Arvinas, Inc. (ARVN) Earnings Call Transcript & Summary

Hello, and welcome to the ESMO Data Presentation. [Operator Instructions] Please be advised that today's conference is being recorded. It is now my pleasure to introduce Vice President of Investor Relations, Jeff Boyle.

Hello, everyone, and thank you for joining us to discuss the Phase I/II bavdegalutamide data that was presented earlier today at the European Society for Medical Oncology in Madrid, Spain. Today, we will also be sharing new interim data from our second PROTAC AR degrader, ARV-766, as well as providing an update on development plans. Earlier this morning, we issued a press release outlining this presentation, which can be accessed in the Investors section of our website at arvinas.com. With me today are Arvinas' President and Chief Executive Officer, John Houston; and Arvinas' Chief Medical Officer, Ron Peck. Also joining at the end of the presentation is Dr. Dan Petrylak of Yale University and an investigator in the bavdegalutamide in ARV-766 trials. Dr. Ian Taylor, Arvinas' Chief Scientific Officer, will join for the Q&A portion of the call. Before we begin, I want to remind you that today's discussion will contain forward-looking statements that involve risks and uncertainties. These risks and uncertainties are outlined on Page 2 of the presentation in today's press release and on the company's recent filings with the Securities and Exchange Commission, which we urge you to read. Our actual results may differ materially from what is discussed on today's call. And now, I'll turn it over to our CEO, John Houston. John?

Thanks, Jeff, and thank you all for joining us this morning to talk about the significant update to our AR programs, including the very exciting bavdegalutamide data that shows an impressive radiographic progression-free survival of 11.1 months in this post-NHA heavily pre-treated patient population. We're also going to walk you through some intriguing new data from our second-generation PROTAC AR degrader, ARV-766, which we now believe shows that ARV-766 is superior to bavdegalutamide, and allows us to prioritize it for both the early and late-line prostate cancer settings. Now, before I turn the call over to Ron to provide a detailed review of the data from both bavdegalutamide and ARV-766, I want to give you a preview of why we are so excited by the opportunity in front of us. Bavdegalutamide was the first ever PROTAC degrader in the clinic, and has clearly proven the concept of an AR degrader in prostate cancer and provided us with significant knowledge on what it takes to make a differentiated protein degrader. An rPFS of over 11 months in patients with tumors that have the AR-878/875 mutation is impressive, and was certainly beyond our expectations given the heavily pre-treated patient population. In addition, bavdegalutamide continues to show a manageable tolerability profile that is appropriate in the metastatic castration-resistant prostate cancer, or mCRPC patient population. However, we've also learned over time that bavdegalutamide has some limitations. We know that bavdegalutamide purely degrades the AR L702H mutation, and we see that efficacy is greatly reduced in tumors when the mutation is present. We also noticed a mutation that is increasing in prevalence in the mCRPC setting. ARV-766 is our next-generation PROTAC AR degrader designed specifically as a pan AR LBD degrader with an expanded efficacy profile as it potently degrades the L702H mutation that bavdegalutamide does not. The ability of ARV-766 to degrade L702H suggests that its addressable patient population could be 3x greater than bavdegalutamide in mCRPC. So today, we'll provide some updated data from ARV-766, showing a PSA50 rate of 50% in patients with tumors containing the L702H mutation, and a 41% PSA50 in all patients with AR ligand binding domain mutations in the tumors. For comparison, bavdegalutamide has shown only an 8% PSA50 rate in patients with tumors harboring this L702H mutation. Our decision to prioritize ARV-766 for both mCRPC and metastatic castration-sensitive prostate cancer was influenced by not only the promising efficacy data and the ability to degrade all clinically meaningful AR LBD mutations, but also by an excellent tolerability profile, an essentially important attribute in an early-line setting. With this in mind, we have switched our focus from bavdegalutamide to ARV-766, and we plan to initiate a Phase III trial in mCRPC as soon as possible. With ARV-766 broader efficacy profile and superior tolerability, we believe the addressable patient population for ARV-766 could be up to 120,000 patients across the CRPC and CSPC settings. So before I turn it over to Ron, I want to thank Dr. Dan Petrylak, an investigator in both the bavdegalutamide and ARV-766 trials for taking time to join us at the conclusion of this presentation. He can relieve his experience with both bavdegalutamide and ARV-766 in the clinic and will provide his perspective on the path forward. But now, I'll turn it over to Ron to walk you through the bavdeg and ARV-766 data. Ron?

Thanks, John. So let's begin with the bavdegalutamide data shared this morning, starting with Slide 5. As you know from our prior data disclosures, bavdegalutamide has shown great promise in patients who have progressed on novel hormonal agents like enzalutamide or abiraterone, who have tumors that contain mutations in the AR ligand binding domain, which I'll refer to as LBD. The unmet medical need in castrate-resistant prostate cancer is especially high in this group of patients who have become resistant to NHAs. Based on several recently completed studies, the median rPFS in this group of patients is only around 3.5 months to 4 months when NHAs are reused in this late-line setting. Emerging non-AR therapies provide better outcomes, but are limited by tolerability issues, requirement for IV administration and other restrictions. Our new data continue to support the strong activity of bavdegalutamide in the post-NHA setting. Bavdegalutamide degrades all clinically-relevant AR LBD mutations except for the L702H mutation. We also know that AR LBD mutations are associated with worse survival in metastatic castration-resistant prostate cancer based on novel data that we reported at ESMO last year that [indiscernible] to the fact that these mutations are linked to the emergence of NHA resistant. We discovered early on in bavdegalutamide's development that post-NHA patients with LBD mutations are much more likely to respond, and we believe that this is because LBD mutations identify which tumors in this late-line setting remain addicted to androgens in this population. So now let me take you through the data shown at ESMO. On Slide 6, we show the Phase I/II trial design. And on the left side of the page shows the standards we put 3 Phase I dose escalation design that was employed. Dose of bavdegalutamide was escalated to a maximum of 840 milligrams daily. The recommended Phase II dose was identified as 420 milligrams once daily. On the right side, we describe the ARDENT Phase II expansion cohort, which is designed to explore the efficacy of bavdegalutamide in a post-NHA setting. Multiple subgroups were prospectively stratified by AR genetic profiling as measured by ctDNA. The data from today's presentation focused on those tumors with AR LBD mutations with emphasis on the 875, 878 and L702H mutations, the 3 most common AR LBD mutations. Slide 7 shows the baseline characteristics for the study patients, all again, who were post-NHA. Right column breaks down the characteristics for both the total population and the group with AR LBD mutations, the group we'll focus on today. Baseline characteristics were consistent between the 2 groups. As you can see, these patients were extensively pre-treated receiving a median of 4 prior lines of therapy. Notably, approximately half of all patients received 2 or more prior NHAs, and approximately 1/3 had previously received Taxane chemotherapy. On Slide 8, you see that treatment-related adverse events were manageable, but there is room for improvement, especially with regard to GI-related toxicities like nausea, vomiting and diarrhea. As I'll show shortly, our next generation AR PROTAC degrader, ARV-766, has overcome these potential limitations and continues to show a superior tolerability profile compared to bavdegalutamide. On Slide 9, we show the Kaplan-Meier curve for the subpopulation with tumors that have the 878/875 mutations without co-occurring 702H mutations. The impressive rPFS of 11.1 months in this population greatly exceeded our expectations. To put these results into context, I mentioned earlier that the rPFS in patients retreated with other NHAs, specifically enzalutamide and abiraterone, as it consistently ranged in this late-line setting from between 3.5 months to 4 months. As additional background on Slide 10, we look at data from standard of care non-AR treatments, the chemotherapy agent, cabazitaxel, the radioligand Pluvicto, and the 2 PARP inhibitors, which are all approved in this post-NHA setting. Median rPFS for these treatments range from 7.5 months to 10.2 months, although the rucaparib trial was -- which had the PFS of 10.2 months was the upper range, and it was different in terms of the patient populations that were studied and that this population was much less pre-treated. Specifically, these patients were precluded from having received chemotherapy in the castrate-resistant setting. Shown in the right in the first row, bavdegalutamide stacks up very well with a median rPFS of 11.1 months and a PSA50 rate of 54% in this AR 878/875 population. We also included in the table results in the broader AR LBD mutation group as presented in the poster from this morning, showing a median of rPFS of 8.2 months and a PSA50 rate of 36%. While the slide depicts a cross-study comparison and not a true test of how these treatments compare, it is clear that bavdegalutamide is performing at a very high level with a profile that is, we believe, quite competitive with the standpoint of benefit risk and more convenient route of administration. Overall, we are very pleased with these results, and we believe that these results provide evidence that an AR PROTAC degrader has the potential to become an important treatment class for patients with advanced prostate cancer. Bavdegalutamide's efficacy in the patient population is quite impressive, especially in patients with the AR 878/875 mutations. But as John mentioned, upfront, we have seen bavdegalutamide's inability to potently degrade the AR L702H mutation, greatly diminishes its efficacy when this mutation is present. On Slide 11, the first row includes patients with 878/875 alone with L702H, and we see a very robust PSA50 of 54%. However, we see, as shown in row 2, that PSA activity is much less in patients with tumors having 878/875 mutations that co-occur with the AR 702H mutations. 702H action may concur in as many as 40% of tumors with 878/875 mutations. In these patients, the PSA50 rate was 9%. If you look more broadly in the group of patients that have L702H mutations, whether alone or in concurrence with one of the other mutations, the PSA50 rate is 8%. That's shown in the third row of the table. So quite clearly, the presence of L702H significantly impacts bavdegalutamide's efficacy. Turning to Slide 12. I'll wrap up with the update on bavdegalutamide before turning to 766. Overall, bavdegalutamide provides strong evidence that an AR PROTAC degrader can have robust efficacy in post-NHA mCRPC, especially in patients with tumors that harbor AR 878/875 mutations alone. We were really excited to see the RPFS of 11.1 months in this population. But as mentioned earlier, the inability to potently degrade AR L702H diminishes bavdegalutamide's efficacy in patients with bav mutation, which will limit its addressable patient population. This is why we are even more excited by the potential of our next-generation AR PROTAC degrader, ARV-766, which has even better tolerability and a broader efficacy profile that could reach 3x more patients in mCRPC. With that, I'll transition to an update on 766. Today, I'll describe why we believe that 766 could become an even better choice than bavdegalutamide for patients with both early and late-line prostate cancer. ARV-766 was designed to degrade wild-type AR and all clinically-relevant AR LBD mutations, including L702H. When we designed 766 as a backup for bavdegalutamide, L702H was considered to be as prevalent. Today, L702H is the most common AR LBD mutation, representing approximately 11% of patients with castrate-resistant prostate cancer. In total, the prevalence of all AR LBD mutations in mCRPC is between 20% and 25%. In preclinical studies, ARV-766 degraded L702H and all clinically-relevant AR LBD mutations as shown on the graph on the right. Looking at Slide 15. Recall that in June, we showed a strong PSA rate in post-NHA patients across all LBD mutations, including L702H. Notably, safety profile for 766 was extremely favorable. Frequency of TRAEs was low and only 1 discontinuation and 2 dose reductions were reported. Today, we see that activity remains robust across all AR LBD mutations with a PSA 50 of 41%. And in patients with L702H mutations, 50% achieved the PSA 50. As a reminder, bavdegalutamide showed a PSA 50 of 9% in patients with L702H mutations. Importantly, the tolerability profile remains highly differentiated and superior compared to bavdegalutamide as we see on Slide 16. I won't go through all the data here, but it's clear from all the zeros in the dark blue columns that 766 appears to have a remarkably clean tolerability profile and has the potential to differentiate from other therapies for advanced prostate cancer. A particular note in the red box, the GI treatment-related adverse events seen with bavdegalutamide were significantly less frequent with ARV-766. As shown on Slide 17, we also saw deep PSA declines in the trial with ARV-766. The chart shows the PSA response data from 17 patients whose tumors had AR LBD mutations. 41% achieved the PSA50, and several remain on treatment. On Slide 18, we highlight the activity of 766 and L702H mutations. While in the last section, we showed that presence of L702H greatly diminish the activity of bavdegalutamide, with ARV-766, however, we see a robust PSA of 50% in tumors with L702H. This is a meaningful contrast to the PSA50 rate of 8% for bavdegalutamide in the same patient population. And in addition to the 41% PSA50 rate in these AR LBD mutations, we are seeing very encouraging early durability data for 766 and mature PFS data are expected in 2024. All told, these updated data give us the confidence to prioritize ARV-766 over bavdegalutamide for registrational development in mCRPC. While we focus the conversation around the activity of both AR PROTAC degraders in patients with LBD mutations, as you see on Slide 19, we are seeing responses in patients that AR wild type. The activity in this population is hampered by the extensive non-AR independent mechanisms of resistance. Nonetheless, this notable response in a post-NHA patient had a 99% reduction in PSA and remains on treatment beyond 9 months, indicates the potential of 766 in earlier settings where AR independent resistance is uncommon. We intend to advance 766 into CSPC setting in addition to the mCRPC setting. Turning to Slide 20. I'll explain how the expanded profile of 766 has the potential to reach a significantly broader patient population. Bavdegalutamide's addressable population may be limited to about 8% of castrate-resistant prostate cancer for about 11,000 patients across US, Europe and Japan. 766's addressable population on the other hand will be patients with tumors harboring any LBD mutation, which accounts for approximately 25% of CRPC or about 35,000 patients. And as mentioned on the last slide, we have confidence to bring 766 to the setting of castrate-sensitive prostate cancer as well. This could represent an opportunity, which impacts approximately 87,000 additional patients bringing ARV-766's total addressable population to approximately 120,000 patients. On Slide 21, we're summarizing our rationale for prioritizing 766, with the strong belief that this molecule is better suited to become a best and potentially first-in-class treatment for early and late-line prostate cancer. The development of bavdegalutamide, the first AR PROTAC degrader to be studied in patients has provided a great deal of data and learnings that we are applying to 766's development, allowing us to close the gap in timing between the 2 programs and refine our registrational strategy. And most important learning is that while bavdegalutamide has potential to be a great therapy in a smaller population, 766 could be even better and in a much broader population of patients. And now, I'll turn it back over to John.

Thanks, Ron. So to summarize on Slide 23, we're clearly very excited and pleasantly surprised to see the 11.1-months rPFS with bavdegalutamide in such a late-stage patient population. We believe this result demonstrates the unique benefit of a PROTAC protein degrader in the mCRPC space. However, we are very committed to bringing forward the best PROTAC AR degrader possible for patients. And we believe the data now tells us that the best AR degrader is actually ARV-766. Now, we've been able to take a lot of lessons from the design and early development of bavdegalutamide and transfer this knowledge theoretically to the design and development of ARV-766. And the good news is that -- and that has allowed us to move ARV-766 to the point where it closes the gap on bavdegalutamide and is now not that far behind, a fact that also influenced our decision making. ARV-766 efficacy profile, including strong PSA50 [ rates ] in tumors with all AR LBD mutations, early signals of durable responses and its excellent tolerability profile make it clearly the best choice to advance in both mCRPC and mCSPC. And as you've seen, ARV-766 can also benefit a much larger patient population. And so we are excited to begin discussions with regulatory authorities in the first half of next year to move this asset to Phase III as quickly as possible. Now before we open the call for Q&A, I want to introduce Dr. Dan Petrylak. Dr. Petrylak is a Professor of Medicine and Urology, and Chief of Genitourinary Oncology at the Yale School of Medicine. And importantly, he has been very active in both the bavdegalutamide and ARV-766 programs. So as we close our prepared remarks, I'd like to ask Dan to share his thoughts on the bavdegalutamide poster he presented at ESMO Congress earlier today, as well as his clinical perspective on our AR assets overall. After that, he will also join us for the Q&A portion of today's call. Dan?

Thank you so much. Great presentation. And I think this is really a terrific drug. From what we saw today at ESMO, I think it's important to note that this radiographic progression-free survival is really amongst the longest that we've seen for any single agent. And of course, this is in a select group of patients with ligand binding domain mutations. This is going to become a more important problem in castration-resistant prostate cancer. As we know, these ligand binding mutations develop over time and with exposure to next-generation antiandrogens such as abiraterone, enzalutamide and darolutamide. And in fact, it's present in about 3% of patients who are castrate-resistant but have not seen these particular drugs. And as time develops, those patients will develop ligand binding mutation aberrations. In the hormone-sensitive state, prior to castration resistance, we're now routinely using these agents for longer periods of time, meaning the next-generation anti-androgens. So the potential for seeing more frequent amount of ligand binding domain mutations in this disease is there. And I think right now, we're seeing 25% of patients expressed this, we may see this even more frequently in the future. So, I think this is an important target for the treatment of castration-resistant disease. Looking at the 2 different drugs, we've seen clinical activity with both the 110 compound and 766. And my impression is that these drugs do have significant activity, but also 766 does seem to be a better tolerated drug. My patients note that they feel better than they do on next-generation anti-androgens such as abiraterone, enzalutamide. They don't seem to have that fatigue and the brain fog that goes along with those particular drugs. So, I think this is going to be an important development in the treatment of these patients. It's not unusual to see compounds that are similar in mechanism selected or moved forth in this disease process. And I've had the experience of working with many drugs in prostate and bladder cancer, but most recently have worked with both enfortumab vedotin, as well as a second antibody drug conjugate that was being codeveloped at the same time. We decided that enfortumab was the best drug to go forth with based upon toxicity as well as efficacy. And this is a very, very analogous situation where we have 2 drugs that have significant activity, yet we've learned from our experience in Phase I, how to use these drugs, what their potential side effects are and, of course, what the efficacy is. And so I think it's really -- that experience is going to be applied to 766 and its further development.

Great. Great. Thank you so much, Dr. Petrylak. I don't know, Ron, if you wanted to add anything.

No, I think that -- maybe it's a question about how you imagine if we are successful in moving these to patients, how you imagine that these would fit in the landscape?

So, I would see these fitting in the landscape right at the beginning of castration resistance since we are using the next-generation androgens early. Patients have limited choices as to what to go forth with. We generally don't like to use sequential next-generation anti-androgens because the data show that it really does not work. So, we have to go forth with a different mechanism. And then, of course, we're looking at drugs such as chemotherapeutic agents such as cabazitaxel and docetaxel, also Lutetium PSMA, that's going to be looked at in this particular space as well and their advantages to 766 in terms of toxicity, in terms of route of administration. So, I've seen this being right at the beginning of castration-resistance, oral compound, easy to administer and doesn't require a lot of logistics to get these -- get the patient treated.

Maybe one more question is from the standpoint of a clinical trialist who has been doing calls for a very long time. Maybe you can just comment on the consequence of moving to 766 in terms of feasibility of doing a trial versus the where the addressable population is 8% by mutation.

Right. Exactly. So, we're going from an 8% population to at least a 25% population. That's parallel to what we see with the PARP inhibitors in prostate cancer. We know that it's actually a little bit better than what we see with BRCA1 and BRCA2, but that's about the level as to what you would see. So, I think that this is going to be a significant target within castrate-resistant disease. And as we know, there are more mutations to develop us as tumor becomes genetically unstable. So the earlier we use some of these other agents in castration resistance, the more relevant this is going to be.

That's great. Well, listen, thanks so much again for your time. I know you have a lot going on here. Operator, with that, I think we're ready to open up Q&A.

[Operator Instructions] Our first question comes from the line of Tazeen Ahmad with Bank of America.

Happy Sunday. Just as a point of clarification, you mentioned that you're going to start regulatory discussions next year to move into Phase III. Is it your understanding that you would not need to do any other work ahead of starting the pivotal program? Also, can you remind us where you are on doing tox work, long-term tox work for 766? And then the third part of the question is you talked about having a castration-sensitive population of 87,000 patients. Would that sub-population be included in your plans for Phase III?

Thank you. Great question. And obviously, Ron will be able to put some more color on to that. In terms of what we plan to do with the 766, clearly, our game plan is to have a dialogue with the regulatory authorities in the first half of the year. As you know, bavdegalutamide was initially targeted to Phase III a while back. And we're approaching Optimus push us down a path of looking at a lower dose as part of that kind of interaction with FDA. With 766, we've taken all those lessons and feedback from the FDA. So as we look at what our Phase III dose would be, we've looked at 2 doses in a randomized study. So hopefully, the data we've generated there, we'll go forward to the FDA, and we'll have a different scenario is what we had with bavdegalutamide. In terms of all the talk, all the talks was done a while back. And of course, we're running 766 in a normal clinical trial where we're generating that data. Ron, anything you want to add there and also about the CSBC and how that fits into what our plans are overall? I know our next trial is CRPC. So talk to that?

Yes. Yes. I think the comment about project Optimus was just, as John said, this is one of the examples of what we've learned from bavdegalutamide. It's our first trial where we are randomizing between 2 doses and actually, both doses we're very comfortable with. And the safety advantage is seen even at the highest dose. We have 2 doses of 300 and 100 and even 300 is much safer than bavdegalutamide. So, we're well positioned to have the right conversations that we believe for dose. That's the main thing. And then from the standpoint of Phase III plans, I mean, what we could say is that this is going to be a precision medicine approach in post-NHA castrate resistance. We can't get into any more details right now. It's quite early. But we'll, of course, provide those details as we advance our plans. But we are still very -- so it won't include castrate sensitive. Very interested though in castrate sensitive, I mean, [indiscernible] Petrylak and I, who we've known each other for quite some time, and we've talked about what could be a really great advantage for ARV-766 in earlier settings. I mean, this is where -- there's more data from Embark being presented. So, we even think about even getting that early. But not for this Phase III, that will be coming down the road.

And our next question comes from the line of Tyler Van Buren with TD Cowen.

Thanks for the presentation. The prioritization of 766 is certainly rational. I have a couple for you. The first one is, as of the June update, I believe you guys had 4 RECIST-evaluable patients with 1 confirmed and 1 unconfirmed. So can you give us an update in terms of RECIST-evaluable patients and the response rate and put that into context with what we've seen with competing agents like radiopharma therapies? And then the second one is on durability. So in the deck, when you state early durability data for ARV-766 are encouraging, can you elaborate on what exactly you're seeing in these initial patients?

Ron, do you want to take that?

Yes. So the first question was around RECIST. So, we didn't have the RECIST data detailed in this presentation for 766. We will have -- our aim is to have a disclosure plan around the Congress in 2024. So, we'll have all those data. I will say that since June, we have been hearing about more RECIST responses, including -- we're starting to see even in patients with wild type. So that's -- we are positive about that. And then can you restate your second question? I think I may have missed that.

Ron, durability of 766?

Yes. Yes, certainly. Yes, I mean, one thing that we've done is, while we don't, of course, have mature data for PFS for 766, we've done a variety of different ways to sort of look at duration as a surrogate, let's say, for PFS. And one thing that we did was to look at an apples-to-apples comparison at the same point of development between bav and 766. The metric that we looked at was a percent of patients who were still on treatment after 6 months. And we're very much in line with what we're seeing with bav for 766, both all comers and then in the relevant mutations. So, we're quite confident on that. [indiscernible] next question, I do want to make a point. And this is actually one that Dan has basically fed back to us is, it goes without saying when you have a drug that has a better safety profile, then you have a lot of confidence that they can stay on therapy up until progression. That's always one of the limitations for any drug that's in development for cancer. If you can't -- if you have to have modifications or interruptions or things like that, that compromises your efficacy. That's just another point where we feel really good about the 766.

And our next question comes from the line of Derek with Wells Fargo.

Maybe just first, are you planning to have the PFS data for 766 when you initiate the discussions with the regulatory agencies for the Phase III in the second quarter of 2024. So that's the first question. And then just in terms of like spend. So shifting to 766 now kind of increase the runway at all. Obviously, it seemed like you were planning to develop both into registration. So now it's only one. Just thoughts on that.

Thanks, Derek. I'll start with the second one and Ron can talk to the PFS. Yes, clearly, by not initiating bavdegalutamide Phase III by the end of this year and shifting to a start on 766, clearly, we won't be running the costs there. We'll move those costs out into either tail end of this year or beginning of 2025. So, Sean and the team are obviously looking at how that positively affects us and it is a rational decision. When we realized that 766 was pretty close to where -- it would be an odd decision to run 2 Phase IIIs in close proximity. I think we made this, and we saw the data that was coming in from 766. So, I think it was a rational decision for us to say, let's spend the money most effectively in the drug that we think is going to win. And we believe that's 766. Sean and the team here will -- are incorporating all of that into our kind of forward planning. Ron, the PFS discussion?

Yes. So, what we said today is that we would expect to have PFS next year, 2024. I will say with regard to the question about do we need this for the FDA, the answer is that at least for bavdegalutamide, it was not a necessity. The FDA was more interested in other evidence to support dose, and we have really good exposure response data that helps us in taking the right dose. So, PFS was not a necessity for the FDA discussions for bav.

And our next question comes from the line of Ellie Merle with UBS.

Just thinking about the L702H patients relative to the 878/875 patients, maybe just in clinical practice today, any differences in patient outcomes between the mutations and then also just in terms of the overlap between mutations, any info on the overlap between L702H mutations and BRCA? And then just a second question on the regulatory strategy. So just for CSPC, I guess, how should we think about, when we can get clarity on that strategy? And just how long and how large of a trial do you think this will need to be? And just give us a pretty early line. I guess, how are you thinking about if you'd want to still do this alone or potentially think about collaborations there?

Thanks, Ellie. Again, Ron, and maybe Dan can talk to that first question. But the second one, clearly, we'll be mapping out a regulatory plan and the overall plan for how we get into CSPC. Obviously, a much bigger enterprise in terms of trial size than CRPC. And as we've said in the past, that scenario clearly would lend itself to having a partner. So, we will progress as normal with our approach to initiate our Phase 3 on 766 on mCRPC. But yes, having a significant strategic partner for 766 as it moves to CSPC would be, I think, a relatively smart thing to do. Ron, and maybe even, Dan, on the profile of 702H, 878 implied BRCA?

Yes. I'll start and then maybe I will ask Dan if he wants to add anything. I think, back to outcomes, I mean, I think -- and I'll just kind of refer back to the data that we had at ESMO from a Guardant partnership. They have the marketed ctDNA test, and there was an analysis last year at ESMO that showed that outcomes overall for 878/875 and that included patients with co-occurring 702H did worse. So, I mean, that was important for us to understand that because the first question always is, is this just a better population? The answer is, if anything, this population actually seems to do worse. And then the overlap with BRCA, I think, as I understand, there hasn't been a whole lot of relationship here. But maybe, Dan, do you want to comment on the...

I don't know of a formal relationship, but just from my impression, thinking back to the patients that do have positivity for the androgen receptor mutants, I can't remember an association with BRCA, at least in my clinical experience. So, I don't recall of anything published, but it certainly needs to be looked into.

[Operator Instructions] And our next question comes from the line of Brad Canino with Stifel.

And congrats on the progress with the franchise here. As I look at the 766 data, you're seeing that 50% -- PSA50 in the L7 patients, but a 41% overall, which I guess might imply you're seeing 30-ish percent PSA in 15 other mutations. I guess any comments you can provide there? Because really, what I'm trying to understand is, should we expect that you get that headline 50%, 11-month PFS with 766 in this expanded biomarker cohort when you report data in 2024? Or is like 40% 8 months like we see in perhaps broader AR LBD population, probably the better benchmark to think about?

Thanks, Brad. Great question. Ron, do you want to -- I think you touched on this earlier in some of your answers, but do you want to go through this again?

Yes. I think -- I mean, there's a couple of things that I would like to comment on. Of course, they're all relatively small numbers, I think. But when looking at 766, a couple of points to make is, is that 41% is based on an ongoing data set. There are still patients who are on treatment. One thing that even Dan and I have been talking about is that there's natural heterogeneity here in the population. So, for instance, we have learned that non-AR mutations, the big drivers for AR independent resistance, P53, AKT pathway aberrations, these things are -- we've found highly prevalent in this post-NHA setting. We've had that data presented at [ ASPRG ] a year and a half ago. So if by the luck of the draw, we have more P53 in the patients, and we haven't done that analysis in 766 or not. So for me, my sense is that the answer may be somewhere in the middle, but I would say biologically and pharmacologically, 766 is, let's say, just from a pharmacologic perspective a better drug. It's a better drug from a pharmacokinetic perspective. It's much less variable from the exposure relative to preclinical thresholds, even at the 100 lower dose that we're testing. It's at least as good as what 420 delivers for bavdegalutamide. Preclinically, it performs exactly the same way with the exception of 702H where it does cover it and bav does not. So from all that totality of the data, we feel like these 2 are going to be quite comfortable, what turns out in the end of the day and maybe it's somewhere in the middle. But I don't know, Dan, do you want to have anything else you want to add to that?

No, I think the key here is the heterogeneity of the disease. And as time goes on, it becomes more heterogeneous because of the mutations that develop. And this has reflected itself in how we measure response in this disease. So years ago, when I published the first data with docetaxel, we actually came up with this PSA50 and [ PSA30% ] in terms of cytotoxic therapy. It may be very, very different for a hormonal agent in the situation. So, that's why we look at PSA declines. That's why we look at rPFS. My sense has been with the patients that we've treated that we've had fluctuations in PSA with stabilization of their scans. And so this is one of the things, I think, is really, really important, PSA never kills anybody. It's the effect of the prostate cancer cells on bone, on liver and other organs. So, I think what you have to do is not only look at the PSA declines, look at the rPFS, look at the patient's quality of life. And when we start looking at these parameters together, this looks like a very, very positive drug.