Olema Pharmaceuticals Inc Aktie

Alright. Well, thank you all for coming today and coming to the Morgan Stanley Healthcare Conference. My name is Ryuk Byun. I'm head of West Coast Healthcare Investment Banking for Morgan Stanley. I have the pleasure of hosting Sean Bohen, CEO of Olema.

I think as we kind of think about, kind of just to jump right in, the market keeps lumping every oral SERD together, but you have to, forecast a molecule by its own data and from standpoint, palazestrant doesn't look like everyone else's SERD. Why is treating this as one monolithic class the core mistake that investors are making?

Yes, so thank you, first of all, for the opportunity and the people here for listening to the Olema story. I think that there are a number of reasons why lumping these molecules together is a mistake, I mean, beyond an oversimplification. First of all, mechanistically, there are key differences. So palazestrant is a complete estrogen receptor antagonist. Binds, shuts off the estrogen receptor signal, growth and proliferation signal completely. That's true in the context of the wild-type receptor, where it competes for estrogen, but also the ESR1 mutated receptor, which is turned on without estrogen needed. Some molecules are SERMs. They're agonists in some contexts, and you do not want to turn on the estrogen receptor in these cancers.

In other cases, it's really got to do with exposure and pharmacology. You need to have a high level of drug to force receptor binding and keep the receptor off all the time because estrogen receptor is a transcription factor. So its signal is highly amplified, and we have by far the best exposure within the class. And then finally, combinability becomes very important. I mean, our first Phase III to read out in Q1, OPERA-01, is a monotherapy trial, but the larger opportunity with this class of drugs is in combination with other targeted agents. And we have found, uniquely, that we are able to combine with multiple different modalities without having to compromise our dose and without enhancement of toxicity.

Why do investors do this then? Why do they lump it all together? Well, I think the simple answer is it's complex. But if you decide to do that, then you decide to ignore some very important data that can distinguish the molecules.

Got it. Thank you. Maybe just since it's topical, on the SERENA-4. It seems like, from my perspective, the first line misses are about exposure and dose, not necessarily mechanism. And camizestrant carries, as you said, the lowest exposure of all the oral SERDs because of its tolerability ceiling. Isn't that the very problem palazestrant designed out from the very beginning?

It is. It's one of the many. So when the founders of palazestrant really took this on a little less than 10 years ago, other companies were working on this. And by the way, they were addressing as well that they had also got into the concept that you want a complete antagonist. Camizestrant molecularly is a complete antagonist. Giredestrant, the Roche molecule, is a complete antagonist. So they had made that observation as we did at Olema. But in looking at those molecules, it was seen that there were these liabilities, that they weren't, they didn't have high enough exposure. They had tolerability problems, and then those tolerability problems are exacerbated in combination. And so the objective in designing palazestrant was, let's address all these things.

We have successfully achieved that, that's all demonstrated. But one of the obvious conclusions of wanting to address those things is also saying, hey look, these liabilities are going to turn into limitations when you test these things for efficacy. Now, we don't know what the data is from SERENA-4. All we have is this cryptic, numerically different data for PFS. We do know what the data is from persevERA, from the Roche compound in its first line Phase III. And that data clearly indicates that there is better activity of an oral CERAN than an aromatase inhibitor. They had a 5-month delta-PFS. They had a clear trend for hazard ratio, but didn't quite make statistical significance. And that in spite of some design flaws.

And so I think those molecules demonstrate two things. One, we're leaving efficacy on the table with AIs. We can improve upon it. And two, these liabilities in terms of exposure and combinability are turning into liabilities when you look at achieving a clinically meaningful outcome.

Thank you. Since you mentioned it, persevERA. What, kind of, folks may flippantly call a negative trial, still delivered about a 5-month PFS delta, while they were carrying about 10% endocrine resistant patients which diluted some of the treatment effect and efficacy signals. In terms of your own trial, OPERA-02, can you tell us about how you've thought about patient selection exclusion and also your decision to run a ribociclib backbone? I guess as we're looking at what happened with persevERA and even SERENA-4, a competitor miss may actually potentially raise your confidence given your trial design and some of these molecule differentiations, but would love to hear your perspectives.

Yes, so there are multiple questions in there, which are all good ones. So the first one has to do with the patient selection. I must say, OPERA-02 is not the unique trial in terms of how we've defined our patient population. That is to say, the endocrine-sensitive patient population. What that looks like in these first-line trials is for the patients who have had prior adjuvant therapy. In order to be eligible for OPERA-02, you have to have completed your adjuvant therapy and had at least a 1-year of treatment-free interval without recurrence of disease. And that's the clinical definition of endocrine sensitive. And so that's what we do in OPERA-02. By the way, that's exactly what was done in SERENA-4 as well. AstraZeneca used the same criteria.

The unique thing was that Roche decided, for some reason, to include patients who had progressed within that year of completion of adjuvant. As you said, it ended up being about 10%, but that was after they stopped that in their first amendment. So it must have been much higher at the beginning of the trial. They did very poorly, right? So this is a trial where, yes, 28 months in the control arm, letrozole plus palbo, 33 months, that's the 5 months you were talking about, median PFS, giredestrant plus palbociclib. If you go to that subset of patients that had that shorter treatment-free interval, the control arm wasn't 28, it was 19. The giredestrant arm wasn't 33, it was 14. They did very, very poorly. And so this actually not only diluted the treatment effect, it actually fought the treatment effect in terms of the hazard ratio. So this is a really big, I would just say, mistake to include those patients.

SERENA-4 didn't do that. We haven't seen the data. I think SERENA-4 is very well designed. The challenge with SERENA-4 is camizestrant is not -- it's got the lowest exposure. I think it's got limitations as a drug. Both of those trials, as you mentioned, use palbociclib as their CDK4/6. Now, that was not a mistake. At the time those trials were designed, Ibrance dominated the first-line market and that continued to be the case until Overall Survival started to read out from the CDK4/6 inhibitor pivotal trials and what happened there is the standard of care got flipped on its head. The third most used drug was Kisqali, ribociclib, but it had three out of three trials positive for Overall Survival. The delta, the improvement in Overall Survival, is about a 1-year. That's significant obviously for these patients.

And so oncologists did what oncologists do. It's very simple. I am one. It's not being pejorative. They just follow data. And so when they had a survival benefit, they said, okay, this is it. We're switching our new patients onto this. We designed OPERA-02 with that knowledge in hand. We actually had done the palbo combo first. We thought that was going to be an Ibrance trial, but we were able to capture that change in standard of care.

Thank you. Now, giredestrant, going back to that, my understanding is that they cut from 100 mg to 30 mg such that they can manage bradycardia with palbo. You have an 8-day half-life and high exposure. And so I guess, as others may have to make some trade-offs on the exposure versus tolerability equation, you think based on your PK, looks like you have a, what seems like a durable moat. Can you elaborate on kind of that a little bit more?

Yes, so it turns out our half-life, and we'll publish on this here, our half-life is even longer, that's about 14 days. And so our steady state exposure is even higher than we have published. And that 14-day half-life really allows us with daily, once daily dosing to achieve this very high exposure. Again, the objective with this treatment modality is to shut this signal off completely. And the way you do that is by forcing the binding of palazestrant onto the receptor. We had predefined the exposure threshold we felt we needed, right? We weren't first. We saw liabilities in the others and we thought, okay, this isn't worth doing these Phase III trials if you can't address those liabilities. We're able to easily cover 24/7 exposure threshold.

Now, the giredestrant had pretty nice exposure, not as high as ours at 100 milligrams. And that was their original recommended Phase II dose. The problem was they combined with palbo and they found, as you said, they had this with this, this increase in rate of bradycardia. And they decided that was not acceptable and so by mitigating their dose going down to 30 mg, a threefold decrease in exposure, as you might expect, that they did actually control the bradycardia problem. We think, however, they sacrificed their receptor occupancy. And that is the kind of flaw that we were seeking to address.

Yes. I mean, even a great degrader leaves plenty of receptor behind. So what controls the tumor is really keeping the residual receptor completely silent and believe that's what you set out to do with designing and developing palazestrant. So now does that reframe the next-gen SERD debate away from the degradation depths?

It should. Unfortunately, we have, it goes actually back to fulvestrant, this sort of red herring that degradation could be a mechanism of action. Look, if you could absolutely eliminate all the receptor from the cell, probably that would be a reasonable thing to do. But in the very best circumstances, you still have 20% intact receptor. Now, remember, this is a protein versus the DNA binding sites, the promoters. It is in massive excess to its binding sites. So going from estrogen receptor positive to estrogen receptor positive is not a significant therapeutic effect. And that's what happens with the degraders.

Look, palazestrant is as good a degrader as anything. It's just that there's all that receptor remaining. You have to turn that receptor off. And that's the exposure. That's the complete antagonism that really adds up to what is the formula for doing this successfully.

Thank you. Now, talking about going to OPERA-01 dosing choice, it seems like, your dose selection is, almost like a non-issue for you. Your 90 mg, 120 mg have equivalent exposure and both clear your preclinical target. Can you talk a little bit around what drove and guided your dose selection and how investors should feel about that?

Yes. So the first thing that you said is right. When we show everybody our exposures at 90 mg and 120 mg, they far exceed the threshold, even with the 14-day half-life and the newer PopPK data. It's even more than what we had previously said with both doses. So 90 mg and 120 mg are essentially, from an exposure occupancy standpoint, the same. But it's a great question as to what drove the dose selection. How the dose was selected. I cannot tell you what drove it because we didn't decide. Our independent data monitoring committee, which was unblinded to the Part 1, 90/120 data, decided and then that data was provided to the FDA, who concurred with their decision. But they were provided both safety and efficacy data at 90 mg and 120 mg from these 40 patients on each dose arm in order to make this assessment, made the recommendation of 90 mg.

We had felt comfortable, comfortable with 90 mg all along because we knew the exposure easily achieved our objectives. And the FDA concurred with that decision. But as to the specific factors within safety and efficacy, I can't actually share what that was.

Talk about your ESR1 wild-type activity that you've seen. 5.5 months, which I believe is even competitive with your competitors post in the mutant setting. And I think that's really the part that the street might be not paying focus on. Can you talk about kind of the conviction that you have?

Right. So, I mean, I think there's an underlying principle. It gets a little bit to your question at the beginning about comparing all the members of this class. This is such an obvious thing to say, but it does seem to need to be repeated. The best way to predict the future outcome of a drug or a regimen is to look at the past clinical outcome of that drug or regimen. Now look at a different drug or regimen. Look at that drug and that regimen. So if you look at palazestrant, compared with the others in the class, we have outperformed in our Phase II. No one has really seen any evidence of activity in the wild-type. We had 5.5 months. Again, this is uncontrolled. It's Phase II, admittedly.

We had over 7 months in the ESR1 mutant. Again, 5 is about the best people do. It's usually more like 4. So again, in both cases, it seems like they're superior already. In the ribo combo post-CDK4/6, we had over a year, which again really stands out. So of course, the question here is, and what we're answering in our clinical trials more proximately OPERA-01 is, do we duplicate the Phase II experience in the Phase III randomized setting? That is always a risk. I will say the OPERA-01 patients are somewhat less heavily pretreated than the Phase II group were. If we are able to duplicate that effect, then we really have a chance of being differentiated in the mutant subset by greater efficacy and being successful in the wild-type subset where no one has been. But that's the question, right? That's the risk that we're bearing as we go into that trial, and it is tested to answer those specific questions.

Got it. Thank you. Can we talk a little bit around, your palazestrant's unique combinability at full doses without drug-drug interaction and the fact that yours is the only first-line trial on ribociclib. Now, how have you thought about kind of your, maybe going back a little bit on your backbone choice, but also how you haven't compromised on dosing to be competitive in a first line setting?

Yes. So it's interesting. Some of this is structural. Some of it is preclinical screening. So there is some testing you can do in preclinical both metabolism testing and in combinations to look at risk of drug-drug interaction. It's not perfect. It was, I think, done more extensively than some of the other molecules. There's then an empiric component where you have to go into the clinic and see what happens in terms of exposure and what happens in terms of tolerability. And we have combined at full doses of palazestrant with full doses of palbociclib, ribociclib, everolimus, alpelisib, atirmociclib, which is the Pfizer CDK4 selective molecule, and OP-3136, which is our KAT6 inhibitor. And we find that we are able to do this without enhancement of toxicity with preservation of good exposure.

Yes, so that was an objective. It is unique within the field and we do think it is, it conveys a very significant potential efficacy benefit by virtue of being able to maintain this exposure and thereby complete estrogen receptor antagonism, either in the monotherapy or while combining with all these various targeted agents.

So OPERA-01 reads out this year, later this year.

No, Q1.

Okay, Q1, okay.

Q1 2027.

Yes, and then can you talk a little bit around the read-through to OPERA-02? And how people should be thinking about the value inflection to expect from O1.

Yes. So the first thing that's really interesting is, and this is again something that's easily confused. ESR1 wild-type is not the same throughout lines of therapy. So ESR1 wild-type in OPERA-02 is endocrine sensitive. So OPERA-02 is the only endocrine sensitive first-line trial in combination with ribociclib. As I mentioned, one of the things we thought we knew before but was proven in persevERA is that in that first-line setting, the endocrine-resistant population doesn't do that well. They need a bigger switch in therapy.

We exclude them, as did SERENA-4, from OPERA-02. Now, when you get into the OPERA-01 setting, the second-, third-line setting, those patients are by definition, including the ESR1 wild-type, endocrine resistant. They progressed on CDK4/6 plus AI, right? So that biologically is a different population. So the thing that predicts the outcome of OPERA-02 is actually the Phase II combination data from ribo and palazestrant.

OPERA-01 has relatively little correlation with OPERA-02 because they are biologically different. That said, OPERA-01 opens up a potentially very large market opportunity. The wild-type is a $2 billion annually market opportunity. I'm sorry, the mutant is $2 billion. The wild-type, which is probably about 60%, is about $3 billion, right? So there are two ways to really access significant opportunities here. One is to differentiate for efficacy and then you get more than this 2-month delta in PFS that has been seen. In the wild-type, just showing efficacy is a meaningful differentiation because everyone's failed. So, so you're alone there. So this is what our first readout does for us. It really gives us this market opportunity. It validates that this increased exposure with a complete antagonist is a meaningful differentiator. I think separately, we know that, for instance, molecules that really failed in the second, third line setting, like giredestrant, which failed in acelERA, clearly show a signal for activity in endocrine sensitive patients in first line. So OPERA-02 is really, really built on that first line endocrine sensitive data set.

Got it. Okay, well, let's shift gears to KAT6. I think obviously, yes, Pfizer has been pioneering the field. Now, you've engineered out some of the KAT5, KAT8 liabilities and obviously there were probably some learnings from seeing Pfizer develop and progress into the clinic ahead of you. Now, what do you think is kind of the unique differentiation for your KAT6 molecule versus the field? Because I think it's an evolving field and people are trying to understand kind of what, which KAT6 family may or may not matter for a variant.

Yes. So I think it's exactly right. So what, what we did was we made a more potent and specific KAT6 inhibitor in OP-3136. Now from the standpoint of level exposures we're achieving, like Pfizer, who really did pioneer the field, they validated this target for ER-positive, HER2-negative breast cancer. Our hope was, and our early Phase I data suggests that possibly we're doing this, is that by dialing out KAT5 and KAT8, we would preserve the efficacy of inhibiting 6 and 7 and maybe dial back toxicity, particularly the cytopenias caused by this class of agents. And it seems like we might have done that, particularly based on the breast cancer patients.

The way to differentiate within that, obviously, is tolerability, and then the other thing that we saw, this is from preclinical xenograft data, is that the endocrine partners weren't always the same. Certainly with the KAT6s, as with all targeted therapies, in breast cancer, adding an ER targeting agent, fulvestrant, enhances the efficacy. What we found preclinically was that happened, but if you added palazestrant, you had a much more profound increase. Obviously, we are the only company that combined with palazestrant. We're the only company other than Pfizer that has clinical data from KAT6 inhibitor that we've shared.

That palazestrant combo, in addition to fulvestrant, is ongoing right now. And so we're hopeful that one way to distinguish from the whole class is that by having the better endocrine agent combination, you get better efficacy, which is the main driver. We also are hopeful that as we expand this experience that a favorable tolerability profile emerges and is preserved. We did one other thing in our Phase I trial, which was based on our preclinical data, which was we included castration-resistant prostate cancer. Pfizer had done this as well in their Phase I experience. They did not see activity. They did not continue. We saw monotherapy activity in the castration-resistant prostate cancer cohort. And so we subsequently, the logical thing you do then is you combine with an androgen receptor inhibitor. And so in looking across that landscape, which is complex, we identified Nubeqa, darolutamide, the Bayer androgen receptor inhibitor as the most desirable. It has the best side effect.

Perceived as the best-in-class.

It's the best in class and it's based on its side effect profile. Side effects often translate into efficacy. So obviously, talk to the people at Bayer. They have an amazing prostate development team. They were interested and so signed this clinical trial, supply agreement, collaboration. Q4, we will start the dosing of that prostate cancer cohort. So that's a new area for us as a breast cancer focus company.

The KAT6 opportunity in breast cancer alone is $5 billion plus a year. I would argue that right now, if you look at the Olema valuation, we are undervalued just for KAT6, not even considering the palazestrant opportunity. We haven't valued prostate yet. It's new to us, but that will come out in the billions of dollars a year as well.

And not a small cell, I'm sure.

We have one patient whose tumor did get smaller. I don't know what that means. We're still evaluating what to do with that. It's not quite so clear what the development pathway is in non-small cell lung cancer. Just, it probably involves immunotherapy of some kind. But we're deciding whether or not we think we should explore that more.

Right. I think, in any event, I think on top of breast, where having a very tolerable KAT6 agent giving you the combination flexibility and having palazestrant to your point. That plus, potential indications to think about, I think is important. Now, let's talk a little bit around your runway, financial position, and your upcoming catalysts and timing.

Yes. So our cash on hand the end of Q2 is about $461 million. And in that quarter burning a little bit north of $40 million within the quarter. And that gives us runway into the second half of 2028. Now, obviously, we have a lot of catalysts coming in that period of time. As we talked about Q1, we have the OPERA-01 readout, mutant and wild-type. We have KAT6 data coming in, as I said, maybe some fulvestrant data by the end of the year. We'll have to see as that data matures. Certainly, in the first half, we'll have combination data in breast cancer with, with our KAT6 inhibitor to be able to share.

OPERA-02 is enrolling very, very well, won't read out in that timeframe, but certainly is progressing nicely. It's a very large market opportunity. And then, as we get the prostate cancer enrolling, we'll update on when we'll have a catalyst there or some data to share, but definitely should be in the timeframe of our runway, so quite a few things. And I should say that runway includes OPERA-01, OPERA-02 execution, also includes the spend needed for commercial to enable the registration, the filing, and the launch of palazestrant based on OPERA-01. So all of that stuff is incorporated into that runway forecast.

Thank you. Now, if you had to leave the investors here and listening in with one thing about Olema. What would that be?

Yes, I mean, I think we are a leader in ER-positive HER2-negative breast cancer, which is a big unmet need and a very, very large market opportunity. And I think that the important thing to do as you assess us and handicap our ability to perform in that space is to look at the data we have generated with our molecules, because that's what tells you what our potential is. And I think when you do that, you're going to see a company that's undervalued because it's over-associated with other molecules in the class, with a molecule that was designed to and has been shown to be differentiated from the others in that class. And then a further pipeline opportunity in KAT6 that complements the lead molecule palazestrant, but also diversifies us in risk into another MOA and more recently now, even then into another tumor type and becoming a prostate cancer-focused company as well.

Great. Sean, thank you so much for your time. And, hope you have a good rest of your busy day with investor meetings. Thank you.

Thank you very much, and thanks, everybody.

Here for the afternoon session on day 2 of Citi's Back-to-school Biotech Summit. I'm Yigal Nochomovitz, senior biotech analyst at Citi. Our next company for the afternoon session is Olema Oncology. I have with me, of course, Sean Bohen, who is the President and CEO of the company. So we have a lot to discuss a lot of developments in breast cancer over the last year or so.

So maybe, Sean, maybe just give us the -- set the stage in terms of what's in the pipeline and what are the key readouts coming up. There are several things.

Yes. Thank you, Yigal. Thanks to both of you for attending. The -- so obviously, our lead asset is palazestrant. It's a complete estrogen receptor antagonist for the treatment of ER-positive HER2-negative breast cancer. And we're studying it in Phase III in 2 contexts. One is as a monotherapy in the second, third-line settings. These are patients who progressed on a prior CDK4/6 plus an AI, now going on to another therapy. And so the control arm is fulvestrant or exemestane. Experimental arm is single-agent palazestrant. And that trial is -- it's finished enrollment and randomization. It is -- we're awaiting readout, and we forecast that we will have our top line data in Q1.

And that -- in that population, as you know, it's very interesting because it's really 2 separate groups. There are those individuals who progressed on their prior therapy with an ESR1 activating mutation. It's about 40% to 50%. The remainder still have estrogen receptor in the wild-type form and is not mutated. And there's been prior success in the mutant population, but no one's been able to do better than fulvestrant or exemestane in the wild type. So we're testing both of those populations, both of those hypotheses in the trial. In total, it's about a $5 billion a year market opportunity. So for us, very significant.

The other trial that's ongoing and enrolling very well is in the first-line setting. And in that case, we are combining with the gold standard CDK4/6 inhibitor, which is KISQALI. And that trial is called OPERA-02. So the control arm is KISQALI plus letrozole, an AI. Experimental arm is KISQALI plus palazestrant. That will take -- it's enrolling very well. It will take a couple of years to read out just because of the effectiveness of that treatment. But that's a $10 billion-plus market opportunity should we be able to access it. Both of those trials are based on Phase II data that suggests that we can do better than the existing therapies and have activity in these different settings we're describing.

Okay. So let's start with -- let's go in order, I guess, and start with OPERA-01. So I guess the first question is, so there was a bit of a -- originally, the data was the second half of the year and now it's 1Q '27. This is like the age-old question of some of these event-driven trials, the significance of moving the endpoint or moving the data out a little bit. Anything you want to say there? Or is it just...

Yes. I mean I wouldn't overinterpret it. First of all, the trial obviously is -- it's not a blinded trial, right? It's an open-label trial, but the reading of the endpoint is blinded. It's a blinded independent radiographic review. Progression-free survival is the primary endpoint of both OPERA-01 and OPERA-02 trials. Yes, I mean, we do blinded event rate. And so that's in there to some extent. Mostly, the slight delay had to do with a slowing toward the end of enrollment in the enrollment of the ESR1 mutated subset of patients.

And we think -- we're not 100% sure. We think from our investigators that, that might have been related to greater availability of ORSERDU in Europe. Again, it's past us. We are completely enrolled in the trial. We did not compromise the number of patients in either population. So it's fully powered for the statistical plan. And I think the other important part about this is that we -- overall, we had predicted 40% to 50% of patients would be ESR1 mutated. We actually did end up in our predicted range. So I think that part isn't different. It's just that we were in the higher percentage earlier on and it sort of fell a little bit toward the end.

Okay. So well, you mentioned, of course, the 2 populations, the mutant and the wild type. So the mutant, obviously, is the lower bar. But more specifically on the wild type, what -- tell us more about what gives you a confident view that palazestrant can show a difference there versus standard of care? What is the -- what evidence do you have previously that would support that? Because you pointed out that together, I think it's $5 billion, although even with just the mutant, it's probably like $2 billion or something.

Something in that range, yes. Yes. So I'll go into what molecularly we think might be going on, but I think the strongest evidence is our Phase II data, right? The question is, obviously, can you replicate that in the Phase III setting. So in the Phase II setting, post prior CDK4/6, in that case, a little more heavily pretreated patients because a significant number had had prior chemo, that's not allowed in OPERA-01. We saw over 7 months median PFS in the mutant setting, 5.5 in the wild-type setting. And that is better than anyone has been able to see in either of those settings, but certainly in the wild type.

The bar in wild type is to extend PFS by about 2 months, right? Lilly got approved with imlunestrant at 1.7, but -- which is probably a little on the edge, but it did lead to approval, but you'd say about 2 months. And so recognizing that the control arm really should be 2 to 3 months, if we can replicate that 5-month range, we should be able to access that population, and that's what's being tested in OPERA-01.

Why might that happen when others haven't been able to do that? Well, in addition to being a complete antagonist, we have very high exposure, 14-day half-life and a very high steady-state exposure compared to other drugs. And we think that, that is important in the context of maximizing the benefit you would get.

Okay. Let's also go through just the statistical. You mentioned the statistical plan because you have the 2 populations. So how does it -- remind everyone how it works in terms of the process of analyzing these 2 populations and how -- where you can win and how you -- in the order of which things are analyzed.

Yes. So we haven't disclosed in detail the statistical plan, but I can tell you basically the performance characteristics. And the performance characteristics are the trial can be positive in 1 of 3 ways, right? There's the obvious one, which is it shows a significant benefit over the control arm in both mutant and wild type. Mutant and wild-type subsets are tested separately. So the way the trial is designed, you can actually have 2 other types of positive trial. One is ESR1 mutant only, which shows the significant difference, wild-type does not. You then get a positive trial in that mutant subset. Not trying to explain why there would be a biological rationale, but from a statistical standpoint, you can do the opposite as well.

Although, it would be unlikely.

It doesn't make a whole lot. Yes. If that happened, I would -- we'd all be wringing our hands and wondering what went on. But we could statistically have ESR1 wild-type be positive, ESR1 mutant not be positive and still end up with a positive trial.

Right. Okay. All right. So that makes sense. And then as far as the commercial opportunity, you kind of alluded to it a little bit in terms of the numbers up to $5 billion. Yes. Anything further to add on that in terms of how that works geographically? Is that U.S.? Is that global? What are we talking about there?

Yes, it would be global in that situation. Usually, if you look at markets in oncology, the U.S. -- in revenue terms, not patient number terms, it's usually about 2/3, 70%. So it is the majority United States.

Two ways really to differentiate in this space. One is to do better than the 2 months prolongation of PFS in the mutant setting. And again, we saw 7. So instead of 2 to 4 -- 2 to 3 to 4 to 5, we could see 7. That would be significant. The other is to get a benefit in the wild type, which is at this point is unmet, right? So there's nothing that's been successful in that subset. And it's probably, as you said, you kind of alluded, it's probably split up around $2 billion and change per year in the mutant, $3 billion.

Yes. But ORSERDU got -- I mean, they worked in mutant with like 3.9 versus...

3.8 versus 1.9.

Yes, 3.8 versus 1.9. So they worked if the 2-month delta, meaning that's a good argument for potentially while you could work -- I mean, it's a different setting, but in wild type, if you saw 2 months, you would be working.

You would be -- yes, you would -- I think that's the basis for approval, would be the basis for use. So that's the question. Can we replicate this Phase II data? And can we show that delta? Obviously, the market dynamics are very different in these 2 places because wild type, there's no endocrine agent competition really, whereas there are sort of 2 molecules certainly launched, maybe 3 coming in the mutant subset.

Yes. Yes. And then I think earlier you mentioned the Phase II data as anchoring your conviction. But I think in that data, I believe the -- some of the patient characteristics were less favorable than in OPERA-01, right? So can you speak to that because that's sort of like a headwind on your 5.5 number. So how does that figure into your math?

Right. We think it is. The most -- the biggest difference in that respect was that in the Phase II experience, we allowed prior chemotherapy. And we know from a variety -- it's been known for a while, but I think the EMERALD data's retrospective analysis really showed that, that's a pretty strong negative prognostic. So we eliminated that from OPERA-01. You couldn't have prior chemotherapy in the metastatic setting.

And the other thing that we did is we said, "Look, if you -- whatever your prior endocrine regimen was before going on this trial, you had to be able to be on it for at least 6 months without progression." And that's an effort to avoid primary endocrine resistance. This isn't -- these aren't strong selectors, but they do seem to have some power. So the 5.5 was achieved in that, and obviously, in the Phase II, we didn't make that criteria. So 5.5 was achieved with the chemo, with the enrollment of patients who progressed relatively quickly. And then in OPERA-01, we don't do it. So the hope is that those truly refractory patients, we kind of somewhat select against their enrollment.

Okay. All right. So then data, as you said, 1Q '27, unless there's a further change, but that sounds like where it's headed.

I think that's where we're going to be.

Okay. Where are you with regard to thinking about the commercial build-out? Is this is a tractable market, the second and third-line setting that you would be running the launch yourself? Is that right? Or...

In the United States, yes. So a couple of things, right? What is our -- I'll do our strategy, and then I'll do the commercial. I'm going to reverse your questions a little bit. Our plan is to launch this initial indication, second, third-line monotherapy in the United States, promote it ourselves. And that is a doable. That's probably less than 100 field sales that is needed to do that effectively. We do not -- we are enabled to file outside the United States, so to progress the regulatory packages. But we do not plan to launch and promote. So we will have to seek a collaborator. Obviously, we're 6 months maybe and change from the data. So our assumption is that a collaborator will want to see the data before they enter an agreement. So that's kind of where we are with that part of the strategy.

With regard to that U.S. launch, we've already started the commercial build. We've hired people. We've done market research on it. We have a full plan to ramp up. Some of it will continue ahead of the data. Obviously, the data being supportive of launch, there will be an inflection point, and we'll ramp it up quite quickly at that point, probably early next year, right?

Okay. One other question I forgot to ask, but maybe you haven't disclosed this yet. You're counting the PFS events. Is it across both mutant and wild type? Or do you need a certain number of PFS events in mutant and a certain number in wild type? Or how does that work?

Yes, it's interesting. So the way the trial is designed, if you look at the trial from like the standpoint of execution or a patient coming into it, it's one trial. We have one inclusion/exclusion criteria. There's one randomization. It's the same. You're stratified, right? So you get tested, you're stratified, so you make sure it's even between the arms. When you go to the analysis plan, it really kind of looks like 2 trials, actually. It looks like an ESR1 mutant and ESR1 wild type. So there are actually statistical design that are different between the 2. So what happens is you have to achieve a certain number of events in each of the populations. The thing is there's one unblinding. There's one closing of the database. There's one unblinding.

So it's not like...

Whichever one comes later will be the one that triggers that unblinding. So it's not like you can read them out separately.

Right. Even if one meets the threshold on the events.

We just wait. It will probably have more. We'll get a little -- there'll be a little more power in that particular population than we had planned in the statistical design, but that's fine.

Okay. Cool. All right. So that's second, third line. Then you mentioned frontline and OPERA-02. And there's a lot of interesting things that have happened with persevERA, and we have the SERENA-4 obviously coming up soon. Well, tell -- first of all, we learned a lot of things a little bit from persevERA. You learned something about the control arm performance, which maybe helped you in thinking about your frontline trial. Is there an opportunity to revamp the powering now that you have a cleaner sense of the control, the modern control arm performance? Maybe just speak to that first.

Sure. Right. So just to set the context here, one of the things that happens in oncology fairly broadly, not necessarily specific to this, but seems to be applying to this is that a given regimen often performs better over time. And what that probably is it's probably learning curve from the oncologists. They are very good at learning how to manage, particularly the AEs, maintain dose intensity. And so you will see in many different tumor types that the initial approval of a given regimen has a certain PFS benefit.

And then as you look at what happens over time as more trials are done with that, it improves. And we suspect that, that might be the case here because what we're using for the design of OPERA-02, which is a 1,000-patient trial now, 500 per arm. It's a 1:1 randomization. And again, that's with KISQALI. Letrozole is the control arm. Palazestrant is the treatment arm. We had always suspected that the control arm might outperform the 24, 25 months that was historical. And persevERA suggests that, that is the case.

In the overall population, the median PFS in the control arm, which this again is -- that's not KISQALI, it's IBRANCE. But for PFS, they were similar. It's 28 months. So that's 3 months longer. But actually, remember, they made a mistake. They enrolled endocrine-resistant patients, patients who had progressed within 1 year of completing adjuvant. Those patients did very poorly. So if you exclude those patients, it's actually 33 months. So it's almost 5 months longer than I'm sorry -- 31 months. So it's almost 5 months longer than the historical. And so we may have to revise our statistical assumptions. What can you do about that?

So what it does is, obviously, you're doing a hazard rate. The way you design a trial is you have, "Hey, what's my control arm going to do? How much delta do I need to show to be clinically significant?" And you calculate out a hazard ratio and you decide how many events you need and then how many patients you need at risk and what will the timing be? So the only variable we really can control right now is patients, number of patients. And so we may increase the size of the trial.

Now what would be great, persevERA is informative. It tells us 2 things. One, maybe the control arm is doing better than it did historically, not a big surprise. It's not a ridiculous amount, but it is significant. Two, don't enroll the endocrine-resistant patients.

And you're not.

We don't. Nobody does. SERENA-4 doesn't either, and AstraZeneca rightly has made this significant point about one of the differences in their trial. OPERA-02 never enrolled them.

But for persevERA, they erroneously enrolled some of these endocrine resistant or they slipped into the study or they just -- they weren't careful enough?

They did it on purpose.

They did this on purpose.

Initially, right? Because if you go back and look at the history of it, they allowed these patients on. It is not done. None of the MONALEESA, MONARCH, if you look at the pivotal trials for the CDK4/6s, they didn't do that. To your point, SERENA-4 does not do that. OPERA-02 does not do that. They did this on their first amendment, they stopped. So clearly, at some point, somebody decided, wait a minute, we don't want to be doing this through this trial. And so they then removed the eligibility of those patients progressing who are endocrine-resistant and went to the more traditional. But at this point, they already had 10% of the total. And those patients did very poorly on the trial. There -- overall data that you saw there was 28 months in the control arm letrozole, 33 months in the giredestrant arm. So a clear signal, though it did not achieve statistical significance.

Interestingly, in that group of patients, about 100 who had treatment-free interval less than a year, they did poorly on the control arm. It was 19 months instead of the 28. But even more poorly on the giredestrant arm, 14 months versus what was 33 in the overall population. And so even though it's only 10%, it can hurt you. We didn't do that.

And I think the other thing we learned is maybe there's this outperformance of the control arm. So why haven't we changed the trial and told everyone what we're doing? Well, SERENA-4 has the same control arm basically. It's palbo plus AI. And it would be great to have 2 things. One, 2 data sets, right? It just helps you refine what's really happening here. The second thing is as we've discussed, the SERENA-4 population is the OPERA-02 population. So it's a more relevant trial to learn from.

Okay. So we're going to get that relatively soon.

We have to as it is what they communicate. So I...

And so you'll see that and then you'll assess the situation.

With both data sets, we'll be able to take a look. And this is part of the reason we aren't communicating. I mean OPERA-02 is enrolling brilliantly, but we aren't communicating a time line for readout yet because you don't communicate it if you think there's a reasonably high likelihood you're going to change the trial.

Yes. Okay. So then speaking about probabilities of success, I mean, persevERA 0.89, as you say, it had an effect, but it didn't make it statistically. SERENA-4, we'll see what happens. We've made the argument in our research that palbo has got some potential advantages, obviously, on PK/PD in terms of exposure and mechanism. So if SERENA-4 hits, then talk about how you think about the probabilities of OPERA-02. If you need to up -- raise the power, you raise the power. If not, you don't. But how would you think about the likelihood of the frontline trial working?

Yes. So first of all, we have quite great confidence in OPERA-02. That confidence is based on -- this is a fairly obvious thing to state, but I must say that people and investors in particular, do get a little lost here. The best way to predict the future outcome of a drug or a combination is to look at its past performance in the clinic. So when we did the ribo-palazestrant combo in Phase II, those were patients who had progressed on prior CDK4/6. So they got CDK4/6 plus AI. They're now getting a second CDK4/6 now plus palazestrant. Actually, about 30% of the patients had had 2 prior AIs. So they would have had fulvestrant -- 2 prior CDK 4/6s. So they would have had fulvestrant probably as well. And we got a median PFS in that population of over a year, which is pretty extraordinary. That's not been seen before. CDK4/6 after CDK4/6 doesn't work very well in general. So that's what gives us confidence in the OPERA-02 trial.

Now that said, if you have an agent which we think is inferior in camizestrant and yet it is able to beat the AI in this context, I think your probability of success has to go up for OPERA-02. I think the other aspect that is really important to us is differentiation. Obviously, one great way to differentiate is to prolong stability of disease longer.

The other thing that's really important is that had persevERA been positive, if SERENA-4 is positive, which we hope it is, there is still a challenge, which is doctors and patients don't want to take IBRANCE anymore, right? They get a survival benefit from KISQALI. So we are the only company doing a trial with a next-generation endocrine agent, a CERAN, in endocrine-sensitive patients with KISQALI. And that is the standard of care. So should OPERA-02 read out positive, doctors and patients don't have to sit there and try to make this choice. They just give the CDK4/6 they want to give and substitute in the end.

Okay. And then -- okay. And then the other bigger...

And that's, I should say, a $10 billion a year plus.

And then back when lidERA worked last year, everyone got very excited about you guys in adjuvant, right? Stock was up crazy, 200% or something.

That's not crazy. It was appropriately valued.

So is that -- where does the -- that's like obviously a big and very expensive study. So that...

That's our biggest -- to be perfectly honest, those attributes, size and cost. Size less so. We -- once you're doing a trial, once you're at 1,000 patients, 1,400, going to 6 or 7 isn't that big a deal actually, the cost, right? So if you think about this, this is -- in order to get the events, you're going to do this in at least a moderate to high-risk adjuvant setting. Well, the standard of care in that patient population right now is really CDK4/6 plus AI. It's Verzenio or it's KISQALI, both of which have labels in that adjuvant setting.

What that means is you are giving that CDK4/6 for 2 or 3 years, depending upon which one you use, to every patient on that 4,000 or 5,000 patient trial. You need well over $1 billion to do this, a large proportion of which is drug cost. And we don't have it. So we anticipate that when we get to the collaborator discussion thing that, that will probably be a topic people want to talk about.

The lidERA data is impressive. It really is an excellent treatment benefit. It looks like it's better tolerated than AI, too, which is really attractive in the adjuvant setting. The challenge with lidERA, and it was -- I did my little bashing of persevERA. The challenge with lidERA is it was designed appropriately when it was designed. Doing monotherapy AI versus monotherapy giredestrant was appropriate at that time. The problem is that for most of the population in the trial, the standard of care has moved to CDK4/6. And then what do you do? How do you decide that? Roche, to their credit, has said we're going to go run a CDK4/6 adjuvant trial, which is absolutely the right thing to do. It's just going to take a long time.

Okay. All right. Well, let's -- we've got to speed up here and cover some other territory because you have other programs. So can we try to rapidly summarize where you are with the 3136, the KAT6 inhibitor? What -- you had some data. I was at the poster at ASCO.

In June. Yes.

Right. So yes, just sort of summarize where we are with that one.

Yes. That molecule is -- we haven't selected a dose yet. So it's kind of continuing in Phase I. We just -- we don't have a maximum tolerated dose. We don't have dose-limiting toxicities. But we hope to get that resolved in the not-too-distant future. We have already started the combinations in breast cancer. So fulvestrant and palazestrant, both at full dose of the endocrine agents are currently dose escalating 3136 in there. Preclinical data suggests that palazestrant should differentiate there. So we're very excited about that data. Fulvestrant is a little ahead because, obviously, it's a well-established approved agent. So we had to do a little more safety running with palazestrant, but that's progressing nicely.

The other thing that we saw that was really interesting in the monotherapy data we presented at ASCO was monotherapy activity in castration-resistant prostate cancer. This was also tested by Pfizer with their molecule, and they didn't see a signal. So we -- in Q4, we -- around ASCO, we announced a collaboration with Bayer. They're providing darolutamide, NUBEQA. We're going to start our prostate cancer cohort with darolutamide in Q4. So we're now doing breast and prostate. We will have an update on the combination data certainly in the first half of next year. There is some possibility, depending upon what we see, that we might be able to get one in there by the end of this year, but we don't know yet.

Remind us, you picked daro versus apa. Is there...

Yes. So there are 2 factors that went into that. We did talk to both parties. One -- we did 2 things. So our internal team did an assessment. One was talking to the prostate cancer experts. And patients prefer NUBEQA. It's better tolerated. It has less potential serious side effects. The other thing that we noted in looking through the profiles, through drugs is that pharmacologically, NUBEQA is cleaner. So we didn't identify any real liability we were worried about, but we thought, look, hey, better tolerability and cleaner pharmacological profile, this is the one to go with. And obviously, Bayer was interested in the data we were generating. So that is helpful as well.

Okay. One last question on AI, and I don't mean aromatase inhibitor, I mean artificial intelligence. The one company where we have to make that clarification. Yes, just can you briefly -- we're asking all the companies this, are you -- to what extent is AI featuring in your workflow internally in terms of data analysis, looking through the literature, preparing materials for the FDA, et cetera?

Yes. You're hitting on where it really is useful. We have a collaboration with the Bay Area company called Collate. And what we found is that the part of AI that really works well for us is not trying to find some biological association or discover a drug, but actually analyzing these complex data sets and synthesizing and simplifying. So there are 2 things. One is what we used to do when we were doing a global trial is we would say, we have to make an amendment or do the trial and we would have the thing translate it. We would spend hundreds of thousands of dollars and wait a month, and we would get back all the verified translations, then we'd be able to send it to the sites. This is done automatically now. It takes like hours. And it's verified and it's fantastic, and it doesn't cost us anything.

The other thing is we do anticipate in the data analysis, not so much the analysis, but the assembly of the package for the regulatory filing that we will use it to help us put those things together. You still have to review it. And by the way, the regulatory agencies want to know exactly what you did because they don't want a filing that's just done by AI. They want the sponsor to really review the data. So I think it's going to be a great assistant, but we still have to review it.

Are there specific platforms or modules that you use? There's Copilot, there's Gemini, there's a whole bunch of different ones or that's...

No. We do -- we have a licensed version of ChatGPT that we kind of -- the company knows how to use and can use for their everyday work. But really, when you're dealing with highly regulated, controlled documents like clinical trial protocols, consents, data that comes from the trial, we have to have a verified system, and that's the one we use is this from this company.

Okay. Very good. Last question, just catalysts. I know, of course, the big -- the readout in 1Q on OPERA-01, but anything that...

SERENA-4 is a catalyst.

And SERENA-4, of course.

We've got to say that. Love it to be positive, make my life easier. Then OPERA-01 in Q1. I do think KAT6 as we start to generate more combo data is definitely a catalyst. That, again, is a $5 billion-plus market opportunity just in breast cancer. Prostate cancer, we haven't forecast it yet. We're still working on it. We know what we want to do in the trial, but we haven't really done a commercial case. We think it will be quite compelling. I think those are really our major catalysts for the near term.

Okay. Awesome. Well, great. Thank you very, very much.

Thank you, Yigal. Pleasure. Thank you all.

All right. Let's kick off the next session. Good afternoon, everyone. It is my pleasure to be hosting Olema Oncology and Sean Bohen, CEO of the company. Sean, welcome.

Thank you, Rich.

Glad to be hosting you for another year at the GS Conference. Before I -- we have a lot to talk about. There's a lot going on, a lot of stuff coming out later on this year as well. Before we go there, I'm going to turn it to you for opening remarks.

Great. Thank you, Rich. Well, thanks, everyone, for your interest. Just reminding you, Olema is a company focused on changing the treatment paradigm for ER-positive/HER2-negative breast cancer. This is the most common malignancy in women. It's the second most common cause of cancer death and ER-positive/HER2-negative 70% of it.

And we have 2 clinical stage assets. The first is palazestrant, which is in 2 Phase, three programs ongoing. The first readout, as we will talk about, to be in the fall from OPERA-01 or monotherapy. And then we recently presented data on our KAT6/7 inhibitor at ASCO showing monotherapy activity, both in ER-positive/HER2-negative breast and also castration-resistant prostate cancer. And the combinations are ongoing for breast and to be started for prostate cancer with that molecule.

Great. And can you remind us of the cash position you guys have, the runway guidance and what does it include that not include?

Yes. So at the end of Q1, we had about $505 million, just a little worth of $0.5 billion on our balance sheet. That will take us nicely into the second half of 2028. And that is with the execution of OPERA-01, continued execution of OPERA-02, our first-line trial with Kisqali in breast cancer, certainly the remainder of the Phase I/II for OP-3136 and also our efforts to file assuming OPERA-01 is positive on palazestrant, but also to start commercialization.

I see. Okay. Fantastic. Do you guys -- let's kick it off with the KAT6, because you guys presented that data at ASCO. So what are the key highlights there?

The key highlight here, this is so I should first set context, this is monotherapy dose escalation data with the molecule. This is an oral daily pill for inhibition of KAT6. The trial allowed 3 histologies, that allowed ER-positive/HER2-negative breast, where KAT6 is validated target. It allowed castration-resistant prostate cancer and non-small cell lung cancer, based on our preclinical data. With non-small cell lung cancer, we had only one patient, so not really much data there. But we saw single-agent antitumor activity in ER-positive/HER2-negative breast cancer and in castration-resistant prostate cancer.

In addition, PK supporting that once-daily dosing with about 12-hour half-life and very good exposures, good pharmacodynamic markers even at the lowest dose and clinical activity across a variety of doses. We also saw what we think is more favorable tolerability. There was Grade 1 and less so Grade 2 dysgeusia, the taste alteration that is a class effect. But we saw less cytopenias than at a similar phase what Pfizer saw. So in breast cancer, we saw 22% Grade 3 neutropenia, which is about half of what Pfizer saw. So we are hopeful that, that will carry through as we get into the combinations. The fulvestrant and the palazestrant combos are ongoing. We did not present any data. And we recently signed a supply agreement in collaboration with Bayer to combine with their androgen receptor inhibitor, NUBEQA.

Right. So when we look at the data, like you said, it's monotherapy only, there's no combo data yet.

Yes.

That's going to come potentially later on this year or...

The optimistic as we might be able to have some, particularly from fulvestrant. Fulvestrant is only one dose level behind monotherapy by the end of the year, certainly first half of next year.

Okay. So given that we only see the monotherapy.

That's right.

And then I think for Pfizer, we've seen their monotherapy data. We see some combination data.

Yes.

But it's hard to kind of compare the monotherapy data set, because it's hard to know what the follow-up period is when you look it.

Yes.

I mean, is that a fair statement?

Yes.

It's still too early to know how like from a safety perspective. But we have seen from the Pfizer's KAT6 program that they have the data -- the combination data, I think they have like with fulvestrant with the 2 different dose levels. And we have seen what that looks like from a grade 3 neutropenia perspective. So really to compare -- you have to really compare the combination, right, because of the more -- you know the follow-up period versus monotherapy. Is that a fair statement?

Well, you could. The thing is that for the tolerability, follow-up period is less important because this neutropenia shows up very early in the treatment. Certainly, for the response, it's important that there's not as much follow-up because this is primarily a cytostatic, not a cytotoxic mechanism. And so it does sometimes take -- we saw it in our data set, but certainly, Pfizer saw that patients responded over time. And so more follow-up can be useful.

But I think that we have less, neutropenia is probably pretty certain. We also don't see dose dependence of neutropenia. They did see dose dependence of neutropenia. So I think by dialing out KAT5 and 8, we may have created a different tolerability profile. I do think that for response rate and certainly response in combination, which we haven't shown any combination data, that's the really relevant efficacy marker. It does require more follow-up.

Right. Okay. Got it. And also, like does it make sense to think about the KAT6? I know the combination is just a KAT 6 plus Pala or fulvestrant. Does it make sense to do -- to think about a KAT6 plus Pala plus CDK4/6 in that setting. Or am I jumping the gun?

Yes. No, you're not jumping the gun. I think we do need more tolerability data. The reason I say you're not jumping the gun it's actually written into the protocol. So we've that option already. So yes. So it's not to bring up something that we had anticipated. With the dependency as everyone knows, CDK4/6 inhibitors are primary AE is neutropenia. And so the question was, will we have a low enough neutropenia rate in the breast cancer patients that we thought we might be able to bring that in. I think we're still evaluating that, but the initial data suggests it may be a possibility.

Right, right. Because that -- I mean, when we first looked at Pala, Pala has higher neutropenia than other SERDs. But when you combine it, you don't see that additive effect. That's an interesting observation.

It's exactly right. So we've a kind of mid-single-digit rate of neutropenia. Most patients with a pause are able to continue on the therapy, sometimes at a lower dose. But I think the big concern that primarily investors had, well, when you combine with CDK4/6 is, are you going to exacerbate this thing? And remember, our first CDK4/6 we combined with is the one that causes the most, which is palbociclib (IBRANCE). And there was no enhancement we've seen that as well.

So that was interesting. So I've an idea. I've been thinking about this even before ASCO and can't wait to ask you this. Have you thought about the possibility of going to like the first line with just KAT6 and Pala and just get CDK4/6 altogether? Because in case there is an overlapping toxicity between KAT6 and CDK4/6, why not -- I mean, why not just go KAT6 and Pala? Do you have to have CDK4/6?

I don't want to -- I'm thinking from a regulatory standpoint. I won't do that right now. Let's just think about it from an efficacy standpoint. I think if the Pala combo data, which initially will be in post-CDK4/6 treated patients, okay, obviously. If that really is compelling, then I think it does raise the question, could you use that combination in the first-line setting. Now obviously, if you can, then you have the opportunity for a triplet. And I think that's a pretty straightforward thing, if the tolerability is adequate. It has to be...

If not?

Yes. If not, I think it depends upon the efficacy we see in that post-CDK4/6 setting. And then I do think we've to think about what would be the regulatory pathway because we won't have OPERA-02 data yet, if we were to do that. So I'd have to think about the regulatory pathway.

Right. And it would be 2 novel agents.

That's what I'm worried about. That's exactly.

But then by the time you would kick that study off, Pala would have been approved.

Potentially by OPERA-01 in the second or third line setting.

Yes. Yes. Okay. And you also showed KAT6 in that NSCLC and CRPC. What's the development plan now looking at like these 2 new areas? You guys have been traditionally focused on breast cancer now. Is there an expansion into these other areas?

There is. We've always said that we will not develop an agent unless it has an indication of breast cancer, ER-positive/HER2-negative breast cancer. And that certainly is the case with KAT6. But we've also said that, that's not how cancer works. Cancer pathways -- the signaling pathways that contribute to evolution of cancer are often used in multiple cancer types. And that's the case here for KAT6. And so preclinical data said castration-resistant prostate and non-small cell lung. We only got one lung cancer patient. So we really don't very much to say that.

We got 10 prostate cancer patients, most of whom were treated with prior chemo and/or prior radioimmunotherapy, and we saw clear antitumor activity. So our next step there is to expand in Phase Ib2 with NUBEQA in the castration-resistant prostate setting. And I think it's that signal that will tell us where to go. For lung cancer, we have to think about whether we want to try to expand there. There was also great preclinical data in ovarian cancer and the standard of care is very complicated. But now that we have a path forward in other histologies, it might be worthwhile.

Okay. Got it. And how is the OPERA-01, OPERA-02 trials going? Remind us when should we see data? I know you said fall or early fall, late fall. Like how do you -- how should we think about it? And also for OPERA-01, what data will you present? Like what -- is there any of this data that you think is mature enough to present?

Yes. So the OPERA-01 is going very well. It's certainly on target, and we're reiterating the top line data in the fall. I anticipate that, that will be a top line press release, right, sort of it hit. It didn't. I don't -- beyond that, it depends on -- you don't want to ruin the embargo for a scientific meaning. So we'll see -- we'll try and get as much out there. No, no, no, no. We'll wait for a scientific meaning. But certainly, positive, negative based on hazard ratio. Can we add a little more color? We'll have to see what precedents are and where we think we might present.

Or will you show the mutant or the wild-type?

We will, because the reason that we will do that is because the way that the trial is written, those are analyzed independently. So you're right. It's kind of 2 top line announcements. Mutant hit or didn't hit. Wild-type hit or didn't hit. Yes. So that most definitely will be in there. And obviously, this's highly material to Olema. So we would do the analysis, make sure we get our conclusions right, but then that's the kind of thing we would announce publicly. The details, one would expect will come at a subsequent scientific medical meeting.

I see. Okay. So let's go to some of the readout.

In fall. Fall was the you asked -- I wanted to make sure -- we're still reiterating not yet. Maybe in sometime in Q3, later in Q3, we'll be able to refine a little bit for everybody.

I see okay. So I guess you're still waiting for like these events to play out.

It's event-driven, right? So obviously, enrollment is important, but really, we're not so much worried about enrollment, but that the event rate gives us the number of events required to trigger the statistical analysis. And so we need to have a little more observation time to get a sense of when that might occur.

I see, okay. So let's go to some of the ASCO redo. There's a lot of redo there, a lot of very exciting year for breast cancer. So I think the 2 very relevant presentations there were persevERA and VIKTORIA-1. Let's just go do the VIKTORIA-1 first. We have a lot -- we'll say persevERA a little later. So the redo there, they have Celcuity, they have data being developed in that sort of a second-line setting in both the PIK3 mutant and then the wild-type, and we saw the mutant at ASCO. How do you think about that just given the data that you saw now in that mutant group? How do you think that strategy -- I mean, that regimen is going to change that second-line setting? You guys have the OPERA-01, which is also going to be a monotherapy agent. How would all that change?

Right. So I don't think it changes it much. So let's just talk about the standard of care right now. Obviously, the first line is pretty well set. It's Ribo unless you're one of the few patients in whom it's contraindicated plus AI. That's the gold standard. And obviously, we're trying to displace the AI of that in OPERA-02. After you've progressed on that regimen, assuming you do, then it gets more interesting because it's a selection of different targeted therapies or with endocrine therapy or endocrine therapy alone, right? So endocrine therapy alone is OPERA-01. VIKTORIA is targeted therapy plus endocrine therapy. But in that case, the most recent one was with PI3 kinase mutated.

So some of it is dictated by mutational status of the tumor. In other cases, it's really just other factors like comorbidities and will the patients tolerate a more intensive regimen. Now the objective is very simple. However you order these things, you want to put off chemotherapy as long as you can. So there are usually multiple targeted agents given in that line of therapy. So really, what order it's a physician and patient preference. The VIKTORIA data where that fits in is it would potentially give another option for the PI3 kinase mutated patients to consider now. Right now, obviously, there's alpelisib, which is the oldest. But right now, what we hear is more patients get palbociclib, because the diarrhea, which is the main side effect of that's easier to manage and tolerate than the hyperglycemia and the rash that comes with alpelisib.

So the question is, are physicians and patients wanting to get a weekly IV regimen. The fulvestrant is the same. So I don't think that's really different versus a daily oral regimen. And I think that -- I think patients like oral. From the standpoint of sort of competitive space, if the geda regimen becomes really prevalent, then it doesn't actually compete with palazestrant, but it becomes another targeted agent with which we could combine, because it's given right now with fulvestrant, but it would be -- it's always preferred to have a more active agent and to not have those injections.

Right, right. I mean with that said, I mean, geda is being studied in that VIKTORIA-2 trial in that first-line setting and also could challenge the standard of care there. How do you think about sort of that regimen moving up as a triplet in that setting? And then also, does it make sense for Pala 2, I think you mentioned potentially combining with geda. Does it make sense to start exploring those -- that opportunity?

I mean I think you'd rather see what happens in terms of practice patterns to say what's exploring the opportunity. I would say in the first-line setting, I don't think the stomatitis, the mouthwash and the IV infusions are going to be viewed as very attractive compared to what is considered a relatively easy to take well-tolerated CDK4/6 plus AI or potentially something like palazestrant. But again, remember, in either case, you're talking about 2 oral daily medications with the CDK4/6 and the endocrine agent, be it AI or for instance, palazestrant or if camizestrant is successful, SERENA-4 is another one that's out there playing. So I just don't think IV in that setting is really going to be very attractive.

I see. Is it just the IV? Or is it like a triplet just not...

I don't think -- I think of a triplet where if the quality of life were -- and IV here is a quality of life issue as is the stomatitis. I think if it well tolerated and it didn't disrupt life like IV daily, I think more efficacy will be attractive to patients to have a triplet. On the other hand, I do think that there are liabilities that are quite over.

Got it. Okay. You guys presented the Phase II Pala/Ribo study a year ago, and it showed very impressive 14 months in all patients and 13 months in patients after CDK4/6 use. So these were, to me, like they look very competitive compared to what VIKTORIA showed either with the wild-type or the mutant population. So why not just given that, why not do a Phase III combination with Ribo in the second-line setting? That way, like you don't have to worry about ESR1 mutant or wild-type. I mean just is it going to be all covers?

No, it's a very good point. So I'll explain it in 2 ways. I certainly agree with you that the data is very compelling, and it was a compelling in the mutant and the wild-type subsets. Here's the thing -- and we know for instance, that prescribers gave CDK4/6 after CDK4/6, that's a common existing practice pattern. Now it's done with fulvestrant, but Pala has -- certainly, if it has more efficacy, but also then it has the daily oral convenience.

The one thing they don't like to do is they like to switch the CDK4/6. And so while that data is compelling and some of it is post Ribo, patients and oncologists tend to like to switch the CDK4/6 if they've progressed on it. And almost all patients are getting Ribo now in the first line, right? So Ribo after Ribo is less attractive. So I think we're thinking about do we want to do a combination in the second and third-line setting? And if so, it's probably not ribociclib because of the first line.

You leave it up for physician choice.

There are multiple ways to do it. The thing right now where we are it's probably useful to see how OPERA-01 reads out. It's not that far off.

Right. I see. Okay. So sort of let that lead the way in terms of the fulvestrant.

Yes. And then if we get the wild-type there, that sets obviously a very different situation. It's very differentiated. And then I think we can sit down with a different -- with a more full picture in mind about what do we want to achieve with combination in that setting. It is absolutely true that there are physicians and patients who say, "Geez, I don't want -- I'm not ready to take just a monotherapy now. I want to get a targeted agent. Do I want to get the most active things I can. And so you want to be able to provide both.

Right, right. Okay. So let's move on to persevERA. That's another big trial, a lot of redo from that. So me and you discussed this trial many times well ahead of ASCO. And I was fairly bearish about how this trial would read out. On day 1 when lidERA read out, I was -- we put a notes saying that I see high risk for persevERA. So we finally saw the full presentation at ASCO. What is your overall impression? And is there any concern to OPERA-02?

Yes. So my overall the trial was negative. That's absolutely true. In terms of its hazard ratio of 0.89 did not achieve statistical significance. On the other hand, there's very clear evidence of activity. In other words, the underlying hypothesis of these first-line therapies, persevERA, but also OPERA-02 is that aromatase inhibitors are not completely suppressing the growth and proliferation signal from the estrogen receptor and that you can do better by hitting the receptor harder with a complete antagonist and ideally by doing that with a higher exposure where you completely shut off the receptor all the time.

I believe that giredestrant lower exposure probably was a liability there. But even so, they had 5 months delta in median PFS. That's meaningful. It didn't hit statistical significance, but it's meaningful. And so I think where we have better Phase II data than giredestrant had, it really reads through nicely to OPERA-02. My opinion, it increases the probability of success of OPERA-02.

Now on the other hand, you asked about things to learn or concerns. One thing that happened in persevERA that I think is hard for me to understand, but I think it was definitely a liability was they enrolled 10% of their patients were endocrine-resistant patients. And those patients didn't do well. And I think they would have deleted -- I'm sorry, diluted the treatment effect in the endocrine-sensitive patient population. Now we don't enroll any of those patients in OPERA-02. I should say SERENA-4 doesn't either. So I think that's one thing we suspected you shouldn't do, but now it's confirmed. Now we didn't do it.

There's another thing that's interesting to watch, which is that the control arm, palbo plus AI outperformed historical a bit by about 3 months. That's normal in oncology. Over time, a regimen often gets better. Oncologists get better at giving these medications. I think we will want to look at that and ask ourselves, do we want to make any changes to OPERA-02 going forward. Now we won't -- if SERENA-4 stays on time in the second half of 2026, we'll wait for that because then we'll have 2 data sets, and that's fine. But if that gets pushed out, we might not be able to.

I see. Okay. Yes. So I think when we also looked at that trial, besides the PFS sort of missing with that hazard ratio of 0.89 that you mentioned and then the p-value being 0.156. I think the ORR, CR, PR, SD, CBR were basically identical between the treatment arm and the control arm. So I agree with you, there's a 5-month improvement. And I think in the past, you guys called out that 6 months would be static. And then you look at the Roche's plan that stats plan where they were powered to like 89% to show hazard ratio of 0.77, but then they set the threshold -- the boundary for success at 0.85. I mean, do you agree with that statical plan to begin with? Maybe I just wanted to just ask you that. And what is sort of your hazard ratio and powering assumption for OPERA-02.

Yes. So we haven't discussed our plan for OPERA-02. The biggest reason for not discussing the plan is because if we see data from SERENA-4, we've already seen persevERA, we may change it. So you don't go out and say something and then go change it. But we do -- so 6 months is a slam dunk, right? It will change the practice pattern. Five months, if you were statistically significant, would be -- if you go ask the investigators, the breast cancer docs, they'll say, okay, 6 months, if we see that, we change our practice pattern 5 months. Yes, that would be good, too. You get down to 4, they start saying, well, tolerability. So definitely, 6 months is clear.

I go back to this plan. I really wonder -- and we can't do it, but Roche's could do it. They could remove those patients who were endocrine resistant and say, what does the curve look like? And I think it would separate earlier. The separation was then maintained. So I really think that it's not necessarily the stats plan that I wonder about that trial. It's the inclusion criteria in the patients they studied. I think that trial design might have been perfectly fine, if you didn't put on endocrine-resistant patients.

I see. Yes, it's hard to tell because they never -- we didn't see...

Well, yes, they get 12 minutes. So maybe down the road, we will see it. But now, we haven't seen that so far. You're right.

Yes, exactly. So you mentioned about that control arm being a little higher than sort of -- it was basically the same. I think same with that MONARCH 3, about 28 months. I think it was higher than the PALOMA-2...

Yes, by about 3 months.

By about 3 months. Exactly. So -- but when you think about sort of if the control arm is now, I think like what you said with the modern-day treatment, better care that you're now going to see more of that higher or higher end of that range. Do you believe that now you need more than 6 months to be static just because the control arm is stronger?

No, it's not the more than 6 months. It's just that you change your statistical assumptions around how many events you need, right? And so -- and obviously, when you're doing something like that, you only want to do it once, if you're going to do it, and you want to be as well informed as you possibly can be. So if there's a second trial that you can get, that would be huge.

But what you do is you just go through and you calculate, okay, here's the irony, right? Hazard ratio is how the primary endpoint is done. Hazard ratio is how the trial stats plan is designed. Decisions about treatment are made by delta and medians. So you are kind of extrapolating from the one to the other. And what you do is you just take the delta you're shooting for, you take what hazard ratio you get and then you decide how many patients do I need, how many events do I need? How long do I have to wait? And those would be the calculations.

I see okay. Okay. Got it. So I think you mentioned in the past that after looking at persevERA, you may go back and change the size of the study. Is that still on the table that you guys are evaluating on the side? Okay. So based on that, how -- I mean...

We'd like to have SERENA-4 though to complete that evaluation.

We should just wait for that. You're not.

Yes, yes. No, you don't do these kinds of things twice. In particular, if -- again, if -- and I'd just take them at their word, if AstraZeneca is able to stick to their time line of half 2, we have time to use both.

Because SERENA-4 is a larger study, so you kind of see that.

It's a larger study, which we like, but the point is that the patient population is more appropriate to OPERA-02, because like OPERA-02, SERENA-4 does not allow any endocrine resistant patients on the trial.

Right. Okay. Got it. So now given that higher performance of that, that placebo arm into the better care out there. How would increasing the size would help mitigate some of this risk?

Yes, it does 2 things, right, which is a 6-month delta on top of a 25-month control arm and a 6-month delta on top of a 28-month control arm have slightly different hazard ratios. So that's the first thing you do is you want to say what hazard ratio am I trying to detect in order to see my clinically significant benefit. So that obviously changes the stats plan, right, because that's your primary endpoint.

The second thing it does is it changes the time, changes how long you need to wait to get the events you need. First of all, your event rate is slower because you're control arm has got a longer median. But then as well, you're kicking out what 6 months is. And so there's another calculation, which is how long does it take for the trial to mature. There are 2 ways to get those events, right? Wait longer or have more patients at risk. That is to say more patients treated. And so you put both of those factors into the calculation.

I see. Okay. Got it.

And then you go to regulators, then you go to the steering committee and it's a real process.

Right. So now you look at the persevERA trial, I think you pointed out that 10% patient progress, right. So there's other stuff to it, too. I think the de novo disease and then there's higher an alpha-2 -- how is it designed differently that you think? And what are other ways that you believe besides that 10%?

That's the main thing, actually. I don't know why they can't de novo disease. That's interesting. So it was a bit lower than you would see. I don't know why they had more visceral disease. I didn't see anything that Roche's did in its design or execution that would cause that to happen. They stratified for them. Yes. I don't know. It was -- you're right, it was a bit on the high side. So again, these are aspects that I think with 2 data sets are kind of things you look at and say, are we seeing a change in who gets enrolled in these trials? Or is this an outlier versus what other trials obtained.

I see. So SERENA-4 will be reading out probably could be around the same time frame as OPERA-01.

Could be.

How do you -- is there any reason to believe that trial could succeed? And then if it doesn't succeed, what does it mean for you guys?

Yes. I think -- so first of all, it doesn't succeed, it really doesn't mean anything for us. The control arm will still be interpretable. It's palbo plus AI and Letrozole in that case. Secondly, look, OPERA-02, and you mentioned the data already, the long period of progression-free survival post CDK4/6 with ribociclib and palazestrant. Our trial is based on our data. And our data uncontrolled Phase II looks better than the others have. And so I think it doesn't change our view of OPERA-02.

In fact, as I said, persevERA gives us higher confidence because of the level of benefit they did see without demonstrating statistical significance. Your question was, could SERENA-4 be positive? It's interesting. I think if SERENA-4 without the endocrine-resistant patients with the higher end with the same level of benefit maybe could be positive actually. The concern I have is that camizestrant has the lowest exposure of all of these agents, because of the tolerability profile. Is that enough or is it not? The...

I see. Any learning from SERENA-6, because that was -- there was an updated presentation at ASCO with the updated PFS2. Is there anything there that you feel like you can apply to either SERENA-4 or OPERA-02?

Nothing. Nothing. Yes. Yes, the learning is don't do that.

Fair enough. Okay. Let's spend the last 2 minutes on OPERA-01 trials reading out in fall. This's very -- designed very differently from VERITAC-2 in some way, right, even though you guys both follow the EMERALD data. So one big difference is that you guys allow prior fulvestrant and then also adjuvant therapies where VERITAC-2 did not. So as you think about some of these differences that could either benefit or not benefit OPERA-01, how do you think about that compared to VERITAC now after you see that data? Do you think you made the right choice to not allow -- sorry, to allow fulvestrant and also adjuvant use?

I do. And the reason I say that is because I think that more mimics the standard of care. It also -- you're absolutely right that we're different than VERITAC-2. We're much more similar to EMERALD in that respect. So we do have some differences. We didn't allow prior chemotherapy. EMERALD did. We require 6 months on your prior endocrine regimen before you get on the trial, and there was no limitation on that in EMERALD. But we feel like EMERALD was the right trial. It was in this patient population, it was best mimic the practice pattern that we're seeing. Now you control for some of these things, right? You stratify by if they had fulvestrant or not, you do things to make sure you're equally distributed. But we really felt like EMERALD was very informative.

I see. Okay. Final question for you. Your confidence level in that ESR1 wild-type. If you don't succeed, what does it mean for Pala in that second-line setting? What does it mean for OPERA-01? Do you must need it to succeed?

I don't think we need it to succeed. I think that there's a way to differentiate just in the mutant potentially by having more than 2 months extension of PFS, and that would be quite meaningful. It is -- I don't mean to downplay. It is a really meaningful differentiator if we're able to get it. We saw 5.5 months in the wild-type in our Phase II setting. If we can recapitulate that, obviously, uncontrolled error bars, everything. If we can recapitulate that, it should be compelling. And then that gives a group of patients who are currently have an unmet need that's unaddressed a treatment option. The trial is well designed to address that question.

Fantastic. Thank you so much.

Thank you.

Pleasure hosting you. Always an interesting discussion. And I'll turn it to you for final remarks.

It's a busy year for Olema and for this space, and we look forward to our first Phase III trial readout in the fall to updating on KAT6 with combos as soon as we can with palazestrant and fulvestrant. And OPERA-02 is enrolling well. So a great opportunity in the first-line setting, I think, supported by the data we've seen recently.

Great. Thanks so much.

Thank you.

All right. Welcome, everyone, to the next session. This is day 2 of Citi's Virtual Oncology Summit. I'm Yigal Nochomovitz, biotech analyst here at Citi in New York. Remember, if you have questions for our speaker, who is Sean Boone, the CEO of Olema, and we'll start the conversation in a moment. If you have questions for him, just e-mail me, and I will relay them over.

So Sean, thank you so much. Welcome. I appreciate the time. A lot going on in the world of breast cancer, as you know, a lot to discuss. But before we get to all of that stuff, maybe just for those a little bit less familiar with Olema, give us a high-level overview of the company, tell us a little about palazestrant, tell us about the studies you're running. And we'll, of course, get into some of the key debates soon.

Okay. Great. Thank you, Yigal. Thank you for the opportunity to talk about Olema and have this discussion. Olema Oncology is a company focused on improving the standard of care and improving the lives of patients with ER-positive HER2-negative breast cancer. Our lead asset. palazestrant, is a complete estrogen receptor antagonist. It's a once-daily oral pill. And it's in 2 pivotal trials, 2 Phase III trials. The first to read out will be OPERA-01 that will read out in the fall of this year, and that's a monotherapy trial versus fulvestrant or exemestane physician's choice in the second or third-line setting, so meaning after patients have progressed on a CDK4/6 inhibitor plus an endocrine therapy.

The other trial, which is currently enrolling is called OPERA-02, that is a first-line trial. That is ribociclib or Kisqali plus AI versus the experimental arm, which is ribo plus palazestrant. And that trial soonest it can read out is probably '28, maybe more likely 29. We'll have to update as we move along in that trial. We have one other clinical program, which is OP-3136, which is an oral KAT6/7 inhibitor, which is in Phase I and moving into Phase II. It's still in dose escalation as a monotherapy, but it's also being explored in combination with fulvestrant and again, our own endocrine therapy, palazestrant.

Okay. Well, let's talk more about palazestrant and its design and how it's differentiated from the pretty substantial class of these oral SERDs. There are many, as you know, from many from pharma in particular. But palazestrant is different quite arguably. In fact, the KOL comments we have heard yesterday from a prominent breast cancer KOL made reference to some of those differences in terms of better full blockade of the estrogen receptor and other properties of the molecule, other properties of the PK, but I don't want to answer the question. I'll let you answer the question. So tell us about why palazestrant is different and potentially better than, say, a giredestrant or camizestrant.

Yes. Thanks. You were doing great. So I was kind of enjoying that one. I guess I'll do my job. Yes. So palazestrant, the key molecular characteristic to maximize inhibition of the estrogen receptor is complete estrogen receptor antagonism. So just to remind everyone, in the breast tissue, the estrogen receptor is a -- it signals a very complex transcriptional signal, a ligand regulated transcription factor, which promotes the growth and proliferation of breast cells. Now what happens in breast cancer is what happens in many cancers is the cancer co-ops a normal physiological signal to grow inappropriately. So in ER-positive HER2-negative breast cancer, you want to turn that signal off all the time. That is the cornerstone of therapy. So all -- until you get to chemotherapy, which the objective is to put that off as long as possible, you always have an endocrine therapy present. It may be alone, it may be with another targeted therapy, but it's always an endocrine therapy.

The current endocrine therapies do not turn the receptor off completely. Part of that is molecular. Drugs like aromatase inhibitor don't even bind the estrogen receptor. They do not, in fact, inhibit its signaling. They just decrease peripheral estrogen. Others, the SERMs, so drugs like Elacestrant, Vepdegestrant, Lasofoxifene, they aren't complete antagonist. They're partial agonist, partial antagonists. So they turn the receptor down in some situations on in other situations. And so you want a complete estrogen receptor antagonist and drugs like camizestrant, giredestrant, palazestrant are that molecularly.

The other part of that, that's important is you have to have enough drug around all the time to keep the receptor off. So in the wild-type receptor setting, that's to block estrogen binding and signaling in the ESR1 mutant setting, that's just to turn it off because it is a constitutive transcription factor in that setting. So PK becomes extremely important. You want to have a high level of exposure at trough at steady state so that there's plenty of the drug around. And our PK is much better with an 8-day half-life and a very high exposure than the others in the class. So in order to get that, you have to have the pharmacological properties, but you also have tolerability, right? Because to have that much exposure, your drug has to be very clean from a toxicity standpoint.

And then the last part that becomes very important, particularly in a trial like OPERA-02 is to be able to combine at the full dose so that you can maintain that high exposure, that complete antagonism while you're combining with another molecule. And this has again been very challenging within the field. We have not had to dose reduce. Either agent when we combine palazestrant with ribociclib, palbociclib, alpelisib, everolimus. We're doing atirmociclib right now that's in the clinic. We're doing the OP-3136 I mentioned, and that property is unique.

Okay. So then it would be helpful if you could perhaps provide some perspective on what we've seen from the competitive landscape. We've seen that you've been quite active in discussing this in our research as well in terms of what we've seen from Roche with lidERA, what we may see with their frontline study persevERA. I'm just curious what your perspectives are. What -- from your perspective, what do you believe we learned from lidERA in terms of how the complete SERM could be functioning in the ESR1 wild-type setting, which seems to be a new finding and a promising finding potentially? And then, of course, your thoughts about this fairly highly debated persevERA trial, which could, if it does end up working, could be very interesting in terms of thinking about your value proposition, especially given what you just pointed out regarding palazestrant's properties.

Yes. I think you're absolutely right that the evolution of this field over the course of the past even several months has been really interesting to watch. The challenge that people have faced is that they haven't seen randomized controlled trial activity in the ESR1 wild-type setting in the endocrine-resistant patient, right, patients who've progressed on a CDK4/6 plus an endocrine therapy. And I think first of all, the best way to predict how a drug or a combination is going to do in the future is to look at how it's done in the past. So our data is what we think really supports OPERA-01 and OPERA-02, where we have seen evidence of activity in Phase II post CDK4/6 and ESR1 wild type and mutant, both as a monotherapy and in combination with ribociclib. And that is unique. And of course, we'll test it in OPERA-01 as a monotherapy and get the data in the fall.

lidERA threw in a really interesting piece of information that I think we are all struggling a little bit to interpret not in the context of the adjuvant setting because the lidERA result is excellent. it is a compelling demonstration of increased patient benefit of giredestrant at their 30-milligram dose, which is the one they carry through the program versus an AI, right? So one question had always been, well, can this next-generation molecules even beat the AI? I think that's pretty soundly answered at this point. And the answer is yes, and giredestrant has done that in lidERA.

The next part that you get to is, okay, what does that mean for other trials like persevERA? So in oncology, we're very used to going from later lines to earlier lines. So if we have success in a later line, we go to the earlier line and we say, oh, we're likely to have success here. And oftentimes, it's actually greater, right? You get a greater effect if you haven't had so much prior treatment. We're not so good at going from, for instance, a very early line like an adjuvant setting and asking what's going to happen in the metastatic setting, which is persevERA and OPERA-02 and SERENA-4.

So there are a couple of reasons that, that's complicated. One thing that really, I think, bodes well for persevERA from lidERA is that here you are now with this ESR1 wild-type population. And not only that, they're endocrine sensitive in both cases. right? Now the adjuvant, they'll have lower disease burden. You don't have measurable disease when you start adjuvant therapy. Obviously, if you have metastatic disease, you have evaluable disease at that time. The adjuvant is different as well in that the patients are all endocrine naive. That's the first therapy. They've never seen anything before. They're endocrine sensitive in the first-line setting, but they're not endocrine naive often, right? About 70%, 75% of the patients will have had prior adjuvant therapy then gone on to metastatic disease. The other 25% to 30% are the de novo metastatic patients. Their first diagnosis is metastatic disease. And so those are endocrine naive. So we have the situation where we're trying to figure out how to handicap going in that direction. There has to be some positive read-through. From lidERA, I would say, to persevERA in the first-line setting. But the magnitude of it can be a little hard to parse out.

Okay. But presuming we do see a benefit in persevERA, I would think that you would strongly agree that, that would be a very big positive for you in terms of your OPERA-02 frontline trial for palazestrant, would set a good precedent now?

Yes. Well, in comparable -- in data sets where you can kind of compare the patient populations, we have done better than any of the others in combination. So I would definitely say not even if it is positive, it's positive, that's very clear. But I would say even if there's a decent trend toward positivity, even if it misses statistical significance that it bodes very well for us because we pretty consistently, very consistently show superior activity to the others in the class. And that probably has to do with these molecular properties that we described before.

Right. Okay. Well, let's switch over a little bit to the second-line study. So that one is reading out sooner. I think people maybe sometimes forget that although it's a second-line study and there's been a lot of discussion of persevERA in frontline, the second-line market is a pretty substantial market in and of its own right. So can you expand on that? And then just help us understand what you need to show for that OPERA-01 second-line trial to hit?

Yes, right. It is a substantial market and a substantial unmet need, right? So if we just go back and look at the -- again, the treatment paradigm here, the treatment paradigm in this disease is to put up chemotherapy as long as possible, right, delay progression as long as possible with targeted agent. And so the first line of therapy is pretty well established in the metastatic setting. It's Kisqali plus an AI now, right? With trials like OPERA-02, our hope is that, that changes in the future to, Kisqali plus palazestrant. But after you progress on that, then you get a variety of options, some dependent on mutational status, some dependent on the patient's wishes in terms of tolerability and also sometimes comorbidities. So how -- what kinds of therapies will they tolerate well. So monotherapy endocrine therapy is used in that setting quite commonly. That's what we're testing in OPERA-01.

And just to remind people, in that setting, we saw in a second, third-line population that could have had chemo, about 30% did, we saw 7 months overall, 7.3 months in the ESR1 mutant subset, 5.5 in the ESR1 wild type. If you take that whole group of patients, the market size is about $5 billion a year. So as you mentioned, it's sizable. If you get only the ESR1 mutant, it's about $2 billion a year. It's about 40%, maybe a little north of that is the mutant subset. That market is more competitive, right, because we have other agents that have demonstrated activity there, Elacestrant is approved and Imlunestrant is approved. The ESR1 wild-type subset is completely unaddressed at this point. So it is wide open and represents a significant unmet need.

Again, the objective here is this delay of progression and the bar is 2 months increase in median over the standard of care. The standard of fulvestrant or exemestane care is going to be about 2 to 3 months post CDK4/6. So if you get 4 to 5 months, then that supports approval that supports use of the new agent. And so that's what we're shooting for in the context of OPERA-01. Again, in the wild-type, we had 5.5 months in more heavily pretreated patients. You can't have prior chemotherapy in OPERA-01, you're allowed to in our Phase II and also you have to be on your prior endocrine therapy for at least 6 months. So we feel like there's a reasonable likelihood that OPERA-01 will read out positive in both populations.

And talk a bit about the differential scenarios, like is there some sort of a hierarchical the typical way this is done where you have different populations. If you test one and then one works, then you test the other? Or it does it have to be everything? Just walk us through the math on all those things, which everyone loves to hear about.

Yes, they do. And we haven't disclosed the details of our analysis plan other than to state that we are testing mutant and wild-type separately. We don't do an intent to treat where you mix them all together. That has been done several times before. The thing is that when it comes out positive, when you pull the populations out for the other drugs, it's all the mutant that's driving it. So that's why the labels don't reflect that wild-type population. We rather went out and said, no, we're going to test them independently. It's a bit like one trial from the standpoint of operations, right? You enroll it all at once. It's the same sites, you stratify based on mutational status. But it's almost 2 trials from the standpoint of analysis. And so that's the way we've designed it. It allows you to be a bit more explicit with regulators, with investigators about how you're actually designing the trial and what you're looking for.

But as I said, we're expecting readout from that trial in the fall of this year, assuming that there's a positive readout, so 2 versions of that, positive in ESR1 mutant, we have pretty strong confidence in that based on precedent and based on our data with the possibility to differentiate by having a longer PFS than has been seen previously. And then obviously, an extraordinary differentiator being the first to be able to address this ESR1 wild-type population.

Okay. So you're not going to get into details, but it sounds like you're checking both of these populations and one isn't like one isn't necessarily going to be conditioned on winning on one isn't necessarily going to condition you to check the other one. I mean if I'm reading between the lines, that would seem logical.

Yes. Yes, yes. They are tested independently. And the way that the trial is designed is around this, you had asked what is the benefit you're looking to show and be significant. And it's 2 months. Imlunestrant was approved on 1.7 months. That's kind of on the edge. We don't think -- we think if you get below that, it's not a good basis for approval or a change of standard in care. So it's that 2-month delta over the control arm that really is what determines effect size that you're trying to measure for and power for.

So that's coming second half of the year or in the fall? -- fall like what, like October-ish, November? Or how -- what's the time line?

Fall is before December and after August.

Okay. All right. And then the plan there, assuming you hit is you would proceed to launch this product yourself? Would you seek partnership?

So we will file, and we can file ourselves in the U.S. and EU quite easily. We can launch in the United States, and we're building the commercial infrastructure to enable that with launch potentially coming next year. We would not try to market palazestrant in the rest of the world, that it just is -- this is the second, third-line market is something that a medium-sized biotech can take on. Globally, it's not something we can take on. And so we would seek a collaborator for the purposes of the worldwide launch of palazestrant. Now those what the terms of those agreements end up being is obviously a result of negotiation. There's some profit sharing. Is there a co-promote in the United States, that's a negotiation thing, sharing development costs. We would want to book sales in the United States because that preserves upside for our shareholders. But I think that the collaborator is going to be vitally important in order to gain access for all of the patients worldwide to a drug that we think is very promising.

And then you mentioned just quickly going back to OPERA-02, which just so everyone understands OPERA-02 is the first-line trial. You said could slip into 2029? Or that's -- I mean that's projected.

Well, I mean, we don't know. We'll learn a lot more when we see persevERA, right? So yes, first of all, for OPERA-01 and OPERA-02, OPERA-01 is 1 drug, OPERA-02 is 2. It's pretty easy to remember. It is not by line. The -- yes, so I think one of the questions that we have from persevERA, really from a SERENA-4 as well, which is a lot of us are designing our trials based on assumptions around the control arm, right? The control arm is in the case of persevERA and SERENA-4, it's palbociclib plus an AI. For OPERA-02, it's ribociclib plus an AI. From a PFS standpoint, those weren't very different actually. It was OS that really brought Kisqali to the forefront and took years to actually get that to read out. And those were all in the kind of the 2 years in change, let's say, 27, 28 months. But we do have trials subsequently that had quite a bit longer median PFS for that treatment combination, right? So a trial like PARSIFAL, its control arm, palbo plus AI had 32 months, right?

So being able to understand what the modern performance of this combination is, is also going to influence both the trial and the time lines for the trial. For us, it's vitally important because we can actually change OPERA-02. So if our assumptions, if we go back and look at our assumptions and say, oh, we're not as confident as we were because the newer data is suggesting that there's a difference, then we can go back and remodel the trial, remodel the statistical assumptions, decide if we want to change anything, there are really only 2 things you change. You can change the number of patients and you can change time. You're basically looking at how many events you need in the way to alter how many events and when you get them as number of patients or how long you wait.

I mean, yes, we looked -- I mean, you made an excellent point, obviously, about PARSIFAL. We looked at that, too, and it's clearly the outlier with the -- But then the other ones, right, like PALOMA- 2 and MONALEESA...

MONALEESA-2 and...

MONA-3, like they're all in the -- and we did -- in our note, we wrote the other day, like I calculated it out, including PARSIFAL, and it came out to like 27 and change. So it wasn't wildly off.

No. And I think that -- and I think everyone's done that calculation who's designed one of these trials. I will say, however, something -- somebody is making different assumptions, right? Because if you look at the design of the trial. Let's take the 3 trials. let's take persevERA, SERENA-4 and OPERA-02. persevERA and OPERA-02 look very similar. okay? The big difference, right, obviously, is giredestrant versus palazestrant and palbo versus ribo. That's the difference. But if you look at the numbers of patients and the inclusion/exclusion criteria, they're very similar.

So my belief is that assumptions used by Roche are probably pretty similar to the assumptions we used. So there are each about 1,000 patients. SERENA-4 is about 1,400 patients. So it's considerably larger. But again, the control arm is palbo plus AI. It is essentially the same as persevERA. And as you point out, as I said before, for PFS, they weren't really different. So ribo shouldn't necessarily -- in OS, we expect there may be a difference. In PFS, there wasn't really a difference there. So something is going on that people are looking at this differently. It will be very interesting to see what happens.

By the way, one other point I checked was over. I mean, of course, you've heard the comments from Roche that they've driven to ensure an endocrine -- not endocrine naive but endocrine-sensitive population.

That's right.

Just underscore the point for you for your frontline trial that you've driven to do the same.

Yes. The way that looks like, if people love to dig into the details, you can go into the inclusion/exclusion criteria and where that will show up is that, obviously, this is first line. You can't have had any therapy for metastatic breast cancer. And the second place it shows up is that if you had adjuvant therapy, you had to have completed that adjuvant therapy and had a minimum of 1 year post the completion of that therapy without progression. And that's how that endocrine-sensitive selection manifests itself in the trial design.

But I guess therein is the a little bit of the subtlety in the sense that you've made it through 12 months post the adjuvant benefiting from the estrogen sensitivity, but it's -- I guess there's some not complete clarity as to the status of that patient in that point time period afterwards, right?

It's the reason that I say we have a little trouble handicapping in that direction. Right. What we know about the biology is that there's not -- unlike when you progress on the endocrine therapy, right, where you have this high prevalence of ESR1 activating mutations, 40% to 50%, you're still in the low mid-single digits when you go into this first-line metastatic setting. So you don't see this resistance mechanism cropping up. So that suggests that the biology of the tumor remains more of the endocrine sensitive because when you get true endocrine resistance, you see it reflected molecularly. But is there no impact of having seen maybe 5 years of endocrine therapy, that's a tough one.

Well, I'll just -- I'll put in a quick plug for the analysis I did is that in one of the pieces we wrote a couple of weeks ago, I just assumed that I just said, look, assume 15%, 20% of the people in persevERA are endocrine-resistant and just delete them in the sense that they're not going to contribute to power because you're not going to get an AI to work, you're not going to get a SERM to work, it's not going to happen. And so you effectively lower the power, right? And still good, still plenty of cushion. So if you assume those, the 27 months we were talking about earlier and then the 80% 0.8 hazard ratio. But anyway, that's for people to read on their weekends.

Yes, it's an interesting read. It's a complex situation. You parse out the considerations nicely.

Yes. So okay. Let's talk about your other asset, which is the KAT6, OP-3136. That one was -- we actually asked the KOL about that one yesterday. He seemed quite optimistic about that, especially just for the class itself across all the KAT6/7 developers that it's very well combinable to -- with other mechanisms potentially, which is interesting. But tell us about yours and the significance for targeting the domain the subdomains, 6A, 6B 7, why do you need to hit them all? That's clearly an important design feature.

Yes. Yes. I mean I think it's what you hit and what you don't, right, is always the complexity here. I think Pfizer was first. They're in a pivotal trial with their first KAT6 molecule, which hits 5, 6A, B, 7 and 8 at the exposures that they get. And I think in terms of efficacy, consistent with your KOL, in particular, with fulvestrant, it was quite encouraging, right, 38% response rate post CDK4/6. That's in a pivotal trial. In terms of tolerability, not so attractive, right? Quite a bit of cytopenia. The other, it's a bit of a class effect of epigenetic modifiers, but I think the severity might be something we can titrate in and out based on selectivity is dysgeusia, which is a taste alteration, which is a sort of quality of life issue until you find that patients and they did find this with the Pfizer experience, decrease their caloric intake enough to start losing weight. You don't want breast cancer patients losing weight, obviously.

So they did run into tolerability problems at their 5-milligram dose, which is their Phase III dose, they have about 50% dose reductions due to AE, which is quite high. What we're testing is by keeping 6A, B and 7 and dialing out 518, can we get a better tolerability profile, leading then again to better combinability. The other aspect of it is that what we found preclinically was, as is always the case with targeted agents, they have very limited activity on their own. So you add in an endocrine agent. And that was definitely true with the Pfizer KAT6 and fulvestrant. But when you add palazestrant, the combination, it synergizes and is much more effective. And that was true actually preclinically of the Pfizer KAT6 and of LP3136. The thing is that we are able to test it in the clinic, and it's ongoing right now. That will not be in our data set at late in the first half of the year, just so people know that will be mostly monotherapy.

The interesting thing about monotherapy here is that based on our preclinical data, we did see activity in other tumor types. So our monotherapy portion of the trial tests not only ER-positive HER2-negative breast cancer, but castration-resistant prostate cancer and non-small cell lung cancer. So we'll show what we have from the patients that enroll in that monotherapy section. So we are interested in seeing if we can expand beyond breast cancer with that mechanism as well.

And that you said data is coming second half of the year.

No, it will be -- it will probably be late Q2. When we get an abstract accepted to a meeting, we'll communicate with everybody where that will be. We don't have that yet.

Okay. And then what more are you doing in terms of portfolio expansion? Or have you got your plate full with pala and 3136 for the time being?

Well, no, we actually do continue -- we have a research program. We have targets nominated. And we are focused on breast cancer, ER-positive HER2-negative breast cancer. It's a massive indication. And obviously, we are a small company in a place that is mostly a big pharma space. So we think our focus is very important. It's also something we're very good at from the standpoint of understanding the biology through regulatory and clinical execution and hopefully soon commercial. So we do have a pipeline. We don't talk about it much. We'll tend to announce things as they get to the development candidate IND-enabling stage of development.

There was one that was speaking of being nimble and being careful with your cash, which is critical. There was one big topic I kind of crossed over, but it's important is given lidERA, some people are saying you could do an adjuvant study. Now that would be a big check to write, to say the least. But what are your thoughts? Like it's not something that you can't just dismiss out of hand. I mean it could be very valuable potentially.

No, you can't dismiss it out of hand. I agree with that. I agree with that completely. And I think lidERA -- Roche is very clear in their enthusiasm and excitement about it. And I think that's absolutely right. I think it's going to help a lot of patients. It is very exciting for Roche. There are 2 things that I think are important elements here. One is what does the next trial look like? I don't think it's a monotherapy trial. When they started lidERA a long time ago, they were able to do this monotherapy AI versus monotherapy giredestrant. They have a very small expansion with CDK4/6s, which I think is mostly tolerability, which they didn't report on yet. But really, the pivotal trial, the practice-changing part is that monotherapy. I don't think you can do that anymore in the moderate to high-risk adjuvant setting because CDK4/6 is, right, both abemaciclib, verzenio and ribociclib, Kisqali have labels in that space.

So I think going forward, one element is it most likely has to be a CDK4/6 combination trial. And then that really changes both the design characteristics in terms of the numbers of thousands of patients you would need, but also the cost of the trial because you either have to buy or have a source of those CDK4/6 inhibitors.

So when you're talking about -- and it's very interesting. It's a very large opportunity. I think with deeper pockets. It's something we think about on our own going out and implementing a trial that's 5,000 patients and north of $1 billion to run if you're buying the drug, that's out of our reach at the moment. Now for us, with a market cap of around $2 billion and a market potential just with palazestrant of the ongoing trials exceeding $15 billion a year, we're in a good spot. But I think as we start to open up opportunities in terms of collaboration, in terms of being able to launch and turn cash flow positive, I think we do have to go back and very seriously address this question.

I guess to some extent and more than just to some extent, perhaps to a large extent, it will depend on the strength of the treatment effect in persevERA because if that's really big on a CDK4/6 background, that would inform probabilities for an adjuvant trial also on the CDK4/6 background, I would think.

Yes, I think that's right. I mean we've already seen, though, that our -- with ribociclib in combination, right, we got a year post CDK4/6. The bar in the OPERA-02 persevERA setting for a clear win is a 6-month extension of PFS. And again, we went into a situation where you were on the CDK4/6 plus AI, you progressed to the point where the tumors were visible now, right? And then you go back with the CDK4/6 again in the form of ribociclib and you add now palazestrant as the endocrine agent and you get a year in the overall population, 14 -- almost 14 months in the mutant, but nicely over 9 months in the wild type. So I think our ability to demonstrate superiority with that CDK4/6 setting is pretty compelling now.

Very good point. Okay. Well, thank you very, very much, Sean. Excellent discussion. Maybe we'll have you back for a debrief post the persevERA and get your updated thinking on the landscape then. So thank you very, very much.

Yes. Thank you, Yigal, It's a pleasure.

Thank you.

Okay. Great. Thanks, everyone, for continuing to join us. My name is Brad Canino. Happy to be sharing the stage with Sean Bohen from CEO of Olema. Sean, thank you so much for joining us.

Thank you, Brad.

Maybe a quick intro to the company would be helpful. You also did have an executive change recently. So maybe speak on that, and how you're preparing the company for the next stage of its evolution.

Yes. Well, thank you, Brad, and thank you, everyone, for attending. Olema is a company focused on transforming the standard of care for patients with ER-positive, HER2-negative breast cancer. So this is a large unmet need. Breast cancer is the most common cancer diagnosis in women worldwide. It's the second most common cause of cancer death. And ER-positive, HER2-negative is 70% of breast cancers by far the majority.

Our lead program is palazestrant. It's a complete estrogen receptor antagonist. Endocrine therapy is the backbone therapy for ER-positive HER2-negative breast cancer. It's given in every line until you have to give chemotherapy, which is the treatment objective is to put that off as long as possible.

Palazestrant is in 2 Phase III trials, a monotherapy in the second, third-line setting, and that will read out in the fall. That's called OPERA-01 in a combination with ribociclib in the first-line setting. That's the only estrogen endocrine-sensitive first-line trial with ribociclib as the CDK4/6 inhibitor, which is obviously the global standard of care based on survival benefit. And that trial is enrolling right now.

We have a second program, which is a KAT6 inhibitor. It's really a KAT6/7. We dialed out the KAT5 and KAT8 inhibition that are seen with the Pfizer lead compound. And that first data from that molecule will come out late in Q2. That will be mostly monotherapy data. The monotherapy is actually not just in breast cancer, it also has castration-resistant prostate cancer and non-small cell lung cancer. And then the combinations, we don't have an MTD yet, but we have started the combinations with OP-3136, which is the KAT6 inhibitor with fulvestrant and palazestrant.

And so that data, we won't have to share in Q2, but maybe later on in the year, we'll be able to inform people about that. With regard to management change, yes, we had a CFO, COO departure couple of weeks ago. Shane had been with us -- Shane Kovacs had been with us for almost 6 years. And by mutual agreement, he departed. The company is, as I mentioned, Phase III readout in the fall. Companies -- as companies do, if they make it in biotech transforming, and we're transforming.

We've started our -- we made our first commercial hires. We're preparing to build a commercial organization and a sales force. Our vision is to be a fully integrated oncology company, and that means launching and promoting palazestrant in the United States. We will not do so worldwide. We'll seek a collaborator for those purposes. And obviously, that changes kind of the structure of the company, but also the structure of the financials for the company to a revenue-generating company, cash flow positive, hopefully, in the not-too-distant future post launch, could be as early as next year that the launch. And so we are looking for a person who can really have some experience with that and help us with that.

Okay. Makes sense. Now you introduced palazestrant. You generated a lot of clinical data with this, both monotherapy and combo. What would you highlight in terms of what supports its potential to be a best-in-class oral SERD?

Yes. I mean the simple thing here is that the best way to predict the future outcomes of a drug or combination are to look at the past outcomes, the past data with that drug or combination. So if you look at that with palazestrant, what you'll find is that it stands out from this SERD field. So it's a complete estrogen receptor antagonist with higher exposure than the other agents, oral daily pill with an 8-day half-life.

And so you are able to maintain a very high exposure. tolerability profile allows you to do that. And in addition, it's uniquely combinable with other agents. We've combined with ribociclib, palbociclib, everolimus, alpelisib. We're combining with Pfizer's CDK4 selective atirmociclib now. We are combining with our own KAT6, as I mentioned now, and we've been able to give full doses of those agents.

If you look at our monotherapy Phase II data, in the ESR1 mutant setting, we had 7 months of PFS and 5.5 in the wild type. Those -- the 5.5 in the wild type exceeds what others see in the mutant setting. So if we're able to duplicate that in OPERA-01, we have a really unique opportunity to be better in the mutant subset, where others have shown some activity and to address the wild-type subset, which is currently an unmet need. In the first-line setting post CDK4/6 with AI, our ribo, pala combo had a year, which again is an outstanding result and very much supports the potential of OPERA-02 going forward.

We're about 2 months removed now from seeing at San Antonio, the giredestrant Roche data in the adjuvant setting, the lidERA study, where it beat both tamoxifen and an AI. How has the KOL community digested those data? And how has it impacted their thinking on the potential of oral SERDs across the treatment paradigm?

Yes. I think -- so I think there is still digesting going on to be perfectly honest. We've been able to talk to KOLs, talk to our investigators. And the data is impressive. The lidERA data is impressive, and Roche points that out quite rightly. I think there's a mixture of opinions coming into the study. Some people thought it had great potential.

Others thought it couldn't beat the AI. And very clearly, it did and quite soundly. So I think what's being digested is where does this fit into the treatment paradigm, right? Because in much of the population studied, now those patients are getting a CDK4/6 inhibitor, either verzenio or ribociclib and kisqali.

And so the question is, what do we do next? Do we give just giredestrant. We don't have -- there's no data on the combination. That wasn't a thing when Roche started that trial. So I think that, that's what's going to evolve over time. I think there is an attractive aspect to giving the single-agent giredestrant option. And so we'll see how that plays out. With regard to the overall, our investigators mostly interpreted our trials and their interest and they enroll very well based on our data. But I do think that they feel there's a read-through there that the class of drugs has this potential to really advance endocrine therapy.

If you were to design an adjuvant study today, how would you do it?

We talk about this a lot. Not 100% sure. I think what you -- I think the monotherapy, at least in the in the moderate to severe risk adjuvant population, I think that the monotherapy is not what you would study in the future. You would probably pick a CDK4/6 inhibitor and combine with a CERAN if we were to use palazestrant and go against the AI in the context of that CDK4/6 inhibitor, right?

I think that then becomes, well, is that verzenio? Is that kisqali. Verzenio has diarrhea as a side effect, adjuvant is very sensitive to quality of life because you're treating a lot of patients who don't need it. So in that respect, the ribo, the kisqali 400 is pretty well tolerated. I mean I think that's the direction you go in.

Is it feasible for a biotech company to conduct an adjuvant study?

Yes, if they have $1 billion plus laying around, I think it's absolutely feasible. I think the interest actually would be quite high in the current environment or if you have a collaborator with deep pockets or something like that, I think you could do it. It is extensive. It's thousands of patients. It will take a while. The interim readout is really impressive actually. I mean that shortened the time line a lot. And that's why people got surprised, right, by the result coming out. So it is feasible to do. I think there's definitely interest so that you could execute the trial -- the design, you would have to finalize that. And then I think as well, it is expensive.

Well, you have kicked off the frontline metastatic trial, which is also expensive in its own right, the OPERA-02 study. I guess outline the details of that study and how Novartis is collaborating to help with some of the cost on that?

Yes. So that is exactly as you said, it's endocrine-sensitive first-line setting. So most of the patients that go on that trial have had adjuvant therapy and completed it, completed their 5 years, had at least a year disease-free off of therapy, and then they present with metastatic disease.

The other -- that's probably around 70% of patients. The other 30% will be the de novo metastatic. These are patients whose initial presentation of breast cancer, it has metastasized. So they haven't had prior treatment. It's very simple. The patients are randomized to ribo plus an AI, letrozole. That's the global standard of care for first-line metastatic, ER-positive HER2-negative breast cancer.

The experimental arm is substituting for the AI palazestrant. And so this is a blinded placebo-controlled trial. No one knows the treatment assignments and the PFS primary endpoint. It's about 1,000 patients. The soonest it could read out would be 2028. I think it's fairly likely, particularly if we get the treatment effects we saw post CDK4/6 that it may take longer to accumulate those events. It's enrolling very well. And I think the data that we have supporting it from the Phase II setting, both tolerability-wise and efficacy-wise is compelling.

I think we're all feeling pretty good about the superiority of oral SERD CERAN over AI after lidERA, how do you think about the potential impact of the CDK combo partner for lack of a better term, washing away that superiority though?

Yes. I kind of confused where that idea even comes from. CDK4/6 is all targeted agents other than endocrine agents on their own are very weak in terms of efficacy. It is really the combination with the endocrine agent that synergizes to bring out that efficacy. And so I think that the concept of a washout of treatment effect is, I think, misplaced. There are complexities going from lidERA to persevERA.

And to me, it has more to do with the patient population. So if you think about both settings, their ESR1 wild type 95%-ish. They're endocrine sensitive because even if you've had the adjuvant therapy going into persevERA, you had to be able to complete it and have a year disease-free after. The adjuvant setting, they're endocrine naive.

They've never seen any treatment for breast cancer. The majority of the patients, as I said, probably about 70%. I'm sure when Roche presents the data, not in the PR, but when they present the data, they'll tell you how many patients were post adjuvant. But that majority of patients thus adjuvant is not endocrine naive, right? It's not endocrine resistant, but it has seen prior endocrine therapy. So I think that will be an interesting wrinkle that is a bit hard to handicap. A Post lidERA, you have to increase your probability of success for persevERA. I think that's a true statement, but it's not perfect.

And that's the other question, is persevERA a definitive test as you see it? Because obviously, you're running a very similar study that enrolling patients and spending resources on to complete after we've got that data. if it's successful, obviously, that's a great idea and you're well ahead of time. If it's not successful, how do you think about it?

Yes. So another way of putting that is what do we see as the liability of giredestrant. And the liability of giredestrant is its dose, 30 milligrams. Giredestrant is a complete estrogen receptor antagonist as well from a molecular standpoint. It's a very comparable compound in the laboratory setting. The challenge giredestrant had is that when they combined their original recommended Phase II dose, which was on 100 milligrams with palbociclib, they got an enhancement of bradycardia.

And the way that Roche decided to address that was to lower the dose of giredestrant to 30. So threefold lowering of dose, threefold lowering of exposure and also with a shorter half-life than we have with palazestrant. And so I think that was our concern about the property of the molecule versus what palazestrant has done -- as well where you can compare across trials with similar populations, palazestrant outperforms.

Now that caveat said, it did very well in lidERA, the 30-milligram dose. So it clearly has activity over an AI. We view the persevERA result as, first of all, having 3 possible outcomes. One is obviously positive. Within the negative, there are kind of 2 outcomes. There's sort of overlapping curves. You really don't see anything or you see a trend, but it didn't quite make it to positivity in the trial design. And that seems the more likely way to fail post-lidERA.

In any case, we think it is below the efficacy boundary that we would see with the OPERA-02 regimen of ribo plus 90 milligrams of palazestrant. And so we view -- they're completely overlapping would be somewhat confusing result. The other two say to us, we've got a great chance, and we are very excited about what's happening with OPERA-02.

Yes. Well, in terms of the completely overlapping, I mean, everyone still references the persevERA study where fulvestrant was run in a Phase II and that had overlapping over AI. My sense is there's kind of this all roads lead to persevERA dynamic where people are doing a lot of work getting constructive on the idea of post-lidERA, but can't get past that data point. I'd like to hear from you why you don't see [indiscernible] as a strong surrogate for a study like persevERA or your own OPERA-02?

Well, I mean, the first reason is that fulvestrant is just a terrible drug. It's a really interesting molecular tool compound as a CERAN. But its inability to be given orally, it's inability to achieve real exposure is a significant liability. Giredestrant at 30 milligrams, I talked about our concerns about its exposure. It's extremely high compared to fulvestrant. So it's definitely engaging the receptor much more thoroughly than fulvestrant does. The reason parts of what confuses people is [ FALCON ] because [ FALCON's ] interpreted and statistically with p-value 0.049 was positive, but its treatment effect is negligible.

Fulvestrant just really isn't that much better than an AI. What you see in lidERA is something completely different. you see the AI soundly beaten with a compelling hazard ratio, I think a very interesting trend towards survival. That looks to me like a matter of time for Roche. And so it is really a different result. It's a bit sad that people are so caught up in [indiscernible] to me right now. There is something interesting about [indiscernible] though. If you look at CDK4/6 plus AI, and remember, for PFS, they were all quite similar. It was sort of 2 years in change, 27, 28 months was the median PFS you could expect.

In [indiscernible], the control arm was 32. That's a lot. That's a big 4-, 5-month difference for the same control arm. So it really makes me wonder what is the modern day performance of an AI with a CDK4/6. There's a long history in oncology of a given regimen evolving toward a better outcome. And part of that is probably ancillary supportive care things. Part of it is oncologists are very good at optimizing a regimen when they get more experience with it. And so I think it would be very interesting in persevERA to see how the control arm actually performs.

Okay. I'll spend some time on the monotherapy Phase III. You're running one with the benefit of having seen maybe 6 Phase II/IIIs in the same setting with similar drugs, albeit potentially inferior drugs before you. What key features from those trials have you pulled to set up OPERA-01 for the highest probability success?

Yes. So we've pulled some, but not like uniquely, right? Others have -- the trial that most influences that setting by far is EMERALD, the first one, elacestrant, Orserdu, positive in the ESR1 mutant subset with a fairly weak, right, sort of 2 to 4 months median PFS difference, but real. And of course, that drug is a SERM, it's not a CERAN, so we think compromised molecularly on its ability to fully maximize.

They did some amazing things though, out of that trial, did a lot of really interesting retrospective post-hoc analysis and shared them. And we learned a couple of things. One, if you've had chemo, you probably got -- you've probably got very aggressive diseases. It could be very hard with a targeted therapy to go back and capture, significant effect.

So you exclude prior chemotherapy. The other thing is that this ESR1 wild-type population post CDK4/6 plus AI is probably heterogeneous. There are some patients in there that are truly endocrine resistant. They have developed -- probably developed mutations that bypass the estrogen receptor. They're not using it anymore. There are others that are still relying on the estrogen receptor as one of the growth and proliferation drivers.

So what you want to do is try to some extent to exclude those patients where the estrogen receptor is in factor anymore. And what we do -- what others have done is we require at least 6 months freedom from progression on the prior endocrine therapy. So those are some of the things that we have learned there. Otherwise, there are some sort of trial conduct matters, but it's kind of minutia for the outcome. It's important for generating good data.

Yes. And I guess I wanted to ask somewhat similar to that. The selection criteria because it's always that question of with the palazestrant monotherapy, you're only hitting the endocrine therapy pathway. These patients with ESR1 wild-type population that probably even with that selection criteria, not a lot of ER-driven biology still and those cancers are a question of that. So how do you think about that and the ability to really extract monotherapy activity in the wild-type patients?

Yes. I first would argue that, that's probably not true. You have to understand, it's very interesting. There's a circular aspect, and we also think about this with prostate cancer, where you don't call it endocrine-resistant, but you call it castration-resistant, but it's the same thing.

You define this resistance by the therapy you give. So if your therapy is inadequate, you said, oh, they're endocrine resistant. They're not endocrine resistant. They're AI resistant, right? Or androgen receptor antagonist resistant. The pathway is still working. You just haven't fully hit it yet. So I would argue that in a more heavily pretreated patient population, second, third line plus or minus chemo, we didn't use this 6 months.

In Phase II, in the ESR1 wild-type subset, we saw a median of 5.5 months. That exceeds what others have seen in the mutant setting. So if we can recapitulate that, I mean, first of all, clearly, there's a significant subset that are still using the estrogen receptor. And then beyond that, if that can be recapitulated, that would be a compelling therapeutic option.

A lot of physicians like to use combinations in second line. So how do you ensure that patients get access to palazestrant combinations when the initial label would be just for monotherapy?

Yes. I mean that's a reimbursement question. That's a little ways off, although we're heading in that direction. We probably started with that already. What we're seeing currently is that the agents that are used, for instance, CDK4/6s tend to be used in multiple lines. The data is not that strong actually.

But 30% of our patients in our post-CDK4/6 experience with ribo and pala had 2 prior CDK4/6 inhibitors. which means somebody switch CDK4/6s and then added fulvestrant and did that. We see that quite commonly, it's reimbursed. It isn't actually a label indication. So we think access in cancer is probably pretty good. It raises a question, though, which is should we study the combination in the second, third-line setting, and that's something we are evaluating, specifically ribociclib plus palazestrant. If you saw 1 year, and that was more than 9 months in the wild type, almost 14 in the ESR1 mutant. If you saw that as a treatment option in the second, third-line setting with a well-tolerated combination regimen, that would be a very attractive treatment option. And the question is, should we go back and study that more, and we're evaluating that now.

Okay. And maybe one question on the KAT6 because you...

Can I add one thing about that? What's interesting about going from to that 1 year is the second, third-line setting, if you're able to capture the whole group of patients is a $5 billion-plus market. If you turn around and do a trial where you say, okay, actually, it's not 6 months, it's a year. It's a $10 billion market. So the impact of duration of therapy on market size is direct, right? So this is a pretty extraordinary opportunity for a company with about a $2 billion market cap. First line is more than $10 billion on its own, but these things are really meaningful also from the standpoint of revenue opportunity.

Okay. The KAT6 question, do you think that you can differentiate on just the molecule of KAT6 versus Pfizer's KAT6? Or is the differentiation potentially coming from combination with palazestrant where the competitor is running with a fulvestrant combination?

Yes. I think the answer there, and we'll show the data, but the potential answer there is kind of yes, both. We saw -- there was an interesting announcement from Pfizer right ahead of JPM, which is they were very excited to announce that they were putting a KAT6/7 more selective molecule into Phase I. Well, that's great. It's about 18 months behind OP-3136 and you can't combine with palazestrant.

And so we're very excited about the direction in which we're heading. And we think that you have to remember for the Phase III dose that was selected for Pfizer 5 milligrams for their KAT6 inhibitor, they have about 50% dose reduction due to toxicity, which is significant. So if you can address that, get better exposure, you have the opportunity for better efficacy down the road, too. You have to generate the data, obviously, but that's -- we're going to start to show people in late Q2.

Pfizer did a great thing. They validated this target. They were the first to get there. I think that the data they have, particularly in combination with fulvestrant, 38% response rate is quite compelling. But we do think there are many opportunities to improve upon that. And this is common, right, in oncology. The first one often isn't the best one. You learn a lot, you're able to help patients, but you refine as you go.

Okay. Well, Sean, unfortunately, we're out of time. Thank you so much for joining us, and thanks, everyone, for listening in.

Thank you.

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, Priyanka Grover, [ Joyce Zhou ] and [ Rati Pinhe ]. Our next presenting company is Olema, and presenting on behalf of the company, we have CEO, Sean Bohen. Sean?

Thank you, Anupam, and thank you, everyone, for joining us and your interest in Olema. Our objective at Olema is to improve treatments for patients living with ER-positive HER2-negative breast cancer and address the significant remaining unmet need in this very common cancer indication.

I should do that for a second. Normal disclaimers, as you would expect. Consistent with the objective I described to you, we have 2 programs in the clinic, 1 in 2 Phase III trials, 1 in Phase I, Phase Ib. Our lead asset is palazestrant. Palazestrant is a complete estrogen receptor antagonist. We believe the properties and the data generated to date indicate that palazestrant could be the best endocrine therapy for ER-positive HER2-negative breast cancer.

Remember, endocrine therapy is the backbone of treatment of this disease because the estrogen receptor is one of the primary drivers of the growth and proliferation of this tumor. Palazestrant is in a first-line trial in combination with ribociclib, the only first-line trial of a CERAN/SERD in the endocrine-sensitive wild-type ESR1 wild-type setting. It's also in a second third-line trial, OPERA-01, which is ongoing as a monotherapy.

These are patients who have progressed on prior treatment with a CDK4/6 inhibitor plus an AI. This trial is enrolling very well and will read out in the second half of the year. We also have a KAT6 inhibitor, OP-3136. That molecule is continuing dose escalation in Phase I, but we have also started combination studies with endocrine agents, both fulvestrant and our own palazestrant. This is a large disease. This is a large unmet need.

ER-positive HER2-negative breast cancer is 70% of all breast cancer. Breast cancer is the most common malignancy in women in the world, second most common cause of cancer death. If we look at the market opportunity that results from this, it is also very large. In the adjuvant setting, market opportunity for new agents would approach $20 billion globally.

We do not yet have an adjuvant trial, but it is certainly something that is being evaluated and under consideration. For OPERA-02, our first-line trial that I described in combination with ribociclib, that is a $10 billion-plus market opportunity in first line. The OPERA-01 trial, which will read out this year, can access a potentially $5 billion market opportunity in the later lines of treatment post CDK4/6 inhibitor plus an AI, the current standard of care.

OP-3136 in breast cancer alone, I'll talk about potential for other indications as well. Also a $5 billion opportunity would be a targeted therapy to be given in combination with an endocrine agent in that second, third-line setting as well in breast cancer. I won't go through this in great detail, but it is very important to understand that in addition to the molecular properties, which are key to making the best endocrine therapy.

That specifically being binding the estrogen receptor and turning off all transcriptional activity, all of the transcriptional function that promotes the growth and proliferation of the tumor. That is complete estrogen receptor antagonism. That is a property that palazestrant has. But in addition to being potent, it has a long half-life, 8 days.

So you have to have the drug able to occupy the receptor all the time to keep this signal suppressed. And what you can see here in the middle is the favorable PK we have. The top 2 purple lines are 90 and 100-milligram dose. You can see there's really no difference in exposure. This is versus the other agents that are currently being tested, which are below. There is also a degradation of the receptor.

It's not profound enough to actually be the primary therapeutic mechanism, but we just demonstrate here that we degrade as well as anything else in this respect. But it's really the antagonism, which gives us the best-in-class potential. This is a little more detail here. I won't go through it in thoroughly. But just to tell you why this market potential is so large in the first-line setting, this market potential is not theoretical.

So just to remind you that if you look at the CDK4/6 class, the 3 molecules that are there, you're currently in the $10 billion range for the size of the market with those molecules losing exclusivity around the end of the decade in the early 2030s. So the potential here, obviously, is to improve the endocrine therapy that they are combined with in that setting. That trial is now enrolling OPERA-02.

We anticipate top line data possibly in 2028 that would lead to an approval that would be our second approval subsequently in '29. Our data supports this best-in-class potential for palazestrant, both as a single agent and in combination with ribociclib. I'll point you particularly to the right side panel here because this is what allows you to compare what other agents have shown in combination with ribociclib.

These are patients in the prior CDK4/6 treated settings. So this is the second and third line, not the indication we will see in OPERA-02, but the kinds of patients you get in a Phase II setting, you can see that in patients who have already radiographically progressed, on a CDK4/6 inhibitor plus an AI, about 3% of these patients then got a CDK4/6 inhibitor plus fulvestrant and progressed again.

So the tumors have not only developed resistance, but resistance and growth to the point where you can see them radiographically. And even with this, when we go back with another CDK4/6 inhibitor, ribociclib, and we do it in combination with palazestrant, we get a year of median progression-free survival beyond that. We think this reads through very favorably for the probability of success of OPERA-02.

One of the holy grails in this space has been to be able to demonstrate activity in the very hard-to-treat endocrine-resistant wild-type setting. This is different than the adjuvant setting where those patients are almost all ESR1 wild-type, they're endocrine sensitive. The first-line setting, again, almost all ESR1 wild-type and endocrine sensitive.

In this setting, post CDK4/6, they have shown growth of the tumor on an endocrine therapy plus CDK4/6, they are endocrine resistant. And we see remarkable activity in the mutant setting that is not terribly surprising. It's 14 months, but 9 months in the ESR1 wild-type setting with ribociclib is differentiating. Recognizing the caveats of cross-trial comparisons, these are other agents in the class combined with ribociclib and the data that they have generated, again, in these Phase II trials, these are -- they're using -- they're treating patients who have progressed on a prior CDK4/6 inhibitor.

And you can see again, this 12-month median PFS is differentiated. Looking now at our first Phase III trial, our first readout that will occur potentially fileable, which is OPERA-01. This is the second, third-line setting. So these patients will have received a CDK4/6 inhibitor plus an AI. They have to have progressed on that treatment. They can have received one additional endocrine therapy and progressed on there and be eligible for the trial.

They get palazestrant as a single agent. The control arm is fulvestrant or exemestane, the current standard of care in this setting for endocrine monotherapy. As I said, in the fall of this year, we will have the top line readout of that trial, the PFS readout. This trial is designed to specifically examine the ESR1 mutant and the ESR1 wild-type populations separately. There is not an all-comers analysis because there is significant remaining unmet need in both cases.

In the case of the mutant, as I'll show you in the data, we have the opportunity to have better benefit than has been seen with other agents. There are other agents that have been successful here. In the case of ESR1 wild-type, nothing has been successful in this space. So we have a real opportunity to provide a targeted therapy to patients who don't have a targeted oral option for endocrine therapy now.

With a positive trial later this year, we would file an NDA next year and potentially launch late in the year in 2027 in the United States. This is the data that supports success and best-in-class potential in that population. Specifically, if you look at the pink lines, those are second, third-line patients, patients who've had prior treatments similar to what are being enrolled in OPERA-01.

You can see these as ESR1 mutant and wild-type subsets here in the ESR1 mutant subset, 7 months is what we see. The existing agents that are filed or approved show a 2-month benefit over standard of care here. This would be more like 4 to 5 months benefit. No benefit has been shown in the wild-type setting. And here, we show 5.5 months. As I said, that's around the range of what you get in mutant with the other agents if we are able to reproduce it in the OPERA-01 setting.

And again, caveats of cross-trial comparisons. These are the other agents in the post-CDK4/6 setting as monotherapies and the data that they have generated, both in the all-comers experience, where you really see about 4 months where we see 7. And then in the ESR1 wild-type experience where, as I mentioned, there isn't any agent that has demonstrated efficacy over the standard of care, and they're all about 2 months. We have this opportunity to exceed 5.

Obviously, clinical trials are great. This is the way you get to filing. This is the way that you get to commercialization, but the way that you get the drug in the hands of the patients that need it is to successfully launch and commercialize that drug. And so we are planning that right now because, obviously, that launch is less than 2 years away. We anticipate based on the OPERA-01 trial.

So we are planning to market palazestrant ourselves in the United States and to seek a collaborator for the rest of the world. Again, just to remind you, the market potential here is $3 billion to $5 billion. Why the range? The range depends upon if you get ESR1 mutant only or if you're able to capture that 50% to 60% of patients who are ESR1 wild-type after they've progressed on a CDK4/6 inhibitor plus an AI.

Moving on to OP-3136. This is a fascinating target, KAT6. It's an epigenetic target. The mechanism of action, I'll show you in a minute. Again, the population here is not dissimilar to the OPERA-01 population that we're looking at. The difference being now there is a need for further targeted therapies to go beyond the CDK4/6 inhibitor to go beyond PI3 kinase to go beyond AKT and to obviously give another therapy to patients who don't have any of those mutations as well.

The objective, just to remind you, in the treatment of ER-positive HER2-negative breast cancer, one of the major objectives is to put off chemotherapy as long as possible. This is both a quality of life issue and obviously, the ultimate objective to extend life. But again, you have about a $5 billion global market opportunity just in breast cancer. I'll talk about other indications, as I mentioned.

The Phase I is now enrolling both monotherapy in combination with fulvestrant and palazestrant. The initial results, mostly of monotherapy, we anticipate presenting late in the first half of this year and then have an opportunity to update on that subsequently. And we anticipate we would start a Phase III trial in breast cancer probably in 2028.

Again, this is the pipeline just to summarize for you, OPERA-01, OPERA-02 and the ongoing OP-3136. Just to remind you, we were able to successfully raise money in an offering late last year. We're in a very favorable cash position. We have more than $0.5 billion, now that carries us into the second half of 2028 with these Phase III trials, with the advancement of OP-3136. Again, this is a very busy year for us. We have our first Phase III readout in the second half of the year and OPERA-01.

We have our first data that we anticipate sharing with OP-3136, which we truly think has the opportunity to be the best-in-class KAT6 inhibitor, both from the standpoint of efficacy, from the standpoint of tolerability. And just to remind you, the monotherapy portion of that trial has castration-resistant prostate cancer and non-small cell lung cancer patients being enrolled in addition to breast cancer.

We are looking forward to approval and launch of palazestrant. That's in that OPERA-01, second, third-line setting next year. And we think that OPERA-02, the first-line setting with ribociclib could read out potentially as soon as 2028. And with that, I will thank you all for your attention, and we have plenty of time for questions, Anupam.

Yes. Thank you, Sean. And I'll ask the first couple of questions, but then I'll also ask for audience questions, just feel free to raise your hand, and we'll call on you. I wanted to ask a couple of broad questions first, which post the lidERA update from giredestrant, you were at San Antonio. Did you sense any KOL perceptions changing around the SERD/CERAN class or...

Yes, absolutely. So I would say that from the standpoint of the attendees of the meeting and the people that we interact with, there really are 2 schools, right? There was one school that already believed that this class had the potential, particularly the CERAN aspect of it to differentiate from the existing endocrine therapies, really AI and fulvestrant, right?

And so I think those individuals felt this is expected that there would be a benefit. I do think that the magnitude of the benefit was impressive to everyone who saw it. For others, there was skepticism. There was skepticism that you could actually achieve a meaningful clinical benefit by better suppressing estrogen receptor growth and proliferation signal. And obviously, the data was compelling.

And so they -- we saw a lot of people say, wait a minute, there's a lot of potential here. And we need to see where else, right? This can be -- this could make a difference for patients. And obviously, that work is ongoing. Both our work, but then there's the PERSEVERA readout coming in a few months from Roche with palbociclib in the first-line setting.

And so where else can it work on that question that you just posed, right? From your perspective, post lidERA, how are you thinking about any read-throughs to PERSEVERA, which is, I think, expected at the end of the quarter or early next?

Yes. Right. So let's talk about a little bit about the settings in which you're using these agents. So as I mentioned in the talk, in the adjuvant setting, you're treating patients who have never seen an ER-targeting therapy, right? This is their initial diagnosis of breast cancer is limited stage. They get treatment for that limited stage and then they get adjuvant therapy afterwards to try to decrease their risk of recurrence of their disease.

That disease is -- those receptors are almost all ESR1 wild-type because there's been no selective pressure for the mutation for resistance. And obviously, they're endocrine sensitive because they don't -- they haven't had any prior treatment. So that's the lidERA setting. that biologically is quite similar to the PERSEVERA or the OPERA-02 setting. In the metastatic breast cancer setting, again, your vast majority ESR1 wild-type.

And because of the way of the patients who are enrolled, so patients have had about 70% of patients who've had prior adjuvant therapy, they have to have completed it and had 1 year off of it disease-free to be eligible for these trials. So they remain endocrine sensitive. About 30% of the patients are actually naive to treatment. Those are -- that's metastatic breast cancer that the initial presentation, it's de novo metastatic was metastatic disease.

So they never received prior treatment. So with those biological similarities, we believe that activity in that adjuvant ESR1 wild-type endocrine-sensitive adjuvant setting has significant read-through to the first-line ESR1-sensitive wild-type setting.

Question from the audience? Feel free to raise your hand. In your presentation, Sean, you stressed that in OPERA-01, you were doing the wild-type and ESR1 mutant analysis separately. How are you thinking about win scenarios in both? You kind of commented on it a little bit, but if you could expand.

Yes, right. So yes, so the statistical design of the trial is that there are analyses of these 2 separate populations. And the advantage -- that's going to happen anyway, right? That's how regulators quite rightly are going to analyze this data. The advantage of doing it that way is you actually can describe and design around the statistical characteristics of the 2 different analyses.

The win criteria have been pretty well established. You need a 2-month additional PFS benefit in order to be successful. And that's been seen by a few drugs in that ESR1 mutated setting, which is 40% to 50% of the patients post progression on CDK4/6 plus an AI. The criteria are the same for the wild-type setting. The difference being that in this ESR1-resistant wild-type disease, it's never been achieved.

And again, I showed you the data of 5.5 months in that setting. We really think we have an opportunity there. Right now, the current labels are all restricted to ESR1 mutant. And I think really, if you look at the data for things that are about to be filed, even combinations, we anticipate that's going to stay that way.

So it is a significant unmet need, giving another alternative to the wild-type patients. In addition, with 2 months being the bar, if we're able to duplicate the range of the 7 that we saw in the ESR1 mutant setting, that would be a significant benefit over the current standard of care.

And then you talked about that 5.5 months in the wild-type setting, right? Mechanistically, with palazestrant, what gives you the confidence, right, that you can replicate this or be in and around this.

Yes. So from a mechanism...

Or even decreased a little bit, and you'll still be above it.

Yes. So there are several things -- that's true. It's true. There is a little room there. There are several things that when we think about going from that Phase II experience to the OPERA-01 experience that give us confidence. And one of the molecular properties of the molecule.

And that's the complete estrogen receptor antagonism. It's a very robust exposure that we see to keep the receptor growth and proliferation signal suppressed, favorable tolerability in that context. And so those things are very important. The other thing to recognize is that probably the population in OPERA-01 is a little more favorable to response to treatment than the ones that were in the Phase II because in the Phase II, we allowed prior chemotherapy.

We don't allow that in OPERA-01. In the Phase II, we allowed people to go on palazestrant who had progressed within 6 months of the start of their last endocrine therapy. Those patients are excluded from OPERA-01. So we're hopeful that those properties may actually enrich for patients who are more likely to benefit from a single-agent endocrine therapy.

Questions from the audience? In the back?

You mentioned ex U.S., you're going to have a commercial partner. What do you think the timing on that might be? Can you comment?

Yes. That's a great question. I mean I think to some extent, I will say that it will be a partner. So the timing is somewhat dependent upon the partner's timing as well. I think if you think about when to seek a partner, I think the overall objective is you want to make sure that, that partner is there and involved at a time where you can maximize the impact of regulatory filings in these different regions setting up for a good commercial launch in those different regions.

So I think it has to be sooner rather than later is the way I would put that. You certainly don't want to get too close to the U.S. filing and launch to have the partner identified because you run the risk that you aren't maximizing the benefit and the ability of that partner to influence the rest of world launch.

I was wondering if we could get an update on sort of the Pfizer combination study and that collaboration.

Atirmociclib?

Yes.

Yes. So we have a -- so let me back up for a second. One of the key attributes of palazestrant, again, with its pharmacology is its combinability, right? Endocrine agents are given as single agents as very common and viable. It's really the only targeted agent in ER-positive breast cancer that's given as a single agent. But very often, what you want to do is target another pathway that's driving the cancer.

So the most common we all know about is CDK4/6, right? Ribociclib plus an AI right now is the gold standard in the first-line setting. We combine very well at full doses with the variety of targeted therapies we've tried, which are palbociclib, ribociclib, everolimus, the mTOR inhibitor, alpelisib, PI3 kinase inhibitor, but we're expanding beyond that.

Atirmociclib is a CDK4 selective small molecule inhibitor that Pfizer now has in Phase III. And I think their objective is to say, look, we think we can do better than CDK4/6s, which are limited by their toxicity and inhibition of CDK4 by dialing out the neutropenia associated with CDK6 inhibition and being able to hit CDK4 harder. They've presented some encouraging data at ESMO in October. From our standpoint, with the potentially best endocrine therapy, we want to be positioned for the future evolution away from CDK4/6 inhibitors to better targeted therapies.

And we think that atirmociclib is a good candidate for that. So between the 2 of us, we decided it's worthwhile to see if we can create something interesting by combining these 2. That -- that's a clinical supply agreement with Pfizer. There's really no economics. There's no read-through to palazestrant or atirmociclib from us. We co-own the data, and that combination is ongoing in the clinic now.

Questions from the audience?

I've got one more. Yes, go ahead.

I've got a question on the competitive positioning. So in terms of the timing for Phase III readout, so Roche will be the first and AZ is probably the second to the market, and we're probably the third. And just wondering what's your like strategy for kind of improving our positioning?

Yes, it's a great question. I think there are several aspects to that strategy. Some of them have to do with the properties of the molecule, right? So that -- I'll give an example. Oncology is an interesting space, right? Because there's definitely advantage to being first to the market.

But there's a much bigger advantage to having better data. And we saw that in the CDK4/6 space, right? Based on the original PFS readouts, palbociclib, abemaciclib -- so palbociclib Ibrance, abemaciclib Verzenio, ribociclib Kisqali looked pretty much the same. You got 2 years plus a little bit median PFS benefit, definitely a huge advantage over AI alone, which was the prior standard of care.

Ibrance was first, really dominated the market for a long time. Then the survival data came out. Kisqali was the only drug that was able to clearly demonstrate a survival benefit. Not only that, the survival benefit was about a year, which is a very long time for these patients. And what you have seen over the course of the past about 1.5 years is a complete switch in the use of these drugs. Kisqali was #3. Kisqali is #1 and still growing.

And that's based on the data. And so while being first is valuable, being best, is more valuable. And so we think there are really 2 ways to get at that. One, again, is the property of the molecules. If we are able to duplicate something in the range of a year, which we saw in Phase II, in the OPERA-02 study, we believe that will be truly differentiating and that, that will drive patient and physician behavior.

There's one other thing that's interesting here, right? And it more has to do with that CDK4/6 situation I described. Occasionally, there's an advantage to not being first. And in our case, that advantage is we were able to go with the partner molecule, CDK4/6, that is the global gold standard. because it changed. So when AstraZeneca and Roche did their trials, Ibrance was it. It was by far the leader. And that's what they went with. And that makes perfect sense at that time. We, however, came later. Remember, our first combination studies with CDK4/6 were done with palbociclib.

At that time, we thought that's what we were going to be doing. We did ribociclib as well. We had other hypotheses that were interesting to us, but it positioned us very well to be -- we are the only company with a Phase III trial in the first-line endocrine-sensitive setting. And so we think that just by virtue of being able to say, give the CDK4/6 inhibitor you want with this better endocrine agent, that will be a differentiator.

Maybe final question for me, just switching gears a little bit to the KAT6 here, 3136. Just talk to us about the size and scope of the data that we're going to be getting midyear. And just given the competitive landscape, what would be like an encouraging update for you?

Yes. So talk a little bit about our approach to KAT6 here. This is now a validated target. Pfizer very much to their credit with 8144, their lead molecule has demonstrated that in ER-positive HER2-negative breast cancer post CDK4/6, KAT6 plus fulvestrant has pretty impressive activity, and they have an ongoing Phase III trial in that space. They do have some tolerability challenges.

The main toxicities are dyskinesia, a taste alteration and in some cases, being so bad that people don't need enough to maintain their weight. Losing weight is not a good thing for cancer patients. The other main toxicity is cytopenias is cell count decreases, mainly anemia and neutropenia. Obviously, that can be dose limiting, but beyond that, that limits combinability outside of the endocrine agents.

When we designed OP-3136, the KATs are a family of lysine acetyltransferase. KAT6 is what's talked about and targeted because it's amplified in some tumors. So that was what led to the identification of therapeutic target. But truthfully, what we're targeting with most of these agents is KAT6A, KAT6B and KAT7. And that's what we do with OP-3136. We dialed out KAT5 and KAT 8, which are hit by the Pfizer molecule. We do not significantly inhibit them at the clinical exposures we get.

And so our hope is that we may, one, have better tolerability profile as a result of that, particularly along -- around the cytopenia aspect of this. And so that data will be part of this. It will mostly be monotherapy dose escalation data. Obviously, there will be a lot of tolerability data in that, a lot of PK. There will be some clinical activity data presented as well to the extent that we have it as a monotherapy.

I don't think you're going to get -- you might get a little bit of fulvestrant combo. You might not get any palazestrant, I don't think it's ongoing, but I don't think we'll have enough data maturity yet. Obviously, there's an opportunity to update on those things either later in the year or possibly early next 2027.

The other thing I think that people will want to look at is, as I mentioned before, we have other histologies based on what we saw preclinically. So we have non-small cell lung cancer, we have castration-resistant prostate cancer. So there's an opportunity to see potentially as well, is there an ability to expand with this mechanism of action, particularly with a different inhibition profile outside of just ER-positive HER2-negative breast cancer into another indication.

All right. Thank you, Sean.