Hello, and welcome to the ESMO Data Presentation. At this time, all participants are in a listen-only mode. After the speaker presentation, there will be a question-and-answer session. To ask a question during the session, you will need to press Star one one on your telephone. You will then hear an automated message advising that your hand has been raised. To withdraw your question, please press Star one one again. 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 investor 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. Daniel Petrylak of Yale University, and an investigator in the bavdegalutamide and ARV-766 trials. Dr. Ian Taylor, Arvinas's 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 this presentation, in today's press release, and on the company's recent filing 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 pretreated 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 it 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 T878, H875 mutation is impressive and was certainly beyond our expectations, given the heavily pretreated 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 poorly degrades the AR L702H mutation, and we see that efficacy is greatly reduced in tumors when the mutation is present. We also know it's 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 3 times 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 its excellent tolerability profile, an especially important attribute in an early line setting. With this in mind, we've 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's 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 relay 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 bavdegalutamide 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 castration-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 3.5-4 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 castrate-resistant prostate cancer, based on real-world data that we reported at ESMO last year. That is to the fact that these mutations are linked to the emergence of NHA RECIST. 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 then on the left side of the page shows the standard 3 + 3 phase I dose escalation design that was employed. The dose of bavdegalutamide was escalated to a maximum of 840 mg daily. The recommended phase II dose was identified as 420 mg 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 H875, T878, and L702H mutations, the three most common AR-LBD mutations. Slide 7 shows the baseline characteristics for the study patients, all again, who were post-NHA. The 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 two groups. As you can see, these patients were extensively pretreated, receiving a median of 4 prior lines of therapy. Notably, approximately half of all patients received two or more prior NHAs, and approximately1/3 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 T878, H875 mutations without co-occurring L702H 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 abiraterone, as it consistently ranged in this late-line setting from between 3.5-4 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 two PARP inhibitors, which are all approved in this post-NHA setting. Median rPFS for these treatments ranged 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, in that this population was much less pretreated. Specifically, these patients were precluded from having received chemotherapy in the castration-resistant setting. Shown in the right, in the first row is bavdegalutamide stacks up very well with a median rPFS of 11.1 months and a PSA50 rate of 54% in this AR T878, H875 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 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 standard 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 protein degrader has the potential to become an important treatment class for patients with advanced prostate cancer. bavdegalutamide's efficacy in the population is quite impressive, especially in patients with the AR-878, 875 mutations. But as John mentioned upfront, we have seen that 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, without 702H, and we see a very robust PSA50 of 54%. However, we see, as shown in slide in row two, that PSA activity is much less in patients with tumors having 878, 875 mutations that co-occur with the AR L702H mutations. L702H actually may co-occur 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 protein degrader can have robust efficacy in post-NHA mCRPC, especially in patients with tumors that harbor AR T878, H875 mutations alone. We were really excited to see the rPFS of 11.1 months in this population. But as I mentioned earlier, the inability to potently degrade AR L702H diminishes bavdegalutamide efficacy in patients with that mutation, which will limit it, limit its addressable patient population. This is why we are even more excited by the potential of our next generation AR protein degrader, ARV-766, which has even better tolerability and a broader efficacy profile that could reach three times more patients in mCRPC. With that, we'll transition to an update on ARV-766. Today, I'll describe why we believe that ARV-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 ARV-766 as a backup for bavdegalutamide, L702H was considered to be less prevalent. Today, L702H is the most common AR LBD mutation, representing approximately 11% of patients with castration-resistant prostate cancer. In total, the prevalence of all AR LBD mutations in mCRPC is between 20%-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 ARV-766 was extremely favorable. Frequency of TRAEs was low, and only one discontinuation and two dose reductions were reported. Today, we see that activity remains robust across all AR-LBD mutations, with a PSA50 of 41%. And in patients with L702H mutations, 50% achieved the PSA50. As a reminder, bavdegalutamide showed a PSA50 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. Of 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. 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 in L702H mutations. While in the last section, we showed that presence of L702H greatly diminished the activity of bavdegalutamide. With ARV-766, however, we see a robust PSA50 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, AR PROTAC degraders in patients with AR LBD mutations, as you see on Slide 19, we are seeing responses in patients with AR wild-type. The activity in this population is hampered by the extensive non-AR independent mechanisms of RECIST. Nonetheless, this notable response in a post-NHA patient who had a 99% reduction in PSA and remains on treatment beyond 9 months, indicates the potential of ARV-766 in earlier settings, where AR independent RECIST is uncommon. We intend to advance ARV-766 into CSPC setting in addition to the mCRPC setting. Turning to Slide 20, I'll explain how the expanded profile of ARV-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, or about 11,000 patients across U.S., Europe, and Japan. 766 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. 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 development, allowing us to close the gap in timing between the two programs and refine our registrational strategy. 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. 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-month 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 directly 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, remains 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 anti-androgens, 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, a number of patients will develop ligand binding mutation aberrations. In the hormone-sensitive state, prior to castration RECIST, we're now routinely using these agents for longer periods of time, meaning the next generation of androgens. So the potential for seeing more, a more frequent amount of ligand-binding domain mutations in this disease is there. And I think right now we're seeing 25% of patients express 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 two 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 and 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 move 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 co-developed 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 two 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 it's further developed. 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. I would see these fitting in the landscape right at the beginning of castration RECIST. Since we are using the next generation anti-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 it really does not work, so we have to go forth with a different mechanism. Of course, we're looking at drugs such as chemotherapy agents, such as cabazitaxel and docetaxel, also lutetium PSMA, that's going to be looked at in this particular space as well. There are advantages to 766 in terms of toxicity, in terms of route of administration. I see this being right at the beginning of castration RECIST, oral compound, easy to administer, and doesn't require a lot of logistics to get the patient treated. Yeah. Maybe, maybe one more question is from the standpoint of, a clinical trialist who's been doing trials 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, bavdegalutamide, 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, with, with BRCA1 and BRCA2, but that's about the level as, as to what you would see. So I think that this is going to be a significant target within castration-resistant disease. And as we know, there are more mutations that develop as, as a tumor becomes genetically unstable. So the earlier we use some of these other agents in castration RECIST, 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. All right. As a reminder, ladies and gentlemen, to ask a question, please press Star one one on your telephone. If you wish to remove yourself from the queue, please press Star one one again. One moment, please, for our first question. Our first question comes from the line of Tazeen Ahmad with Bank of America. Hi, good morning. Happy Sunday. Thanks for taking my questions. Just as a point of clarification, you mentioned that you're gonna 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 with 766? And then, the third part of the question is, you talked about having a castration-sensitive population of 87,000 patients. Would that subpopulation be included in your plans for phase III? Thanks. Thank you. Great question, and obviously, Ron will be able to put some more color onto that. In terms of what we plan to do with 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 putting Project Optimus pushes down a path of looking at a lower dose as part of that kind of interaction with the 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 will go forward to the FDA, and we'll have a different scenario as to what we had with bavdegalutamide. In terms of all the talks where we've done a while back, and of course, we're running ARV-766 in a normal clinical trial where we're generating that data. Ron, anything you want to add there, and also about the CSPC and how that fits into what our plans are overall? I know our next trial is CRPC, so talk to that. Yeah, yeah, I think that the comment about Project Optimus was, you know, 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 two doses, and actually both doses we're very comfortable with. Mm-hmm. The safety advantage is seen even at the highest dose. So we have two doses, 300 and 100, and even 300 is, you know, much safer than bavdegalutamide. So we're well positioned to have the right conversations, 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 gonna be a precision medicine approach in first-line mCRPC RECIST. We can't get into any more details right now. It's quite early, but we'll of course provide those details as we, you know, as we advance our plans. But we are still very interested, so it won't include castrate-sensitive. Very interested, though, in castrate-sensitive. I mean, 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 mCRPC being presented. So, you know, we even think about even getting that early, but not for this phase III. That will be coming down the road. Okay. Thank you. Thank you. One moment, please, for our next question. Our next question comes from the line of Tyler Van Buren with TD Cowen. Hey, guys. 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 four RECIST evaluable patients with one confirmed and one 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? Thanks. Ron, do you wanna take that? Yeah, so the first question was around RECIST. So we didn't have the RECIST data detailed in this pre-presentastion 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're positive about that. And then, can you restate your second question? I think I may have missed that. It was around- Sure. the durability of 766. Oh, yeah. We said- Yeah, so yeah, certainly. Yeah, I mean, one thing that we've done is, you know, 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 six 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. Thank you. One moment, please, for our next question. Dan, in the next question, I do wanna make a point, and this is actually one that Dan has basically fed back to us, is that 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, is that if you can't, if you have to have modifications or interruptions or things like that, that compromises your efficacy. That's just another, you know, point where we feel really good about the 766. Thank you. And our next question comes from the line of Derek with Wells Fargo. Hey, good morning, and, thanks for taking the questions. Maybe just first, are you planning to have the PFS data for ARV-766 when you initiate the discussions with the regulatory agencies, you know, for the phase III in the second quarter of 2024? So that's the first question. And then just in terms of, like, spend, does shifting to 766 now kind of increase the runway at all? You know, obviously, it seemed like you were planning for, you know, to develop both, you know, into registration, so now it's only one. Just thoughts on that. Thank you. Thanks, thanks, Derek. I'll start with the second one, and Ron can talk to the PFS. Yeah, 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. It will 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 two phase IIIs in close proximity, I think we made this and we saw the data that was coming out from 766. 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. But yeah, Sean and the team here are incorporating all that into our kind of forward planning. Ron, the PFS discussion? Yeah. 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, we, the answer is that at least for bavdegalutamide, it was not a necessity. I mean, the FDA was more interested in other evidence to support dose, and we have really good exposure response data that helps us in picking the right dose. So PFS was not a necessity for the FDA discussions for bavdegalutamide. Thanks so much. Thank you. One moment, please, for our next question. Our next question comes from the line of Eliana Merle with UBS. Hey, guys. Thanks so much for taking the question. Just thinking about the L702H patients relative to the T878, H875 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, just 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 could get clarity on that strategy? And just how long and how large of a trial do you think this will need to be? Just, you know, given it's pretty early line, I guess, how are you thinking about if you'd wanna still do this alone or potentially think about collaborations there? Thanks. Thanks. Thanks, Ellie. Again, Ron, and maybe even Dan, can talk to that first question. But for 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 III on 766 in CRPC. But yeah, 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 L702H, T878, H875, BRCA. Yeah, I can... I'll start, and then maybe I'll just ask Dan if he wants to add anything. I think back to outcomes, I mean, I think, and it's good—I'll just kind of refer back to the data that we had at ESMO from a Guardant partnership that they have, you know, their marketed ctDNA tests. And there was an analysis last year at ESMO that showed that outcomes overall for T878, H875, and that included patients with co-occurring L702H did worse. So I mean, that was important for us to understand that because the first question always is, you know: Is this just a better population? The answer is, if anything, this population actually seems to do worse. So... Then the overlap with BRCA, I think, as I understand it, there hasn't been a whole lot of relationship here, but maybe, Dan, do you wanna comment on this? I don't know, 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. Thank you. And due to time constraints, we ask that you please limit yourself to one question. One moment, please. Our next question comes from the line of Brad Canino with Stifel. Hi, thank you, and congrats on the progress of the franchise here. You know, 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% PSA50 in other mutations. I guess, any comments you can provide there? 'Cause 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 bav's broader AR-LBD population, probably the better benchmark to think about? Thank you. Thanks, Brad. Great question. And Ron, do you want, I think you, you touched on this earlier in some of the answers, but do you want to, to go through this again? Yeah, I think, I mean, there, there's a couple of things that just I would, I'd like to comment on. Of course, we're, you know, they're all relatively small numbers, I think. You know, when looking at 766, there's a couple points to make is that the 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, you know, we have learned that non-AR mutations, the big drivers for AR-independent RECIST, p53, AKT pathway, aberrations, these things are, have—we've found highly prevalent in this post-NHA setting. We've had that data presented at ASCO GU a year and a half ago. So if by the luck of the draw, we have, you know, more p53 in the patients, and we haven't done that analysis, it, you know, if 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 has tighter variability—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 exception as L702H, where it does cover it and bav does not. So from all that totality of the data, we feel like these two are gonna be quite comfortable. You know, what turns out in the end of the day, maybe it's somewhere in the middle, but I don't know. Dan, do you have anything else you want to add to that? No, I think that 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 PSA 50, PSA 30%, in terms of cytotoxic therapy. It may be very, very, very different for a hormonal agent in this 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. Thank you. One moment, please, for our next question. Our next question comes from the line of Yigal Nochomovitz with Citi. Hi, team. This is Ashiq Mubarack, not Yigal. Thanks for taking my questions. I wanted to ask one on Slide 10. You had a really nice comp table, showing the bavdegalutamide data compared with other comparable agents. I guess, how do you think about the response rates in the PFS, in the context of a patient who might have received non-hormonal or a novel hormonal agent but not received a taxane? I think in the context of the card studies, those are all post-taxane patients, but not everyone on bav got a taxane. So I'm just curious, how you think that might affect the interpretation of some of these cross-trial comparisons, especially on PFS. Thanks. Yeah, maybe I'll, I'll do this. I'm sorry. Wasn't waiting for John's cue. I... John, if it's okay, I- Oh, absolutely. I can take this. Sorry. So what I can do is I can provide my perspective, and I'll definitely have Dan provide his. I think for us, and you know, we're from the company side, we're focused, you know, we developed a very, we're very high up on the learning curve for AR mutations and really understand this area. The other thing is that one thing that I would like to make a point about is that all of our patients have to have circulating tumor DNA in order to be tested. And what is that - why is that important, is because it's now coming out, not just in cancer in general, but also in prostate cancer, is that circulating tumor DNA is showing up as a poor prognostic marker. It makes sense. If you're leaking DNA, tumor DNA into your blood, then you clearly have a higher burden of disease. So we know that the outcomes are worse. We don't know about these trials. That's another added sort of wrinkle, and then it's also the real-world evidence that tells us that we believe that these patients actually do worse. So it's sort of like a handicap, if you will. But I know, Dan, you probably have other- Yeah perspectives here. I mean, I think that there's a lot of heterogeneity even in these trials in terms of what, how much treatment these patients have had. For example, the CARD trials took those patients who had been on docetaxel, also had been on either abiraterone and enzalutamide for up to one year. So these are a poor prognostic group of patients. It doesn't include those patients who may have been on one next generation then maybe for a year and then transitioned over to another one. So I think it's just very, very difficult to interpret this data and these rPFS numbers based upon the prior treatment. I think the target's more important here than the actual amount of treatment that's involved. So, you know, it's difficult to try to compare these trials, but certainly, I think the activity here that we're seeing is significant. Thank you. One moment please, for our next question. Our next question comes from the line of Edward Tenthoff with Piper Sandler. Great, thank you. Good morning, everyone, or afternoon, I guess, if you're over in Europe. Two quick follow-ups, if I may. So firstly, do you think we would have 766 data by ASCO GU? And that's what would be provided and discussed with the FDA and the two in the second quarter. And for Dr. Petrylak, you mentioned earlier that you would envision 766 being used right at the beginning of castration-resistance. So does that mean after Xtandi and Abi as they're kind of moving a little bit earlier? Is that sort of the thinking there, they would be used after? Thanks. Thanks. Thanks, Ed. In terms of the, we haven't given any guidance about the specific meeting we'd give data to, but it would be certainly at Congress next year. So we'll be updating that, hopefully relatively soon, and that should be a fairly comprehensive review of all the data related to 766. Ron or Dan, do you want to talk about, or maybe, yeah, Dan, directly to that question? So, I think, you know, it would make logical sense to develop it right at the beginning of castration RECIST. I mean, number one, we're seeing more mutations as time develops with more exposure to the next generations. You get exposure to Abi or Enza of, you know, so a year or two at that particular point, which is longer than what you would see in castration RECIST. So it makes sense to use it there, but then again, akin to the PARP inhibitors, once we've developed it in that particular space, there's nothing saying that you can't use it in a patient who has this particular mutation. And one would think that as time goes on, these mutations develop more frequently. So, you could see, envision a broader use as time goes on. I think the quickest path to registration, in my mind, would be in that early stage that I mentioned before. Thank you. One moment, please, for our next question. Our next question comes from the line of Peter Lawson with Barclays. Hi, good morning. This is Shayan for Peter. Thank you for taking our question. Going back to the 766, efficacy across mutations here. I know you mentioned durability looked encouraging, but is there anything here in terms of durability across different mutation types that suggests a meaningful difference based on mutation? And is there something to suggest that you could achieve better durability or at least similar durability in the 878, 875 mutation patients? Just trying to get a sense, a better sense here on what a phase III trial for 766 might look like, and whether this would be across ligand binding domain mutations. Thank you. Thank you. Yeah, Ron can talk to this, but clearly our game plan is to have a trial that looks at all LBD, and so that'd be a significant difference from the phase III plan we have for bavdegalutamide, because of 766 ability to hit broader, a broader set of mutations. Ron, do you want to add further commentary? Yeah, I think, well, certainly, and we don't have the, you know, a breakdown for today. We'll have a Congress presentation, but I would say that, I don't believe that the information that we have in terms of the state-of-the-art about these mutations would tell us that there would be necessarily any difference that we should expect among these. I mean, even just preclinically, 766 degrades robustly across these common mutations and wild-type. There's nothing that tells us biologically that the outcomes may be... That, that would be different. So, regardless of what small numbers will show, I don't think that we're expecting that there's going to be a difference. Well, as John said, I think our intent is to go across LBD. Thank you. Our next question comes from the line of Michael Schmidt with Guggenheim. Hey, guys. Thanks for taking my question. Just a follow-up on the 41% response rate for 766. As we think about your phase II study comparing the 100 mg and the 300 mg, you know, should we expect a dose response here between those two doses? Just given that the 41 is a pooled analysis, it looks like. Ron? Yeah, so I -- it's a good question. I don't think we have enough information to say. I mean, I will tell you that back to learnings from bavdegalutamide, we did, you know, see, and it's not that, anything we've presented, but there is a relationship between exposure and activity, and that's helped us, you know, feel good about the 420 mg dose. Whether we see that in 766, it's, you know, it's too early to say. But the good news for 766 is that we would be perfectly ha-- we're p- totally equipoised on dose right now because we're seeing activity at both doses. Thank you. And our next question comes from the line of Terence Flynn with Morgan Stanley. Great. Thanks so much for taking the question. I just had one on combinations. I know you are enrolling a bavdegalutamide Abiraterone trial, and just wondering if you have any data from that and how that might inform your development of 766, and if you have any drug-drug interaction work yet completed for 766 with any of the NHAs. Thank you. ... Another one for you, Ron? Yeah. So, abiraterone and the bavdegalutamide, we haven't presented any data, but we have not seen any DDIs for that combination for bav. We are, by the end of the year, we're still on track to start an ARV-766 cohort that was added to the first in human study, and that's due to start before the end of the year. Gonna generate data actually in pre-NHA, so that'll be our first foray after a long time, to go into the pre-NHA setting. We think these two drugs are well suited to combining. It's complementary mechanisms of action. The 766 safety profile means that we can feel really good about combining with almost anything. you know, whether that is our strategy, whether we use that as a strategy, getting in the castration-sensitive, or we, or we think that we can go head-to-head, you know, we have options. So, more to come on the combination with abiraterone. Thank you. Our next question comes from the line of Srikripa with Truist Securities. Hey, guys. Thank you so much for taking my question, and congrats on all the progress. Can you remind me if there's a difference in how quickly you see responses between bav and 766? And also, when you look at the 766 data, it looks like a few patients, I think maybe three of the seven patients that responded, discontinued. Can you provide any color on why they discontinued, or do you think we have to wait for the more detailed presentation at the next conference? Thank you. Yeah. Ron, thanks. Yeah. With regard to the discontinuations, there's only three patients out of a total of 84. It's quite low. I mean, not just the data on paper, but when you talk to folks like Dan Petrylak, and many of our other investigator-investigators who have worked on both drugs, they'll tell you that the profile is really good. We've also even heard anecdotes of patients coming off of enzalutamide or other drugs and shifting over, and they feel better when they come off. So of course, these are just anecdotes, but I wouldn't worry about the discontinuations. We'll have more data, you know, when we present it as a congress. And then I would say, just in general, in terms of activity between these two drugs, I know this question keeps coming up. What As you can imagine, we have done a drill down and a breakdown in terms of what we're seeing, you know, so far in terms of RECIST and PSA activity, duration of response, because as Dan said, PSA 50 is not... It's not the only indicator of response. You may not have a PSA 50, but you still have long. Whenever we look at all three of these parameters, it gives us the confidence that 766 is, you know, every... I I mean, if anything, we're gonna have more confidence in 766, it's because of the fact that these patients are gonna be staying on therapy longer and not having interruptions for safety. Pharmacokinetically, as I mentioned, it is in a really good place and has less variability and actual exposure versus preclinical thresholds, preclinical data. All told, you know, it really gives us, you know, a really good confidence in 766. Thank you. And our next question comes from the line of Christopher Liu with Leerink Partners. Hey, guys. Thanks for the question. Based on prior trials in the post NHA setting, how suggestive has PSA 50 been to durability and PFS in particular? That's a great question. Straight to Ron as well. Yeah, I think the question was relationship between PSA50 and PFS. So that sounds like- Dur- durability Something Dan can comment on. Yeah, I mean, I think it really is dependent on the class of drug. You know, we've seen situations where the PSA declines, and the PFS is not really improved, and we've seen the opposite situation. So I think you have to take each individual class of drugs individually, in terms of mechanism, in terms of what the effect may be on PSA expression, and of course, the heterogeneity of the disease, one that's being used in the overall course of castration RECIST. Yeah, and I think the only thing I would add is that, I mean, we, to Dan's point, PSA 50 is not the be all, end all. The thing that makes us feel good is that we are seeing the PSA. I mean, we'd be, we would be concerned if we weren't seeing a PSA 50. On the flip side, we are also seeing, patients, as Dan had talked about, even with his own experience, patients staying on therapy, even without PSA 50 reductions. And, you know, so, so there's. So for us, at the fact that we're having patients stay on the rPFS, it just gives us confidence. And, and the other thing, just back to the rPFS, is this is in a setting where it may be that these mutations actually make the patient's outcomes even worse. So it actually gives us even more confidence in the rPFS data that we have from bav than what we expect for 766. Thank you. I'll now hand the call back over to President and CEO, John Houston, for any closing remarks. Well, thank you. And thanks, everyone, for joining us on a Sunday for this important discussion about our AR programs. I hope you can tell how excited we are by the bav data, but also the path forward with 766 in early and late-stage prostate cancer. R&D processes are always about learning and taking that knowledge to make better decisions, and I think we're doing that with this choice over 766. And certainly, 766 will start later than bavdegalutamide, but we believe we've got the ability to catch up on time, and we might find that by the time we get to an approval stage, it will be very similar to the time that we thought we'd get with bavdegalutamide. So I think we're in a good shape here, and we look forward to sharing further additional data and plans on 766 in the future. So thank you for all your time and all the great questions. Thank you. Ladies and gentlemen, thank you for participating. This concludes today's program. You may now disconnect.