Ladies and gentlemen, thank you for standing by. Welcome to Olema Oncology webcast. At this time, all participants are in a listen-only mode. After the speaker's presentation, there will be a question-and-answer session. As a reminder, this call is being recorded, and a replay will be made available on the Olema website later today. I will now turn the call over to Courtney O'Konek, Vice President of Corporate Communications at Olema Oncology. Please go ahead.
Good morning, and thank you for joining today's call. Today, we issued a press release that includes a summary of the results from Olema's ongoing phase Ib/II clinical study of palazestrant in combination with ribociclib, which will be presented at the San Antonio Breast Cancer Symposium later this week. During the call, we will reference slides that are viewable via the webcast posted on the event section of our website at ir.olema.com. Today's discussion will contain forward-looking statements that are subject to risks and uncertainties, including without limitation, those discussed in our filings with the Securities and Exchange Commission. Actual results could differ materially from those forward-looking statements.
See slide two of the accompanying presentation, our press release issued this morning, and our periodic reports, including our most recent quarterly report on Form 10-Q and future filings with the SEC for a description of important risk factors that could cause our actual results to differ materially from those expressed or implied in the forward-looking statements. Also, this presentation incorporates publicly available third-party data that we have not independently verified. There are risks inherent in conducting cross-trial comparisons, as noted on slide two. We caution you that any comparisons with third-party data should not be viewed as a side-by-side comparison, and you should not rely on the completeness or accuracy of the presentation of the results of any third-party drug candidate due to differences in study design, how other companies quantify or qualify eligibility criteria, and how results are recorded, among other factors.
We encourage investors to independently review the data. With me today is Dr. Sean Bohen, Olema's President and Chief Executive Officer. Dr. Naseem Zojwalla, Olema's Chief Medical Officer, Dr. David Miles, our Chief Discovery and Nonclinical Development Officer, and Shane Kovacs, our Chief Operating and Financial Officer, will join us for Q&A with covering analysts following prepared remarks. With that, I'll turn the call over to Sean.
Thank you, Courtney. Hello, everyone, and good morning from San Antonio. Today, I'm pleased to share new data from the ongoing phase Ib/II clinical study of palazestrant in combination with ribociclib in patients with ER+/HER2-, advanced, or metastatic breast cancer, which will be presented tomorrow in a poster session at SABCS. Recall, we last presented data from this study at ESMO Breast in May. That showed encouraging safety in 50 patients who had been on treatment for at least one cycle or four weeks and encouraging preliminary efficacy. At the time, the data further supported our thesis that palazestrant possesses key characteristics to make it a potential backbone endocrine therapy of preference for ER+/HER2- breast cancer, both as a monotherapy and in combination with other targeted agents. We have greater confidence in this belief as a result of the data we are presenting here at SABCS.
This morning, we will share the largest clinical data set to be presented assessing a next-generation endocrine agent in combination with ribociclib. We are very pleased with the emerging efficacy profile. The combinability of palazestrant and ribociclib is compelling, with no clinically meaningful impact on the drug exposure of either therapy and an overall safety and tolerability profile that is consistent with ribociclib in combination with aromatase inhibitors. Olema's purpose is to elevate patient care in breast cancer and beyond. Our advantage comes from our expertise in endocrine-driven cancers, nuclear receptors, and mechanisms of acquired resistance. We leverage this knowledge to inject innovation into the design of our molecules. Palazestrant, our lead asset, was designed to improve upon the current standard of care for women diagnosed with advanced or metastatic ER+/HER2- breast cancer.
It is a CERAN/SERD, or a Complete Estrogen Receptor Antagonist, which we believe to be the primary mechanism of action that may best suppress the ER-mediated growth and proliferation signal in certain tumors. It is also a selective estrogen receptor degrader. Palazestrant completely blocks estrogen receptor signaling of both wild-type and mutant estrogen receptors and has demonstrated attractive pharmacokinetics in exposure, favorable tolerability, robust tumor shrinkage, combinability with CDK4/6 inhibitors, and CNS penetration. OPERA-01, the pivotal phase III trial of palazestrant as a monotherapy in second and third-line metastatic breast cancer patients, is underway and on track for top-line data in 2026. We are also pursuing a clinical development program intended to demonstrate palazestrant's combinability with multiple targeted agents, including palbociclib, alpelisib, everolimus, and OP-3136.
OP-3136, our newest molecule in development, is a potent and selective KAT6 inhibitor that leverages our deep expertise in the transcriptional growth and proliferation signal that drives ER+/HER2- breast cancer. At ENA 2024, we presented preclinical data demonstrating OP-3136's robust antitumor activity as a single agent, as well as synergy and enhanced antitumor activity in combination with palazestrant. These data reinforce our belief in the potential of OP-3136 as an exciting new therapy for breast cancer and other cancers. On Monday, we disclosed via press release that the FDA has cleared our IND application for OP-3136, and we are moving quickly to initiate the phase I clinical trial. Investigator interest in OP-3136 is high, and we look forward to sharing clinical data from this program in the future.
The data we are sharing today is from a more recent cut than the data that will be presented at SABCS by Dr. Virginia Borges, Professor of Medicine, Medical Oncology at the University of Colorado. The poster reflects a data cutoff date of September 25th and includes all 62 patients in the study. For the purposes of this call, we are presenting the same set of patients, only with a more recent data cutoff date of November 11th, further supporting the efficacy and safety profile of palazestrant in combination with ribociclib. On slide 6, you will find the study design. Palazestrant is being evaluated in combination with ribociclib in patients with ER+/HER2-, advanced or metastatic breast cancer who have been treated with up to two prior endocrine therapies, with or without a CDK4/6 inhibitor. Up to one prior line of chemotherapy was also allowed.
The primary endpoints are incidence and severity of adverse events and pharmacokinetics. Progression-free survival, duration of response, and overall response rate are key secondary endpoints. The baseline demographics of the study are on slide 7. 62 patients were treated with palazestrant, given orally once per day. 56 at 120 milligrams are recommended phase 2 single-agent dose, three at 60 milligrams and three at 30 milligrams, all in combination with the full and approved dose of 600 milligrams of ribociclib daily. Of the 62 participants, 74% received prior CDK4/6 inhibitor treatment with an endocrine therapy. 12 or 19% had two prior lines of CDK4/6 inhibitors, making this their third treatment with a CDK4/6 inhibitor. 58% of the patients had visceral disease, and 68% had measurable disease. Notably, 28% of the patients had tumors with activating mutations in the ESR1 gene.
Therefore, this cohort includes patients with both ESR1 wild-type and mutant tumors. Slide 8 shows the treatment emergent adverse events, or TEAEs, compared to the published experience of ribociclib plus letrozole, an aromatase inhibitor, from MONALEESA-2. Consistent with the initial data presented at ESMO Breast earlier this year, palazestrant in combination with ribociclib continued to be well tolerated with no dose-limiting toxicities, and the safety profile was consistent with the ribociclib prescribing information. The majority of TEAEs were grade 1 or 2. No patients had a dose discontinuation or dose reduction of palazestrant only due to a TEAE. While the most common reason for treatment discontinuation was disease progression, four patients discontinued both treatments due to a TEAE, and three patients discontinued ribociclib only. Seven patients had a dose reduction of both treatments, and 18 patients had a dose reduction of ribociclib.
The most common reason for dose reduction was neutropenia. It is important to note that the efficacy data from this study continue to mature. 30 patients remain on treatment as of the November cutoff, with a median follow-up of 12 months. All 62 patients have had an opportunity to be on treatment for a full six months. The PFS data presented is a preview of progression-free survival. With a median follow-up of 12 months, we have not yet reached the median PFS. We are therefore showing the six-month progression-free survival rate across several subsets. The six-month PFS rate is a measure of the percentage of patients on study who have reached the six-month milestone without progression or death as assessed using RECIST criteria. On slide 9, as of the data cutoff of November 11, we are showing highly encouraging preliminary efficacy from the combined agents, including in heavily pretreated patients.
Remember, the median PFS was not reached with follow-up of 12 months. The six-month PFS rate was 73% across all patients and 68% in those with prior CDK4/6 exposure. Moving on to slide 10, you can see that the efficacy remained encouraging regardless of ESR1 mutation status. The majority of the patients in the study were ESR1 wild-type, and in this population, the six-month PFS rate was 70%, with a median PFS not yet achieved. In patients with ESR1 mutations, the six-month PFS rate was 81%, and again, median PFS has not yet been reached. In addition to activity demonstrated in ESR1 mutant patients, the robust activity observed in the wild-type patients illustrates that the combination of palazestrant with ribociclib may have an advantage over the current front-line standard of care treatment.
To help put these data into context, on slide 11, we look across the landscape of comparable studies of endocrine therapies in combination with ribociclib in patients previously treated with a CDK4/6 inhibitor. And while there are risks to conducting cross-trial comparisons across studies where we have not independently verified the data, we believe our palazestrant-ribociclib data compares quite favorably. The MAINTAIN study of ribociclib plus an endocrine therapy is the most appropriate benchmark. We also look at outcomes from the MORPHEUS study of giredestrant plus ribociclib, given giredestrant is the only other oral SERD with published data in combination with ribociclib. As you can see, as of our November 11 data cut, palazestrant in combination with ribociclib outperformed these benchmarks in terms of six-month PFS rate. The chart on the right shows median PFS from the same studies for comparison.
Remember, the palazestrant plus ribociclib PFS data are not yet mature. The median PFS has not yet been reached with a median follow-up of 12 months at the time of the November data cutoff. We believe this is quite favorable in comparison to the benchmarks. The waterfall plot on slide 12 shows compelling antitumor activity in both wild-type and ESR1 mutant tumors. Out of the 37 response evaluable patients in the study, 60%, or 22 patients, had a reduction in target lesion size. The majority of those continued on study, including one patient that was still on treatment after 79 weeks, or more than 18 months. 11 responses were observed as of the most recent data cutoff date, including two confirmed complete responses, eight confirmed partial responses, and one unconfirmed partial response.
In summary, we believe these data, while still maturing, are very exciting, with robust clinical activity shown in both ESR1 wild-type and mutant populations post prior treatment with a CDK4/6 inhibitor. We are committed to the further development of palazestrant in combination with ribociclib in a pivotal phase III clinical trial. Slide 14 shows the proposed trial design of OPERA-02, our planned phase III pivotal trial of palazestrant in combination with ribociclib in patients with front-line advanced or metastatic ER+/HER2- breast cancer. We expect to enroll approximately 1,000 patients, half of whom will receive palazestrant plus ribociclib. The other half will receive letrozole, a standard of care aromatase inhibitor plus ribociclib. The trial will enroll first-line patients who have received no prior systemic therapy for the treatment of advanced or metastatic breast cancer. Progression-free survival will be the primary endpoint, with overall survival as a key secondary endpoint.
We anticipate initiating OPERA-02 in 2025. A pivotal study of this nature requires significant investment, and that is why we are extremely pleased to have recently announced a new clinical trial collaboration and supply agreement with Novartis, in addition to the private placement of $250 million in common stock with high-quality new and existing investors. Slide 15 outlines these details. Our collaboration with Novartis helps to enable OPERA-02. Under the terms of the agreement, Novartis will provide ribociclib drug supply to conduct OPERA-02. The ribociclib supplied is valued at up to $275 million over the course of the trial. Olema will be responsible for the day-to-day operational activities, and data generated from the trial will be jointly owned. Importantly, Olema retains all global commercial rights to palazestrant. At the same time, we announced the private placement of $250 million in common stock.
The net proceeds, taken together with our existing capital, will be used to fund the execution of OPERA-01, OPERA-02, generating OP-3136 phase I/II monotherapy and combination clinical data, other ongoing research programs, and for working capital and general corporate purposes. We believe this is a significant accomplishment for Olema, and we are well positioned to execute on the opportunity that lies ahead of us with palazestrant. We continue to generate data that supports palazestrant's potential to become the backbone endocrine therapy of choice for ER+/HER2- breast cancer. We believe that palazestrant could transform the standard of care for patients. OPERA-01, our pivotal phase III study of palazestrant as monotherapy in patients with second or third-line metastatic breast cancer versus the standard of care endocrine therapy, is well underway and on track for top-line data in 2026.
We believe this trial has the potential to demonstrate activity in patients with both ESR1 mutant and ESR1 wild-type tumors. OPERA-02 offers a significant opportunity for Olema in front-line metastatic breast cancer. One of the challenges in front-line treatment with a CDK4/6 inhibitor plus an aromatase inhibitor is that the tumors frequently develop mutations in the ESR1 gene, making the currently available endocrine therapies largely ineffective. Palazestrant is a complete estrogen receptor antagonist, as well as a degrader, blocking both the transcriptional activation domains of the estrogen receptor. We believe that this will allow palazestrant to suppress the emergence of ESR1 mutations and thereby delay disease progression. Given ribociclib's established overall survival benefit and its emerging position as the CDK4/6 inhibitor of choice, combining palazestrant with ribociclib could offer a meaningful improvement versus standard of care in the front-line setting.
If both OPERA-01 and OPERA-02 are successful, Olema has the opportunity to dramatically alter the growing global market for metastatic breast cancer, which is currently estimated to represent a $15 billion market and continues to grow. With the potential to change the treatment paradigm for endocrine-driven cancers, Olema offers a compelling opportunity in breast cancer and beyond. Palazestrant continues to prove in the clinic what we had envisioned in the lab. Palazestrant was purposefully designed and optimized to address a crucial need in the treatment of ER+ breast cancer. That the preclinical profile of palazestrant predicted the activity we are seeing in the clinic is extremely gratifying. Coupled with favorable safety and tolerability and a best-in-class combinability profile, palazestrant is highly differentiated.
We believe the data we have generated for palazestrant, as a monotherapy and in combination with ribociclib, should considerably de-risk our phase III trials and set Olema on the path to success. As we close out 2024, we are focused on executing OPERA-01, advancing palazestrant combinations in the clinic, and preparing OP-3136 for phase I clinical study. In 2025, we expect OP-3136 to enter the clinic. We will continue to enroll OPERA-01, initiate OPERA-02, and present updated palazestrant plus ribociclib data with more mature PFS at a future medical meeting. We expect to generate data from the phase I/II study of OP-3136 and announce top-line results for OPERA-01 in 2026. We plan to submit our new drug application to the FDA for the potential approval of palazestrant as a monotherapy in the second-line or third-line metastatic breast cancer setting thereafter and prepare for potential commercial launch in 2027.
We are well capitalized to take us through OPERA-01 top-line data in 2026, and taken together with our KAT6 inhibitor, OP-3136, we believe we have the potential to change the treatment paradigm for breast cancer. Lastly, I would like to thank the palazestrant investigators, their supporting staff, and most importantly, the nearly 400 subjects who participated in our clinical studies today. Our work to help patients feel better longer would not be possible without them. With that, let's open the line for questions from our covering analysts. Operator?
Thank you. To ask a question, please press star one one on your telephone and wait for your name to be announced. To withdraw your question, please press star one one again. And one moment, please, for our first question. The first question will come from Michael Yee with Jefferies. Your line is now open.
Hey, guys. Good morning. Congrats on the data. We had a question around how you interpret this data relative to how it may stack up against other CERAN/SERD data sets that are coming out, one maybe the Pfizer one that has already been out there, how you would compare to that, but also EMBER-3, which I think people are trying to understand. So given your strong results today and significant efficacy beyond just ribociclib, maybe put that into context so that we can understand how this fits together as combinations. Thank you.
Hi, Mike. Yeah, thank you for the questions. So with regard, first of all, to data that has not yet been presented, it's going to be a little hard to comment on that until after that data has been presented. I will say, however, that we, particularly if you go to slide 11, we make an effort to go through and look at the data sets in previously CDK4/6 inhibitor-treated patients that are available, and what you'll see is that we compare very favorably, both in terms of six-month PFS and who knows where we're going to land in terms of median PFS, but it's very clear that we're headed well into the double digits here with 12-months median PFS and 12-months median follow-up and having not reached the median PFS. One other data set that people consider, other than the MORPHEUS and MAINTAIN here, is postMONARCH. So that's abemaciclib.
The questions people have about that is the fulvestrant control arm, but the actual six-month PFS rate and median were really between MAINTAIN and MORPHEUS. So median PFS about six months, that's in line as well. When you say the Pfizer data set, I guess you're referring to vepdegestrant presented last year?
To the Arvinas Pfizer data set. But I guess to bring it back to EMBER-3, is it your view that stronger industry data would support the idea in a large randomized study that your result, ultimately in a large randomized study, probably would be similar, I guess, is the question. Thank you.
Right. Yes, I'll do both of those. So I think that the first thing is with regard to the Arvinas Pfizer data set, we compare very favorably to that. And by the way, there's a big difference. You can actually give this regimen. We are giving the full dose of ribociclib, full prescribed dose. You see the favorable tolerability. We put MONALEESA-2 on there, MONALEESA-2. That's important because it's not just the current standard of care. It's also the control arm for the OPERA-02 study. So that's what you can expect to see in the tolerability of the study. First of all, I think that there are two things we're doing here, right?
One is validating the overall hypothesis that a CERAN can do better than the existing standards of care, even after not only one CDK4/6 inhibitor, but in the case of a significant number of 20% of the patients here, two prior CDK4/6 inhibitors. So it's very clear that we are validating the overall approach. Imlunestrant, the Lilly drug, is also a SERD molecularly. The trial is quite complicated. So interpreting it, I think, may be challenging. And so there are two things going on here treatment-wise. One is the opportunity for physicians should and when palazestrant launches as monotherapy based on OPERA-01 to combine with ribociclib if they would choose to do so in the second, third-line setting. And obviously, with patients with three prior CDK4/6s, oncologists are doing that. Two prior, this is their third, I should say.
The other thing that it does is it tells you that patients who basically have the treatment of CDK4/6 plus AI has failed them once, maybe with another endocrine twice, we are able to provide a benefit in preventing progression of disease. And that's exactly how you win in the OPERA-02 trial, which is the first-line randomized trial.
Yep. Thank you.
Thank you, Mike.
And our next question comes from Tyler Van Buren with TD Cowen. And your line is open.
Hi, this is Sam on for Tyler. Congratulations on the great data, and thanks for the question. As we think about these data translating to the OPERA-02 combo trial, could you be able to compare and contrast the patient populations based on what you expect to enroll for OPERA-02?
Sure. So obviously, we have a small but significant first-line experience here. I'll tell you, Sam, we aren't presenting it separately at this point because it's relatively immature. Those patients came on the trial late in the enrollment. The enrollment completed in the end of March of this year. So we have an opportunity on the whole population, and particularly the first-line patients, to update next year, which I think will be quite exciting. The patient population in OPERA-02 will be treatment naive in the advanced or metastatic setting. So they will most likely have some adjuvant therapy. It's probably going to be a mixture of an endocrine therapy and aromatase inhibitor or an aromatase inhibitor plus a prior CDK4/6, but they will have completed their adjuvant therapy. They will have had at least one year disease-free after that, and then be diagnosed with advanced or metastatic disease.
Those patients have a very low prevalence of ESR1 activating mutations. So the mutation prevalence will be in the low single digits. So they will then get ribociclib plus letrozole or ribociclib plus palazestrant. We're seeing two things in this data set. One is the continued profound activity of palazestrant in the context of the ESR1 activating mutation. What will happen in the first-line setting, very much like what was seen with Tagrisso in the ESR1, I'm sorry, in the EGFR-mutated non-small cell lung cancer, is when those clones of ESR1 mutations, the most common resistance mechanism to CDK4/6 plus an AI, arise, they'll just grow in the letrozole arm as they currently do. And that's 40%-50% of the progressions. In the palazestrant arm, palazestrant will suppress them. Now, the tumor will eventually find a way around, but it will take longer.
And so obviously, that prolonged freedom from progression is how you win in a PFS endpoint. The other thing that's very encouraging here that we're seeing is activity in that wild-type patient population. It is clear that the current endocrine agents are not addressing all of the growth and proliferation signal that occurs even with the wild-type.
Got it. Thank you for taking the question.
Thank you.
And the next question will come from Anupam Rama with J.P. Morgan. Your line is open.
Hey, guys. Thanks so much for taking the question, and congrats on the data. I'm just wondering, are there any baseline characteristics worth considering for what you're seeing in terms of what's driving the PFS trends that you're seeing? I know you broke out the data in a couple of ways: prior CDK4/6, ESR1 mutant status, but anything worth considering there? And then can you just remind us in the protocol or how physicians thought about those patients who discontinued both therapies versus the ones that were able to stay on palazestrant? Thanks so much.
Sure. So first of all, baseline characteristics. These are pretty heavily pretreated. So I would say there isn't anything in there certainly that favors this population. The things that I would point out is measurable disease at baseline is about 70%. The non-measurable disease patients, 70%/30% is pretty typical for positive, HER2 negative, advanced or metastatic. The non-measurables tend to be bone-only disease, and they do have a better prognosis. But again, this is very typical of what you will expect, what you will have seen in other data sets. Our visceral disease is actually a little high at 58%. 40% is more in line with what you expect. Visceral disease is a negative prognostic. And I think that the thing that's really surprising is 19% of patients had two prior CDK4/6 inhibitors. That also means two prior endocrine therapies.
And yet, we are, and by the way, a lot of those patients are ESR1 mutated. So we're seeing the profound effect in that prior CDK4/6 ESR1 mutant population. That actually is a very unusual patient population. We were actually surprised to see how active palazestrant is in that patient population. Discontinuation of both. I think, Naseem, if you don't mind, I'll hand over to you on discontinuations of therapies.
Yeah. Thanks, Sean and Anupam. So the two patients that discontinued both therapies, one came off for neutropenia and one came off for toxicities really related to ribo, but also had some neutropenia, so they discontinued both drugs.
So it's a physician decision upon what they do. We did have also some education when we started the trial. There were physicians who were holding both drugs for ribo toxicities, and we had to acquaint them with the tolerability profile so that they would maintain the palazestrant while, as is typical for some patients, holding and then potentially dose-reducing ribo.
Yep. Got it. Thanks so much, guys.
Thank you, Anupam.
And our next question comes from Rich Law with Goldman Sachs. Your line is open.
Hey, guys. Good morning and congrats on the progress. A couple of questions for me. So the first question is, any insight on the 26% of patients without the CDK4/6? I see that you guys have a waterfall chart, and there's one CR in there. So maybe just a little more insight on those patients without CDK4/6 and what do we do for the first-line setting potential? And I have a couple more follow-ups.
Yeah. So I mean, I guess the first thing I would say is that it's reflecting what was an evolving enrollment pattern of patients on the trial. So when we started the dose escalation and first started the expansion, we got the two priors. We were suspicious of that because we didn't think much would work there. The investigator said, "We'll stop doing it, but it does work." We see that in the waterfall and in particular the prior CDK4/6 and ESR1 mutant Kaplan-Meier curves. They then moved to one prior. Then toward the end, it was surprising to us, again, toward the end of the enrollments. Remember, the enrollment ended in March. They started to enroll patients in whom there had no prior therapy in the advanced or metastatic setting.
In other words, they're saying, "We're going to treat this like the standard of care, right? Ribo plus letrozole. We're going to have ribo plus palazestrant." So those patients are going to be very interesting. We anticipate that they could benefit for a very long time. They're in the relatively immature part of the curve right now. As I mentioned in answer to a previous question, it gives us the opportunity to provide a meaningful update in 2025 with more follow-up on everybody, of course. And we'd like—we'll get to a median. The longer it takes, the better, of course. But also to be able to start to characterize a little bit those first-line patients. I think, though, as I mentioned before, the activity we see in one and two prior CDK4/6s really validates the hypothesis as we go into OPERA-02 and preventing progression.
I got it. And I know you guys are—I asked you guys before if you guys would start a phase III, like a 2L plus study with ribo. And I feel like you guys said that looks interesting but not committed to it. How would you get this combo into the guidelines if you don't run such a study? Maybe a little bit about how that would be used and how that can be used in the guideline in the real-world setting.
Yeah. So I think there's kind of how it's used in the real-world setting, how it gets in guidelines, and how it gets approved, right? So what you can see, I'll stick mostly to the United States here because that's the largest market, and that's probably the most developed. We've got patients on this trial who this is their third prior CDK4/6 inhibitor. These oncologists are trying to keep off chemotherapy as long as they possibly can, and if it means switching within a class, they'll do that. They'll just switch CDK4/6 and switch endocrine. So the things you need to use it are approval in a line of therapy. In the second, third-line setting, OPERA-01 will support that approval, we hope, in ESR1 mutant and wild type. We think there's a good chance of that, but we'll see in 2026 when it reads out.
All the CDK4/6s are approved in that later line. That's how they started. So you can use the agents and have them reimbursed once they're approved in that setting. You don't have to do a pivotal trial. The thing that is needed to do that is to have an adequate safety data set and some indication that actually the patient might benefit. We think actually with this data and further updates to come, that's pretty well demonstrated with the data that we have right now. Then guidelines are more a judgment thing of the committees that make the guidelines.
We're not feeling like it's valuable enough to go out and run yet another second, third-line phase three trial with this combination when we have what we think is already a compelling monotherapy hypothesis over five months PFS in the wild-type over seven months in the ESR1 mutant just with palazestrant monotherapy in OPERA-01.
Thanks. Then just one final question from me. The QTc prolongation, maybe some color there in terms of what I think you guys have 31% all-grade and 5% grade 3. Maybe it's just a little bit of where are those coming from? The ribo end or is it from?
Well, you can look at slide eight. That's why we put MONALEESA-2 on here. This is the pivotal trial that led to approval of ribociclib in the context of AIs, letrozole in this case. That'll be the control arm, right, of OPERA-01 of OPERA-02, I'm sorry, because that's what we want to compare because that's going to be the way we're looking at AEs across the trial. What you can see is actually our QTc prolongation, if anything, all grades is just a little bit lower. We do not think that we're making ribo safer. Our 5% versus 8% for grade 3, I'd say that's the same. It's pretty clear it's coming from ribo. There's not a contribution. That's not of palazestrant.
That's not terribly surprising because, one, we know that palazestrant has no hERG effect. The second is that we've done well-controlled QT studies as part of the regulatory package for palazestrant, and we don't see any QT effect.
Great. Thank you. Congrats again.
Thank you.
Our next question comes from Sam Slutsky with LifeSci Capital. Your line is open.
Hey, good morning, everyone. Thanks for the questions and great work on the update. So slide 11, you show a few benchmarks for CDK4/6 pretreated patients. I guess you touched on it a bit, but just any nuances on these other studies regarding either trial protocols or baseline characteristics that may help or hurt them as you think about that cross-trial comparison?
Yeah. Not in particular. I mean, I can characterize a couple of things, right? So if you look at, well, you'll see the data. If you look at this study, right, our 003 study and the combo data presented here, if you look at MAINTAIN, if you look at postMONARCH, in the era in which these patients were treated and enrolled, most of the prior CDK4/6 is palbociclib, and that'll probably persist for quite some time. The new starts we know are moving toward ribo, but the people who are progressing at this time predominantly prior CDK4/6 is palbociclib. The Morpheus data set's quite small, so obviously that's. It's hard to characterize beyond that. But other than that, as I mentioned, we think we have a little higher visceral disease. None of these allowed two prior CDK4/6 inhibitors.
So obviously, that is an unusual aspect of the combination, which we were a bit reticent about to start with. But it turns out it works quite well even in that setting, palazestrant and ribo.
Got it. Thank you. Sure.
And the next question will come from Matthew Biegler with Oppenheimer. Your line is now open.
Hey, guys. Good morning. Thanks for this update. Sean, I know it's only a small sample. It's only four here. But the patients that got prior ribo treatment, how are they doing? Is it generally—are the outcomes generally consistent with the rest of the population? The reason I ask is because I think there's a lot of debate right now about whether you should actually switch the CDK4/6 backbone or keep it the same as you go from an AI to a SERD or vice versa. So do you have any kind of high-level thoughts on that? Thanks.
Yeah. So I guess a couple of things. Just to characterize prior CDK4/6, right, I think the number's a little low for ribo that you're giving. So the four that you're citing are from the patients who've had one prior CDK4/6. But if you go down on slide seven, you'll see that in the patients who've had two prior CDK4/6s, there's another four who have had ribociclib in some context. So it's actually eight. We haven't done a subset characterization at this point in time on those patients, but I think the point is that we do really well prior post-CDK4/6, and that's a significant subset of patients, so it's not clear to me that the CDK4/6 inhibitor is driving what we're seeing here. The big change is palazestrant, and we saw compelling activity, remember, as a single agent.
You didn't even have a CDK4/6 present, and that's what we presented at ESMO last year, so it is an interesting question. I don't know that anyone will ever do a randomized trial of, "Do you switch or don't you switch?" or, "Do you just switch endocrine or do you switch CDK4/6?", but I do think it is an interesting question. I do think we're seeing a lot of CDK4/6 use post-CDK4/6.
Yeah. Agreed. Thanks for that color.
Thank you.
As a reminder to ask a question, please press star one one on your telephone. And the next question comes from Emily Bodnar with H.C. Wainwright. Your line is open.
Hi. Good morning. Thanks for taking the questions. I guess I wanted to follow up on the EMBER-3 study. Since they're also evaluating a combo with abemaciclib, I guess if they saw improved benefit there, how do you kind of think that would impact the second-line, third-line setting in the next few years? And would that pose any challenges in terms of using palazestrant as a monotherapy? Thanks.
Yeah. Thanks, Emily. So first of all, you're asking for commentary on a study that's not been presented. So it's a little hard to comment. We believe that adding a better endocrine agent is a meaningful opportunity post-prior CDK4/6 plus an AI. And that's quite compelling here. I think it hasn't been compelling in the prior data sets. I don't know what it'll look like in EMBER-3. I think what we see from EMBER-3 will be really important because, again, we think the relevant comparators, patients who've had prior CDK4/6 inhibitor, and EMBER-3 is a complex study. It's a mixture, as we understand it, of treatment naive and prior CDK4/6. I think that there will be room for both the combination and the monotherapy.
A nd the reason for that is if you look at the practice pattern of physicians, even in the first line, there's almost an ageism from real-world data. Even first-line patients, as they get older, are given monotherapy, endocrine therapy. They aren't given a CDK4/6, and that's probably because physician judgment of their comorbidities makes them concerned that they are going to have difficulty tolerating the combination regimen. And so the decision, it's fine to see the guidelines, but the decision as to what an individual patient gets is an evaluation of the very complex history and comorbidities and prior treatments of that patient in addition to the treatment objectives. So I don't see this as being at all an impediment.
Rather, it's actually an opportunity because you're going to want to use the best endocrine agent you can, regardless of whether you're giving it as a monotherapy or if you're deciding to bring in another CDK4/6 or another targeted agent, right? So our KAT6 inhibitor just had its IND cleared. We announced that yesterday. So that's a promising new pathway. The PI3 kinase inhibitors, alpelisib's tough, evolving toward mutant selective. That's exciting stuff. The capivasertib is going into that space as well. And then, of course, there's everolimus. So I think having the best endocrine agent and having very favorable combinability at full doses of both agents is an opportunity.
I show no further questions at this time. I would now like to hand the call back over to Sean Bohen for closing remarks.
Thank you all for taking the time to join us today. As you've heard, we're excited about the data we've shared and that we will be presenting tomorrow as well. That, of course, an earlier data cut. We believe palazestrant has the potential to become the endocrine agent of choice for patients with metastatic breast cancer, both as a monotherapy and in combination with other targeted agents. We are fully committed to delivering our anticipated milestones in the upcoming year, 2025 and beyond, obviously, as we seek to develop innovative medicines designed to help patients feel better for longer. And we appreciate your continued interest in Olema. Thank you.
This concludes today's conference call. Thank you for your participation. You may now disconnect.