, with regard to CSPC, I'll ask Lori to just sort of talk about some of the translatability you asked about in terms of what we're seeing preclinically and clinically and CRPC, but maybe just at a high level, from a strategic point of view, we are highly interested in CSPC as an indication. Obviously, Matt talked you through the overall prostate landscape and the fact that any single indication within CRPC that we were to pursue as our initial Phase III study is a multibillion dollar TAM in the U.S. alone. Obviously, CSPC is multiples of that. And so with the profile as clean as what we've seen on the safety side of things, thus far with our both 944 combo regimens, CSPC is high, high in our list of future additional Phase III studies and indications that we'd like to go after. Maybe Lori can comment specifically on just translatability.

Yes. Thank you for the question. We have extensive preclinical data sets in CRPC and CSPC models. And the mechanism in prostate cancer translates perfectly between that castration-resistant setting and the castration-sensitive prostate cancer models. ORIC-944 enhances AR signaling and luminal cell state in both settings, which leads to synergy and improved survival in xenografts in both context. Additionally, when you're thinking about different lines of therapy in prostate cancer, in the earlier lines of patients, there is less tumor heterogeneity. Thus a greater proportion of patients have AR-driven disease that would benefit from ORIC-944 and an AR inhibitor combination.

Our next question comes from Michael Schmidt with Guggenheim.

I may have missed it earlier, but just on the PSA response rate. Were there any differences between combination with apa or daro? Just curious, I know it seems like some of the dose range for 944 may be different for either one of those? And then just one of the bigger picture question on your sort of plan registration study in longer-term expansion plans. Is the idea sort of to replicate essentially the ongoing Pfizer Phase III trials just with your drug, obviously, and then 1 of the 2 AR inhibitors? Or is there perhaps opportunity to do different trials, be different combinations or perhaps going earlier into the [ HSPC ] setting to sort of leapfrog them?

Yes. Thanks, Michael. So to answer your question, no difference that we're seeing really in any aspects of the profile between the apalutamide combination and the darolutamide combination with 944, and so that applies to safety, but it also applies to the PSA activities, PSA 50s, PSA 90s -- rate of PSA 50s rate of PSA 90s, I should say, and the durability that we're seeing between the 2, although obviously, we've had just a longer follow-up with the apalutamide patients who started earlier than the darolutamide patients. And then in terms of the future development plan, we touched on several areas within CRPC today, but also the broader prostate landscape that we'd be interested in pursuing. .

Some may overlap with Pfizer's various Phase III studies. I think they've outlined 3 Phase III studies to date, 2 of which they've started and one, which sounds like it may start imminently. We may overlap in some of those, but we also may go our own way in some of those because obviously, the prostate landscape is incredibly large. And so that very well could be the case that we'll have some overlap, but also some areas that are on to ourselves.

Our next question comes from Yigal Nochomovitz with Citi Group.

Congrats on the strong data. I had a question regarding the Phase III. Are you -- do you need to see PFS -- even early signal on PFS before making a determination with respect to apa versus daro? And then you mentioned the first Phase III will be one of those partners, but is there a potential for a second Phase III that would be the other one? Or that's not the intention?

Yes. Thanks, Yigal. So we -- short answer is we do not need to see mature PFS data from the current dose optimization work before starting our first Phase III study. We intend to start the first Phase III study first half of next year. So in fact, we will not have mature PFS data. But obviously, what we will have, as Pratik said, is with those optimization starting imminently with both combo regimens, both combo partners, we will have a substantial number of patients at provisional RP2Ds that will have been followed up. Certainly, several of them will have been followed up for 6-plus months by the end of this year or early next year.

And so clearly, we can do landmark analyses based on what percent of patients are still ongoing at various points in time, 4-plus months, 6-plus months, whatever that might be. And those can be statistics translated into what PFS might look like. If we -- really the point here, you call it, if we were to be as conservative as we possibly could be on a development plan, it also means that we would just be unnecessarily, I think, pushing out the start of the Phase III timing. And given the strength of the results that we've seen to date that we presented today and obviously, the strength of the results we've seen in a randomized setting from Pfizer, we think it behooves us to move as quickly as possible into that first Phase III beginning of next year.

And then in terms of taking one of those combo regimens into the first Phase III study, it obviously -- it doesn't hamstring us from what we would do for future Phase III studies. So I guess we would just keep an open mind as to which agent we would take into which subsequent studies.

Okay. And obviously, given your comments today, it seems like things are looking, at least from this early data set very similar between the 2 that are -- as you pointed out, there are some differences with respect to the DDI, assuming everything continues to look essentially equivalent between the 2 choices, what will be the -- what it's going to tip the balance in terms of which one you decide to go forward with first?

Yes. I think as I alluded to in one of the earlier questions Yigal, I think that because we don't see a difference thus far clinically between the 2 agents because they're both great agents and because both J&J and Bayer have thus far been great partners to us in the work thus far. We also -- and because there's not a mechanistic reason to see a difference between the 2 agents, I think it will come down to strategic considerations, frankly, as to which of those we take forward into the first Phase III study or in the subsequent Phase III studies.

There's a whole host of things that go under the rubric of strategic considerations, which I probably shouldn't enumerate today on the call. But certainly, even buy in on a broader development plan and thinking about unlocking future opportunities like CSPC, those are things that are going to be quite important to us as we think about just what's the right path forward with the right combo agent from the right partner.

So it's really likely to come down to strategic considerations. And then as we think about the future development plan, we talked about CSPC today, but obviously, even before getting to something like CSPC, folks know that we have just recently started dosing patients -- very recently started dosing patients that are post AR inhibitors. So obviously, the results today, we talked about were in patients that were -- the 17 patients that were post-abiraterone that we reviewed with you today. But very recently, as in less than half a dozen patients under our belt in the last couple of months, we've started dosing patients who are being treated after having progressed on an AR inhibitor.

And even in that small data set, less than half a dozen patients, there are reasons to believe that we've seen already that the drug and the regimen will work, for example, post enzalutamide. And so that obviously generating more data in that particular patient population in the coming months and quarters is going to be quite important as we factor in, in terms of what the future Phase III development strategies might look like. So in addition to post abiraterone, maybe a post AR inhibitor or broader post ARPI study, any of the above might be on the table.

Our next question comes from Derek Archila with Wells Fargo.

This is [ Sela ] on for Derek. Congrats on data. A couple from us. First, can you provide a bit more color on what data can we expect in the update later this year? And whether it's possible we get any insight -- early insights on PFS? And the second question is how are you thinking about financing development beyond CRPC? Or is this something you plan doing internally? Or are you open to larger collaborations? And does your cash guidance include any proof-of-concept studies for other tumor types or other prostate cancer patients?

Thanks. Yes, Dominic will take those.

Yes. So with regards to your first question, the guidance for the second half of this year that we provided earlier this year, was to provide about 20 to 25 patients worth of data. Again, that will be from the dose optimization portion of the study. The focus there will be again -- I'm sorry, that be from dose escalation portion of the study and the focus there will be obviously focus on PSA and safety. One thing to note here, as you saw today, the original guidance was 10 to 12 patients. We actually had 12 patients worth of data. And the reason for that is enrollment definitely picked up post the ASCO GU. So we may be on the higher end of that guidance for the second half of the year.

With regards to the durability there, I think the answer there is the focus there is going to be more on the dose optimization portion of the study, which would be in Q4 of this year or Q1 of next year. And then from a cash perspective, taking into account the current financing of $125 million, the pro forma cash balance as of end of March is $349 million that does extend our cash runway into the second half of 2027. And importantly, that does take us passed the anticipated data readout for the first Phase III study for ORIC-944. And then lastly, your question on what's included in that, that is a fully burdened number. So that does assume we're starting a Phase III study, obviously, for 944 in the first half of 2026. We're also starting a Phase III study for ORIC-114 in 2026, and that does assume pretty much all the costs associated with that, including the CMC-related cost.

And there's nothing factored in there in terms of future BD activity or strategic collaborations obviously, for the sake of conservatism, that's the way we budgeted that. But also, obviously, we're quite open to considering strategic collaborations at the right time and on the right terms.

Our next question comes from Soumit Roy with JonesTrading.

Congrats on the data again. If you could just elaborate a tiny bit on the PSA -- kinetics of the PSA drop. Is it -- you're seeing it coming down in the first 2 weeks, 50% to 90% or it's taking longer, but staying more stable? And the second is beyond prostate cancer, should we continue to expect some initial data from the 114 EGFR-mutant programs in the second half of the year?

Yes. Let me take your second question first, which is, yes, you should continue to expect the public milestone that we promised in the second half of this year for the lung program is continue to be on track for the second half of this year. So nothing has changed from that. And then Pratik will take your question on PSA kinetics.

Yes. I mean I think we've seen all of the above rapid decreases and then sort of partial decreases that then improve over time. As I said earlier, we have multiple patients, the majority of our patients are on study. So their PSA responses are evolving. So I can't give you sort of like a definitive read on the kinetics, but it's -- we're seeing different patterns.

Got it. Is there any heavy concomitant usage of steroid for these patients or it's within usual range?

No, no. There isn't any.

Our next question comes from Stephen Willey with Stifel.

Congratulations on the data. Just wondering if there's anything that you can say about baseline PSA, I know it's small patient numbers, but just curious as to how the baseline PSA here compares to what was observed in the baseline of the Pfizer study?

Thanks, Stephen. Pratik will take that.

Sure. You referenced the Pfizer study, but they actually didn't say in their randomized study what the baseline PSA was. So we didn't say that here either. I can tell you though that our median baseline PSA in the patients that we presented today is well within the range of precedent Phase III study. So if you look at these studies and enrolled patients post ARPI, MCRPC like PSMA 4, SPLASH, CONTACT-02, TRITON3. If you look at their baseline PSAs, we're right in there. Sort of just to add to that, we're definitely not -- it was meaningfully higher than the baseline PSA for the Phase II tazemetostat study, CELLO-1 that was in chemo-naive patients. They had a baseline PSA in the mid-single digits. We're meaningfully higher than that and really sort of in the ballpark of all these Phase III. So it's a representative population. I can't comment on the Pfizer one because they didn't disclose theirs.

We're showing no further questions in queue at this time. This concludes today's conference call. Thank you for participating. You may now disconnect.