Thanks, everyone, for continuing to join us. My name is Brad Canino. Happy to be sharing the stage with Sean Bohen, 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. Yeah, 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 is 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 two phase three 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 is 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'll 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, yeah, we had a CFO/COO departure a couple of weeks ago. Shane Kovacs had been with us for almost six years. And by mutual agreement, he departed. The company is, as I mentioned, phase 3 readout in the fall, as companies do if they make it in biotech transforming. And we're transforming. We've 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. Obviously, that changes kind of the structure of the company, but also the structure of the financials for the company too, a revenue-generating company, cash flow positive, hopefully, in the not too distant future. Post-launch could be as early as next year, the launch. So we're looking for a person who can really have some experience with that and help us with that. Makes sense. Now, you introduced palazestrant. You've 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? Yeah, 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. It's an oral daily pill with an eight-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, abemaciclib. 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 2 data in the ESR1 mutant setting, we had 7 months of PFS and 5.5 in the wild type. 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, whether 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 two 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? Yeah, so I think there is still digesting going on, to be perfectly honest. We've been able to talk to the 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? 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? 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 in 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? Yeah, we talk about this a lot. Not 100% sure. I think the monotherapy, at least 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. I think 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'd go in. Is it feasible for a biotech company to conduct an adjuvant study? Yeah, if they have $1 billion plus lying 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 expensive. It's thousands of patients. It will take a while. The surrogate readout is really impressive, actually. I mean, that shortened the timeline a lot. And that's why people got surprised 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. Yeah, 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 five years, had at least a year disease-free off of therapy. And then they present with metastatic disease. 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 endpoints. 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. I think the data that we have supporting it from the phase two setting, both tolerability-wise and efficacy-wise, is compelling. I think we're all feeling pretty good about the superiority of oral SERDs, CERANs, 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? Yeah, I'm 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, they're 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 before. 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 that's post-adjuvant is not endocrine naive. 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. Post-lidERA, you have to increase your probability of success for persevERA. I think that's a true statement. But it's not perfect. That's the other question. Is persevERA a definitive test, as you see it? Because obviously, you're running a very similar study that would be enrolling patients and spending resources on to complete after we've got that data. If it's successful, obviously, that's a great idea. You're well ahead of time. If it's not successful, how do you think about it? Yeah, 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 two dose, which was 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 a 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 mg dose. So it clearly has activity over an AI. We view the persevERA result as, first of all, having three possible outcomes. One is obviously positive. Within the negative, there are kind of two 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 mg of palazestrant. And so we view their completely overlapping would be somewhat a 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. Yeah, well, in terms of the completely overlapping, I mean, everyone still references the PARSIFAL 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 PARSIFAL dynamic, where people are doing a lot of work, getting constructive on the idea post-lidERA, but can't get past that data point. I'd like to hear from you why you don't see PARSIFAL 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, its 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 PARSIFAL confuses people is FALCON. Because FALCON's interpreted and statistically, with p-value of 0.049, it 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 toward survival. That looks to me like a matter of time for Roche. And so it is a really different result. It's a bit sad that people are so caught up in PARSIFAL, to me, right now. There is something interesting about PARSIFAL, though. If you look at CDK4/6 plus AI and remember, for PFS, they were all quite similar. It was sort of 2 years and change, 27-28 months was the median PFS you could expect. In PARSIFAL, 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. We'll spend some time on the monotherapy phase 3. You're running one with the benefit of having seen maybe 6 phase 2, 3s 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 of success? Yeah, so we've pulled some, but not uniquely. Others have. The trial that most influences that setting, by far, is EMERALD, the first one, elacestrant or Orserdu, positive in the ESR1 mutant subset with a fairly weak, sort of 2-4 months median PFS difference, but real. And of course, that drug is a SERD. 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. They did a lot of really interesting retrospective post-hoc analyses and shared them. And we learned a couple of things. One, if you've had chemo, you've probably got very aggressive disease. And this 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 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 their estrogen receptor isn't a factor anymore. And what we do, what others have done, is we require at least six 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 minutiae for the outcome. It's important for generating good data. Yeah, 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, a population that probably, even with that selection criteria, not a lot of ER-driven biology still in those cancers or a question of that. So how do you think about that and the ability to really extract monotherapy activity in these wild-type patients? Yeah, 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've said, oh, they're endocrine-resistant. They're not endocrine-resistant. They're AI-resistant 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 six months. In phase 2, 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? Yeah, I mean, that's a reimbursement question that's a little ways off, although we're heading in that direction. We 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 two prior CDK4/6 inhibitors, which means somebody switched 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 one year, and that was more than nine 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. Now maybe one question on the KAT6 because you. Can I add one thing about that? What's interesting about going to that one year is the second, third line setting, if you're able to capture the whole group of patients, is a $5 billion+ market. If you turn around and do a trial where you say, OK, actually, it's not six months. It's a year. It's a $10 billion market. So the impact of duration of therapy on market size is direct. 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. 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? Yeah, I think the answer there, and we'll show the data, but the potential answer there is kind of yes, both. 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 one. Well, that's great. But 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 three 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. 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 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. Well, Sean, unfortunately, we are out of time. Thank you so much for joining us. Thanks, everyone, for listening in. Thank you.