Thank you for standing by and welcome to the Arvinas ASCO GU Data Conference Call. At this time, all participants are in listen-only mode. After the speaker's presentation, there'll be a question and answer session. To ask a question at that time, please press star then one on your touchtone telephone. As a reminder, today's conference call is being recorded. I will now turn the conference over to your host, Mr. Jeff Boyle, Vice President of Investor Relations. Please go ahead. Good morning everyone, and thank you for joining us to discuss the ARV-110, which we now refer to as bavdegalutamide, phase I dose escalation and interim ARDENT phase II dose expansion trial results that will be presented later today at the ASCO GU conference. Earlier this morning, we issued a press release highlighting these data which can be accessed in the investor section of our website at arvinas.com. With me this morning are Arvinas President and Chief Executive Officer, John Houston, and Arvinas Chief Medical Officer, Ron Peck. Ian Taylor, our Chief Scientific Officer, will join for the Q and A portion of the call. Before we begin, I would like 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 two of the presentation available on our website. In today's press release and in 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. Now I'll turn the call over to our CEO, John Houston. John? Thanks Jeff, and good morning everyone. Thank you for joining us as we provide this major update from our ARV-110 program, which, as Jeff just mentioned, we now refer to as bavdegalutamide. On slide three, I'll begin with a high level overview of the data and briefly discuss the potential development plan for bavdegalutamide as a result of these exciting findings. I'll then hand over the call to our CMO, Ron Peck, for a detailed review of the data that are being presented later today at ASCO GU. We'll then open up the call for your questions at the end of our presentation. You'll see we have now completed the phase I dose escalation trial, and nearly all the patients in the ARDENT phase II expansion trial have been enrolled. We have a significant amount of data and we are thrilled by the progress that's been made by the program. Let me just set the stage for what we've been talking about today. Importantly, we now have additional data that confirms the intriguing signal of efficacy we reported on earlier in the trial in a molecularly defined subgroup in patients with tumors harboring an AR T878X and/or a H875Y mutation, which we'll call T878X, H875Y throughout the rest of this presentation for conciseness. We saw a 46% PSA50 rate in all patients harboring these T878X, H875Y mutations in circulating tumor DNA. Based on the accelerated approval of rucaparib back in 2020, we believe that if we saw a greater than 25% PSA50 rate in this group, we'd feel very confident about initiating discussions with the FDA about an accelerated approval path. These data far exceed that bar and encourage us to take that next significant step in the development of bavdegalutamide. Furthermore, in the seven RECIST-evaluable patients in this subgroup, we saw two confirmed durable partial responses with tumor size reductions in six of the seven patients, giving us even more confidence in a path forward for bavdegalutamide as a precision medicine in a post novel hormonal agent therapy setting. In addition, we also saw activity across all subgroups, including PSA declines and RECIST responses in tumors that don't have the T878X, H875Y mutation. This is despite all patients having received at least one prior NHA, many with two, and a significant number having almost previously received chemotherapy. This suggests that there may be an opportunity for bavdegalutamide beyond only tumors with T 878X, H875Y mutations, and Ron will discuss these findings in more detail. Next, in nearly 200 patients, we show that bavdegalutamide has a manageable safety profile, very consistent with other targeted therapies that are being used every day in patients with solid tumors. Of particular note is the low rates of discontinuation and dose reductions due to treatment related adverse events. Now, the most important point we'll make today is that we believe there is a near-term precision medicine opportunity for an accelerated path to market using a companion diagnostic approach in this post NHA population. Our goal is to initiate a registrational program for bavdegalutamide by the end of 2022. It's truly gratifying to realize that Arvinas has the potential for its initial two clinical programs, first ARV-471 and now bavdegalutamide, to make it into pivotal studies this year bringing them ever closer to benefiting the patients we set out to serve. Now I'll turn it over to Ron to walk you through the full data. Ron? Thanks, John. Before walking through the new data, I'll briefly summarize the treatment landscape for advanced prostate cancer, as shown on slide four. There have been many new developments in recent years in the management of prostate cancer. One thing has remained the same. The most effective agents for the treatment of advanced prostate cancer are those that directly or indirectly target the androgen receptor, the most important driver of prostate cancer growth and progression. Medical castration is nearly always the first choice of therapy in newly diagnosed advanced prostate cancer. However, agents like Lupron and its analogs ultimately lose their effect as tumors become castration-resistant. Fortunately, novel hormonal agents, or NHAs, such as enzalutamide and abiraterone, first introduced approximately 10 years ago are able to overcome castration resistance. A major shift in the treatment paradigm, however, has recently occurred whereby the NHAs have now become standard of care for the upfront treatment of advanced prostate cancer in combination with castrate therapy. The result is that there is now a gap in the availability of AR-directed therapies in patients who become castrate resistant after NHA therapy. We believe the selective AR degrader, bavdegalutamide, can fill this gap. I also want to remind you about where we were at the time of the last data disclosure in December 2020, seen on slide five. At that time, we were in the middle of the dose escalation phase of the trial and had data on 37 patients. Despite extensive prior therapy, we saw PSA responses in several patients despite the high level of treatment resistance. We also observed that patients whose tumors had T878X, H 875Y tumor mutations appeared to be particularly responsive to bavdegalutamide despite the extensive AR independent resistance expected in these patients. At that time, two of five patients with these tumor mutations had PSA50 responses, and treatment duration was longer than expected in second-line AR therapy based on the data that is in the literature. Based on these results, we hypothesized that T878X, H 875Y tumor mutations could represent a signature of retained AR dependency in this post-NHA population. It was also around this time that the ARDENT phase II expansion was initiated at a recommended phase II dose of 420 mg administered orally once a day. The ARDENT phase II expansion cohort was designed to answer three questions as outlined on the left of slide six. Number one, is the safety and tolerability of bavdegalutamide acceptable for use in a post-NHA castration-resistant patient population? Number two, is the efficacy signal sufficiently robust in tumors with T878X, H875Y tumor mutations to support the potential for accelerated approval? Number 3, does a less pretreated post-NHA population have more AR-driven disease leading to a higher PSA response rate for bavdegalutamide? On the right side of the slide is the design of the ARDENT trial. Patients in the ARDENT expansion were prospectively enrolled into one of four subgroups. For the first three subgroups, shown in blue, green, and purple, patients were prospectively stratified based on their circulating tumor DNA profile using a Foundation Medicine blood assay. Subgroup one included patients selected for T878X, H875Y tumor mutations but without L702H mutations or AR-V7 splice variants to AR forms that are not degraded by bavdegalutamide preclinically. Subgroup 2 included patients with tumors with wild type AR or AR alterations other than T878X, H875Y, L702H, or AR-V7. Subgroup 3 included patients with tumors with L702H mutations or AR-V7 splice variants. This subgroup also included co-occurring T878X, H875Y. Patients in these biomarker defined subgroups received one or two prior NHA therapies and could have received as many as two prior chemotherapy regimens. Otherwise, there were no other restrictions in prior therapy. Later in the presentation, we will collectively refer to these biomarker defined subgroups as the more pretreated subgroups. The fourth subgroup was biomarker agnostic and enrolled patients who had only one prior NHA treatment and no prior chemotherapy. Also, these patients were not selected based on their molecular profile. Later, we will refer to this subgroup as less pretreated. On slide seven, you can see a summary of the baseline characteristics for patients enrolled across the phase I dose escalation trial and the phase II ARDENT expansion cohort. As I mentioned, all patients were post NHA. As of the data cutoff, a total of 195 patients have been treated across the phase I and phase II expansion. This represents a significant update in clinical data compared to the last disclosure more than one year ago. The patients enrolled across both portions of the trial had metastatic castration-resistant prostate cancer and a significant proportion were extensively pretreated. Notably, approximately half of all patients received two AR inhibitors. Additionally, 47% of patients had also received chemotherapy. The first question that the trial addressed was, is the safety and tolerability of bavdegalutamide acceptable for use in a post NHA castration-resistant patient population? On slide nine, you can see that bavdegalutamide had a manageable safety profile at the recommended dose of 420 mg taken orally once daily across phase I with ARDENT expansion cohort. The adverse events, which were predominantly gastrointestinal in nature, were mostly Grade 1 and Grade 2 in severity and led to discontinuations in less than 10%. Additionally, only 8% of patients required a dose reduction. There were also no Grade 4 or Grade 5 treatment-related adverse events. Overall, the safety profile is similar to many oral targeted therapies that are commonly used to treat patients with advanced solid tumors. The second question was, is the efficacy signal sufficiently robust in tumors with T878X, H875Y tumor mutations to support the potential for accelerated approval? As I will detail in later slides, we believe the answer is an emphatic yes. Slide 11 shows a waterfall plot of best PSA change from baseline across the four ARDENT subgroups. As you can see, PSA50 responses were seen across all subgroups most notably in patients with T878X, H875Y tumor mutations. I'll now walk you through the key takeaways that led to this conclusion. The first key takeaway comes from the first subgroup on the far left in blue. Six of eight or 75% of patients with T878X, H875Y tumor mutations and no L702H and AR-V7 had PSA50 responses. This finding, combined with the PSA50 responses in other patients with T878X, H875Y mutant tumors across other subgroups shown in hatch marks, supports the hypothesis that this AR signature could be used to identify patients most likely to respond to bavdegalutamide. The second key takeaway comes from the subgroup in purple, third from the left, were selected for the presence of the L702H AR tumor mutations and/or the AR-V7 variants of AR that bavdegalutamide does not degrade pre-clinically. Notably, despite very low expectations, some of these patients did in fact have PSA reductions with bavdegalutamide. In most cases, the PSA reductions were observed in patients with concurrent T878, H875Y tumor mutations. We believe this finding is explained by tumor heterogeneity such that a sufficient proportion of the tumor had other degradable forms of AR. The third takeaway comes from the subgroup selected for wild type AR and other AR mutations in green, second from the left. PSA50 responses were also seen in these patients, although the antitumor activity was modest in this group, likely due to the extensive AR independent resistance in this heavily pretreated population. Lastly, the PSA50 activity in the less pretreated fourth subgroup on the right of the graph in orange had a PSA response of 22%, with most of the responses being observed again in the patients with T878X, H875Y tumor mutations. I will come back to the additional learnings of this subgroup later in the presentation. I will now walk you through the results for all patients with T878X and H875Y tumor mutations across groups. As shown on slide 12, a total of 28 patients across phase I and the ARDENT expansion had at least one of these tumor mutations. The PSA50 rate was 46%, including several deep PSA responses. Notably, except for one patient, all PSA50 responders with follow-up beyond one month met criteria for a PCWG-confirmed PSA50 response. These results confirm the efficacy signal in this molecularly defined population that we first reported back in 2020. Importantly, as shown on slide 13, benefit that was seen in this population was durable in a significant proportion of these patients. More than 40% of the patients with AR T878X, H875Y tumor mutations remained on treatment for a minimum of six months, including eight patients continuing on bavdegalutamide at the time of data cutoff. This is remarkable given that this late-line patient population is expected to progress rapidly, frequently within two to three months. Importantly, the significant PSA50 response rate observed in patients with tumors harboring T878X/ H875Y mutations is beginning to translate into tumor regressions by CT or MRI as shown on slide 14. Slide 14 summarizes the tumor response data among the seven patients with T878X, H875Y mutations who were evaluable for RECIST response. Two patients achieved confirmed RECIST partial responses that have been long lasting. One patient remained on treatment for approximately nine months and is continuing treatment. A second patient remained on treatment for more than 10 months. To put this in context, rucaparib which was granted accelerated approval 1.5 years ago based on a single-arm trial in patients with BRCA1 and BRCA2, had a median duration of response of six months by investigator assessment. While the number of patients with confirmed response is of course limited at this time, the long duration of benefit in these two patients is extremely promising and further reinforces our confidence in a regulatory path for this patient population. Last point to make here, three of the seven response evaluable patients, one of the partial responders and two patients with stable disease are still being treated with bavdegalutamide, therefore, best tumor response cannot be determined yet for these patients. In total, tumor reductions were observed in six of seven patients who were evaluable for tumor response. Slide 15 summarizes how we think about the opportunity for bavdegalutamide in the T878X H875Y population. We are very excited by the results in patients with T878X and H875Y mutant tumors, given the 46% PSA50 rate, the durable responses in two of seven patients evaluable for RECIST and tumor reductions in six of seven of those evaluable patients. When combined with bavdegalutamide's manageable safety profile, we feel we now have sufficient data to engage the FDA on a discussion around a potential path towards accelerated approval. We look forward to taking this important step later this year and intend to initiate a pivotal study of bavdegalutamide by the end of the year. To facilitate that, we are well on the way to finalizing a relationship with a companion diagnostics company. We think that bavdegalutamide could be a next great example of a precision medicine therapy for advanced prostate cancer. I'll turn to page 16 to talk more about this opportunity. We believe the opportunity for bavdegalutamide in this patient population could be a significant opportunity given the availability of a blood-based biomarker to potentially select patients based on molecular profile. The attractiveness of a precision medicine approach where the right treatment is paired with the right patient based on deeper understanding of which biological factors predict for response is a very positive thing. According to the literature, approximately 10% of metastatic castration-resistant patients have tumors with T878X, H 875Y mutations. However, based on the data we see in our trials, we think this patient number or this percent is conservative and is likely higher. In addition, we believe the increasing use of NHAs in the castration-sensitive space will greatly increase the number of patients that enter metastatic castration-resistant prostate cancer with these mutations. We see a clearly increasing need and opportunity for bavdegalutamide in prostate cancer. The final question that ARDENT addressed was, does a less pretreated post-NHA patient population have more AR driven disease leading to a higher PSA response rate for bavdegalutamide? Turning to slide 18, the first part of this answer pertains to a hypothesis that was evaluated in ARDENT based on what was largely become well established in the field of oncology. This is the fact that patients with advanced cancer who progress through multiple different anti-cancer agents are more likely to have higher levels of treatment resistance due to an accumulation of tumor mutations and resistant tumor clones. As you see on slide 19, however, the ARDENT phase II expansion showed that the molecular profiles, as assessed by circulating tumor DNA, were in fact similar between the less and the more pretreated groups. Walking you through the details, the bars in the top half of the slide show the frequency of selected driver mutations associated with AR-independent resistance, for example, p53. The blue bars show the frequency of these mutations among the more pretreated patients across the first three subgroups, and the orange bars show the mutation frequency within the less pretreated fourth subgroup. The bottom bars show the molecular profile between these groups relative to the androgen receptor, also including the frequency of T878X, H875Y tumor mutations. Once again, the frequency of AR alterations were similar between the more pretreated group in the blue and the less pretreated group in orange. Given the similar molecular profiles between the more pretreated and less pretreated groups, it was not surprising that the PSA50 activity in the less pretreated group in orange was largely similar to that observed in the more heavily pretreated group in blue. Although there's a small numerical difference that we saw with the less pretreated group. We therefore learned from this data set that we will need to explore bavdegalutamide in an NHA-naive population in order to truly understand the potential of this therapy in a more AR responsive patient population. Turning to slide 21. In summary, we believe that these new data on bavdegalutamide support a potential precision medicine opportunity in patients with metastatic castration-resistant prostate cancer who have progressed on or after an NHA. Based on a recent precedent in metastatic castration-resistant prostate cancer, we believe there can be a path forward for accelerated approval in patients with T878X, H875Y tumor mutations in tandem with a blood-based companion diagnostic test for this molecular profile. There's a clear unmet medical need in this post-NHA setting, especially now that NHAs are becoming increasingly used as an upfront treatment in advanced castration-sensitive prostate cancer. Concurrently, we are very interested in exploring bavdegalutamide in a broader patient population as both monotherapy in more AR responsive settings and in combination with standard of care agents across both castration-resistant and castration-sensitive prostate cancer. Of note, we initiated a combination trial with abiraterone in the fourth quarter of 2021, which is one of the several potential combinations of combination approaches that could be attractive in early, earlier patient populations. In the first half of the year, we are planning to meet with the FDA to agree on the best path forward for bringing this novel therapy to patients in need of newer treatment options. To support this approach, we are currently finalizing a partnership with a companion diagnostic partner. Our goal is to initiate a pivotal study with bavdegalutamide in this patient population before year-end. With that, I will hand it back to John to conclude the presentation. Thanks, Ron. We can summarize the key takeaways on slide 22. We believe the ARDENT trial has been data-rich and very revealing. The strong efficacy signal, particularly in the T878X, H875Y mutation group and manageable tolerability profile, gives us the confidence to map to an accelerated approval path for bavdegalutamide. The data also show us that molecular tumor profiles post-NHA therapy are very similar. This is a key learning for us. That means bavdegalutamide will be appropriate in post-NHA settings. We also believe that moving earlier in the treatment paradigm and into the broader NHA-naive population will reveal more ER-dependent mutations and further opportunity for bavdegalutamide. From an overall company perspective, we intend to initiate three ongoing pivotal clinical trials, one for bavdegalutamide as a precision medicine, and two for ARV-471 by year-end 2022. With that, I'll turn the call over to Jeff to begin the Q&A portion of the call. Jeff? Thanks, John, and thanks again everyone for joining us. Before I turn it over to the operator for the Q&A portion of the call, I'm going to ask that you limit yourself to one question which I know is difficult but we do wanna give everyone an opportunity to ask a question. You are of course free to rejoin the queue after your first question. Operator, with that let's begin the Q&A. Thank you. Again, ladies and gentlemen, if you'd like to ask a question, please press star then one on your touchtone telephone. Our first question comes from Tyler Van Buren of Cowen. Your line is open. Hey, guys. Good morning. Thank you very much for the presentation. I think earlier in the presentation you mentioned that there's potential for approval with a greater than 25% PSA50 response rate. Can you help put that threshold into context given the TRITON2 results? And was that from a discussion with regulators or how did you get there? Thanks. Thanks Tyler, and great question. Ron, do you wanna take that? Yeah, certainly. This was, considering historically the bar for accelerated approvals in solid tumors, and that's including most recently what's happened in the last year. You'll often see approvals in settings of unmet medical need, where there are really no good treatment options, where about a 25% bar would be. I think your point about rucaparib is, it doesn't necessarily tell us that that's what the bar would be for this population. I think the other thing, just to put rucaparib into a little bit more context versus us is number one, they're different patient populations, right? This would be T878X, H875Y AR mutations. Rucaparib was bracket one, bracket two. Number two is that there will be a potential difference in benefit risk also. From a safety perspective, we have similar results in terms of GI toxicity as rucaparib, but rucaparib has some other adverse events that have not been seen with bavdegalutamide, which include things like 33% AST, ALT elevations, 25% Grade 3/4 anemia, and 10% thrombocytopenia at Grade 3/4. It's a little bit of a different risk benefit. The way that we look at this is we're just looking at historically what happens in solid tumors. Thank you. Our next question comes from Ted Tenthoff with Piper. Your line is open. Great. Thanks guys. I'm really impressed by the data. I just wanna confirm the numbers real quick. It's before it was 12 out of 26, now it's 13 out of 28. Is that correct for the PSA50? Ron, do you wanna go through the details of the numbers? Yeah. There was a different data cut between the abstract and the presentation for today. In essence, the PSA50 rate Is the same. Yeah is the same. Yep. Awesome. That's really helpful. I just wanna get a sense. I definitely see the path forward in these mutant patients and with the T878X, H875Y mutations. What are the opportunities or how would you start to explore ARV-110 in earlier lines? In particular, I was intrigued by what you were saying about pre-enzalutamide or abiraterone. What would that kind of study look like? Thanks. Hey, Ron? Yeah, certainly. Yeah. I mean, there are a number of different possibilities here. I think what I would say is that, you know, we're really thinking quite a bit about this. We're really excited about getting into a naive population. I think also with a therapy like this we can also think about combinations that could really be attractive. As I mentioned in the presentation, we just initiated abiraterone combination. It's using, you know, drugs that will have complementary mechanisms of action. And, you know, we're really excited by that. We're looking at other combinations. Even as a monotherapy, you know, it's really gonna be interesting to think about taking this into more naive populations and even some white space opportunities earlier in the disease course. Great. Thanks, guys. Congrats on the data. Thanks, Ted. Thank you. Our next question comes from Ellie Merle of UBS. Your line is open. Hey, guys. Congrats on the data and thanks so much for taking the question. I was just wondering if you could elaborate a bit on the biology behind the sensitivity in the T878X and H875Y mutations. I mean, I know there's some preclinical literature around how these mutations might turn enzalutamide, say, into an AR agonist, but curious your perspective on what's driving the higher response here with an AR degrader and I guess what we might know and might, I guess, not yet know. Just, you know, a quick follow-up to that, just in terms of the prevalence of these mutations, just I guess, what are you seeing as a prevalence in the later line setting? You alluded that it might be higher than the literature. Just any specifics around there would be helpful. I guess, you know, your thoughts on how the prevalence is evolving, you know, as you move from earlier to later lines of therapy for the, you know, T878 and H875 mutations? Thanks. Thanks. Thanks, Ellie. We have our CSO, Ian Taylor, on the call. Ian, do you wanna talk about the H875Y mutation biology, the prevalence, and how we see that evolving? Sure. Yeah, those mutations are in the ligand binding domain and make the receptor more promiscuous to other hormones or things like prednisone beyond testosterone or DHT, as you noted. One of them turns enzalutamide from an antagonist to an agonist. What we really feel like is that those mutations and, you know, several of our patients have multiple of these mutations independent based on circulating tumor DNA, that it's a signature of that these particular tumors are still using AR to drive the bulk of their tumor growth as opposed to other mechanisms. There's really no difference in the way bavdegalutamide degrades those individual mutations. We've shown that data before. It's really, we think, more of a, again, a signature of tumor dependence on them. In terms of the prevalence, yeah, when you look in the literature, there's not a lot out there, but around 5% of the metastatic castration-resistant prostate cancer patients have each of those mutations, so it adds up to about 10%. We've seen, as you can see from our data, higher than that. So that's one reason we think that as the literature evolves and more studies are done like this, where profiling is done more routinely, that those numbers will go up. As Ron mentioned, we think that the patient number will increase over time because the agents that are driving the emergence of these mutations are going earlier and earlier. Therefore, once patients enter metastatic state they may well have these mutations emerging, whereas before they didn't because the, those agents were used later on. You know, it's hard to know because again there's not been a lot of studies done on this. You know, some of these agents are still relatively new and so, but as time goes on, I think we're gonna see more of them as use goes earlier and earlier. Great. Thanks so much. Our next question comes from Madhu Kumar of Goldman Sachs. Your line is open. Yeah, thanks for taking our question. A little bit of housekeeping. The two RECIST response patients in the study, can you give us some clarity on what the duration of response was? For the phase I patient that had a RECIST response, what was the dose that was administered? Ron, do you wanna take that? Yeah, certainly. The dose for the patient in phase I with the PR was 140 mg, and this is a particularly resistant patient. Did you ask duration of response or duration of treatment? Duration of response, please? Oh, yeah. Yeah, duration of response, we don't have the data for those patients in terms of their progression data yet. What we know is, since the patients have to stay on treatment. They once they have radiographic progression they come off treatment. A duration of treatment is right now a good proxy for that. The patient that I just mentioned was on treatment for approximately just a little bit over 10 months, in fact. The ongoing patient that is from the phase II has been on treatment for nine months and counting. Okay. I guess one big picture question to think about, how do you think about given what you're seeing from bav that you've disclosed today, how do you think about kind of follow-on AR drugs, where they fit in the kind of treatment landscape in lieu of bav based on today's results? Can you restate the question? I'm not sure I understand. Basically, when we think about ARV-110 as compared to the follow-on drugs like ARV-766, kind of the other AR degraders you have in your pipeline. Got it. Where do you think each of these drugs fits in given what you now know about ARV-110 as compared to potentially those follow-on assets? Yeah, that's a great question, and clearly, we're very excited with the ARV-110 data. We see this emerging profile, and we're very encouraged about the possibility of going earlier. ARV-766 is progressing very well in its dose escalation stage of phase I. It does have a very good profile. It does degrade the L702H. We note with interest what the incidence rate will be of L702H through this trial. As we've said previously, we see positioning of both ARV-766 and ARV-110 going forward. Our game plan right now is to move ARV-766 forward as we have been, as aggressively as possible and position it over the next year to find out what that profile actually looks like and compare it to ARV-110. We really believe there's a role for both drugs in this space. Okay, thank you. Thank you. Our next question comes from Joon Lee of Truist Securities. Your line is open. Hi. Thanks for taking our questions and for the updates. You're doing a combination study with abiraterone, the Zytiga, presumably because there's an overlap with target binding site with enzalutamide. Have you looked at Xtandi versus Zytiga experience subgroups, and if so, you know, were there any differences in the PSA50 in those subgroups? Thanks. Great question. Ron, do you wanna take that? Yeah, certainly. I mean, of course, the numbers are small in terms of breakdowns. I would tell you that most patients in the T878X, H875Y gotten both, so that's important to know. And when we look at the data, there's you know, essentially we're seeing activity in both settings. At this stage, there's you know, it's hard to say whether there's any difference, and importantly, we're seeing activity in both settings. That begs the follow-up question, sorry, which is, you know, if the binding sites are the same between Xtandi and ARV-110, how is one ten actually working in those who progressed on Xtandi? Well, I mean, that really takes you into the novelty and uniqueness of PROTACs. We're not inhibitors, we're degraders. We can bind to the same binding site as something like enzalutamide. Because of the unique nature of the proximity-based approach to degradation, we don't have the issues that you see with the enzalutamide. Ian could give you more detail, but this is one of the big advantages we saw with the preclinical data, where in a highly resistant setting, we were showing really positive results because we're a degrader and we're not an occupancy-driven inhibitor. Got it. Ian, I don't know if you want to add anything to that. No, I think that's right. As I mentioned before, these mutations make the receptor more promiscuous to other agonists, and so therefore, antagonists lose effectiveness in great significance. By binding and degrading it, doesn't matter if there's another agonist around, the receptor's not there to respond to it. That is the difference in biology of degrading versus simply inhibiting or antagonizing. That's actually really helpful. Thank you. Thank you. Our next question comes from Tazeen Ahmad of Bank of America. Your line is open. Hi, good morning, and thank you for taking my questions. You know, it's very clear that you've got a very strong signal in these T878X, H875Y patients. As it relates to ARV-110 specifically, how are you right now thinking about the potential beyond that group of patients? And do you have any idea what might be driving the resistance to ARV-110? Yeah, I think in Ron's, Ron can talk to this, but in the presentation, we talk about the fact that we're very excited by that signal. First of all, we saw the signal at the very early stages of the trial, and this confirms in a much larger set of patients that this T878X, H875Y signal is real and strong and reproducible. The ARDENT trial was set up in such a way that we wanted to find out whether or not there was a moving target in terms of mutation profile if you get into heavily pretreated patients. It's clear, post-NHA treatment, these tumor profiles look more or less the same, and therefore we're seeing similar responses, more or less still driven by T878X, H875Y. That means that whole post-NHA population of patients really is opened up to bavdegalutamide because of the H875Y, T878X signal right across the board. In terms of the theory that we could move into a more AR dependent population, that theory is still in play. It's just it means we have to go earlier into an NHA-naive population. That's the game plan that Ron and the team are mapping out. Ron, anything to add there? No, I think that's exactly right. There's, you know, we see that there. I mean, I think the only thing I would do is just echo John's comment that just the post-NHA population because of the dynamic change in the market, is that there's a great need now for post-NHA and we're fortunate enough that we have identified a precision, you know, possibility of identifying which patients are the most responsive. That's a good thing, and it's a good thing for patients, you know, who are progressing on these drugs much earlier in their disease course. Number two is, as John said, you know, the next, you know, the other opportunities that could open up in other settings is to go into earlier settings. This is where combinations are gonna be attractive, as I mentioned earlier, abiraterone as an example. There are other combinations and also, you know, looking at even some opportunities that are still white space. I think, you know, we're looking forward to starting to test this in other settings now. Okay. Just maybe as a quick follow-up, for the NHA-naive patients, you said that you're gonna be studying them. Are those studies set to start this year? Well, right now.[crosstalk] Yeah.[crosstalk] Sorry, go John. Oh, you go, Ron. No, please, you answer, Ron, please. I was just saying that we're right now in the stages of planning and making decisions around how we'll proceed. We haven't provided any guidance in this presentation on the start, but we're very keen to begin the process. Okay. Thank you. Thank you. Our next question comes from Zegbeh Jallah of ROTH Capital Partners. Your line is open. Good morning. Thanks for taking my questions. I think the first one I just wanted to clarify is the logistics around testing for T878X or H875Y, how that's done clinically. Can you just put a dollar amount on what you think the market opportunity is in that setting? The last one here is just about the combo study. I was just wondering what the rationale is for the efficacy since this is not in a molecularly defined patient population? And what are you thinking about in terms of the market opportunity again in terms of a dollar amount, since this is only with patients that have failed abiraterone? Thank you. Yeah, I mean, we haven't obviously gone out talking too much about the market size and dollars, but clearly the profile of one ten really pushes it into a setting post-NHA where there's significant unmet need and a significant number of patients that could potentially benefit from one ten. We're actually excited about the potential there and the opportunity that will be there. Of course, if we can move into the pre-NHA setting, obviously that's an even bigger opportunity, a bigger set of patients. All of this is open to one ten. Nothing has been closed out. There's data. All you hope for in data like this when you're running a trial is that you get clarity over your hypothesis and ability to make clear decision-making. We certainly got that with the AR T878X, H875Y data. The other piece you get is a hypothesis that then gets challenged and allows you to go in a different direction. We got that too. We got that as it relates to the more and the less pretreated patient population. It told us those profiles are similar and allows us now to map to an earlier, NHA-naive patient population. That's why we're so excited about the data. It's given us absolute clarity. It's given us direction in both sets of patient population, and that's what we're going to prosecute on. Of course, all going well and this profile holds out all the way through that, there will be significant unmet need that comes along with that. Thank you.[crosstalk] Thank you. Ron, I think the last bit was just about logistically about testing for T878X and H875Y, just needing no bottleneck in the clinical path towards getting to those patients. Yeah, I can cover that. Yeah. I think the good news is that technology has gotten us to a place where, in this trial, and the way that we would think about this for a registration, is that we're using a blood-based assay, using circulating, determining the molecular profile by circulating tumor DNA. There has been some precedent as of recent in companion diagnostics based on blood-based assays, using circulating tumor DNA. Number two is that we wouldn't be the first in the prostate cancer space. The PARP inhibitor is approved a year and a half ago, rucaparib we talked about and then olaparib are using one of the two has a blood-based assay. They've gotten a start and also just the field is starting to use commercially available circulating tumor DNA assays. There's the Guardant test, for example, where you know patients are getting sequenced and profiled even without the purpose of a companion diagnostic. The field is already kind of ripe for this, and I think that we would also you know take the opportunity to really increase the awareness around this thing, and it's coming at the right time in the field. Thank you. As a reminder, we ask that you please limit yourself to one question. Our next question comes from Alethia Young of Cantor. Your line is open. Hey, guys. Thanks for taking my question, and congrats on this interesting data. I guess, can you just talk a little bit more about, you know, kind of maybe potential sample size in the pivotal study and kind of, you know, how kind of you're thinking about how long it might take to potentially enroll? I understand it's all a little bit premature, but just anything more that you can provide about thinking about details around the specific study that's important. Thank you. Thanks. Yeah, very early in our thinking was based on the data, but Ron's team has been working through that. Anything, Ron, that you can say right now around some of your thinking around the pivotal study? Certainly. Of course we can't provide details, but I mean, the one key point here is that as I, we talked about before, there is a precedent with the drug rucaparib which is sort of a similar. It's a useful analog for us because it was a precision medicine approach. It was, you know, using RECIST response as a surrogate. So that essentially gives us the roadmap. I think your other question was around enrollment. Of course, we can't, you know, we can't provide those details at this time. What I will say, though, is that, there, you know, because of the medical need, because of, as I mentioned in the last answer, the increasing sort of awareness and interest in using, in doing sequencing tests, especially blood-based, and, you know, we would be leading in this area, so there wouldn't be competition for selecting patients for T878X, H875Y. We think that there's gonna be enough enthusiasm around this to help support doing this trial. Thank you. Our next question comes from Brad Canino of Stifel. Your line is open. Good morning, and thanks for the details around this complicated data set. In the T878X, H875Y population, you spoke to 28 patients on slide 12 with that 46% PSA50. That includes six patients that are less pretreated, of which four had a PSA50 decline. The first question is, could you conceivably enroll these less pretreated patients for an accelerated approval population? I see that the rucaparib trial required prior taxane. Second, does the inclusion of these patients benefit the PSA50 versus what would be expected in the intended accelerated approval population? Because I would think additional therapies and chemos might create those co-occurring mutations not degraded by ARV-110, and we see a smaller PSA50 benefit there in that mixed group in purple in slide 11. Thank you. Thanks. Ron, do you wanna take that? I mean, clearly. Yeah ... with the data set we've got, it's actually encouraging that allows us to think of bavdegalutamide in this broader post-NHA population in its entirety. But Ron, do you wanna talk to that? Yeah. Yeah. I mean, I think ultimately, you know, the patient population's gonna be a conversation with the agency. We'll come in with what we think is reasonable based on medical needs and so on. But I think part of your question was getting to the point of, is there any difference in the response? What would the PSA50 be like just in the heavily treated versus the less pretreated? And I can tell you that we have not seen that difference at this stage. In point of fact is that you know, when we looked at prior chemotherapy, you know, the PSA50 activity in prior chemotherapy versus no prior chemotherapy, we did not see any difference, any meaningful difference. Of course, they're small numbers, but there's, you know, there was nothing that deterred us around that. Number two is just to point out an anecdote. The one confirmed PR that was from the phase I was a patient who had gotten cabazitaxel, abiraterone, enzalutamide, a first-generation AR inhibitor, bicalutamide, and PROVENGE. So this is. You know, we haven't yet seen that this is something that would have a different activity in less pretreated, based on the data we have today. Thank you. Our next question comes from Michael Schmidt of Guggenheim. Your line is open. Yeah. Hey, guys. Thanks for taking the question. I just had one more bigger picture question on the sort of the ultimate market positioning of ARV-110 as a monotherapy in the mutation-positive patients. You know, I guess you just mentioned, I think the initial accelerated approval study is presumably gonna be some type of late-line, late-stage patient population. But then I guess ultimately, where do you feel the best place for the monotherapy in the mutation population is? Also, you know, any thoughts on the evolving market here with the PROpel data also being presented at the conference and how it might be positioned to other emerging therapies in a first-line CRPC setting? Thanks. Thanks, Michael. Great question. Ron can clearly give you a nice comprehensive answer. You know, from my perspective we see a significant opportunity, obviously, in this post-NHA setting now and you could call that, you know, second line, third line plus, but that broader population post-NHA, chasing down the H875Y, T878X signal, and that's clearly the direction we're going to go down there. As I said earlier, still a significant opportunity going into that NHA-naive population where we hope to see more AR-driven disease. Ron, do you want to talk to any of that, plus the evolving prostate cancer therapy world right now? Yeah, certainly. I think the point and one thing that we've been talking about internally is, you know, could there be maybe the possibility that we're gonna learn that these mutations occur earlier and thinking about earlier populations. I mean, we have this path forward that we've described and we feel really good about, but could there be bigger opportunities in this mutation subset? I think that's certainly something we're thinking about. Yeah, we're also interested in generating some real world evidence to understand that portion to help us to see if, you know, is there a bigger opportunity beyond, you know, this first, you know, this fast to market scenario. I think. Then your other question was just in terms of evolving landscape. You specifically mentioned the PROpel study. This is the olaparib plus abiraterone versus abiraterone in all comers. Yeah, we're interested in seeing those data. You know, those results, number one, they don't change our strategy for where we are because this is looking at a way to enhance or add to NHA therapy. It's still, you know, the need for treatments after NHA is the same exact issue, right? You know, of course, among combination approaches, PARP inhibitors are something that we're interested in. For that reason, we're actually more interested in it less as a competitor because it won't be. It's more about, is this a good partner for us? Thank you. Our next question comes from Yigal Nochomovitz of Citigroup. Your line is open. Hi. Great. Hi, Ron and John. Thank you for taking the question. I had a very specific question about the definitions in the footnote on slide 12. Just trying to understand what best PSA decline actually means. Does best mean that these PSA 50 declines were confirmed with a second reading? Or does it mean that the patients only needed to cross the PSA 50 threshold one time to get counted as a PSA 50 responder? Yeah, great clarification. Your question, Yigal. Ron, you could take that. Yeah, Yigal, the 46% represent any patients that had at least one decline below 50%. It's basically the typical waterfall plot definition, right? However, importantly of the 13 PSA50 responses, for all those patients who are evaluable for confirmation, which is basically at least one month of therapy, we had all but one who were confirmed responses. So, from the great majority of these were actually confirmed PSA responses by the prostate cancer working group. Great. Thank you. Thanks, Yigal. Thank you. Our next question comes from Etzer Darout of BMO Capital Markets. Your line is open. Great. Thanks for taking my question, and thank you for this update this morning. I guess you touched on this on a little bit earlier, but looking back at slide 19, you know, is it that, you know, the AR independent mechanisms are maybe more prevalent than we assumed sort of earlier on in the treatment paradigm for these patients? I guess related to that, how much of this is a consequence of NHA being used, you know, in, like, castration sensitive or even sort of non-metastatic settings, and then ultimately, you know, the potential even for ARV-110 to be used sort of earlier in that setting in the mutation population? Yeah. Thank you for the question. Ron can talk to that. Yes, we think that whole slide, which was really the kind of aha for us, showing that the mutation profile both from an AR dependent and AR independent scenario, looks similar between the more and the less pretreated. That was surprising but very interesting data. As I said before, it gives it a lot of clarity over what we do next, which is the T878X, H875Y signal is still very strong in both settings and still encourages us to take bavdegalutamide even earlier into that pre-NHA setting, where we expect to see a different mutation profile. Ron, is there anything you'd add to that broader question? No, no, I think it's, as John said, it's you know, we went in thinking one thing, we saw something else. As John said, this is why you do trials, because it helps you refocus how you know, to think about. I mean, for us, we learned about T878X, H875Y from that signal, but we also learned that we need to get into NHA- naive patients. The biological question that you're asking is a very good one. I'm not sure we have any better answer. Thank you. Our next question comes from Mark Breidenbach of Oppenheimer. Line is open. Hey, good morning, guys. Thanks for squeezing me in and congrats on these data. Just wondering, especially since given the rucaparib experience and its approval on RECIST response rate, I'm wondering if you can comment on how cleanly the tumor size reductions you're seeing in the seven RECIST evaluable patients correlates with their PSA declines. That would be helpful. Thank you. Thank you. Ron, any commentary there? Yeah. I don't. We haven't really looked at in depth. I can tell you an anecdote, and then I can tell you about how we've looked at the literature. The anecdote is, I'd mentioned the patient who had a confirmed PR in phase I. It's the yellow bar in the RECIST waterfall. This is a patient who had pretty deep PSA response, and also had a pretty noticeable and very significant reduction in big, large masses in his retroperitoneum around his aorta. So I mean, that's a single anecdote. In terms of the bigger picture, you know, we've spent a lot of time studying, of course, all the trials that have been completed in the post-NHA setting. Trials like the CARD study with cabazitaxel, PROFOUND with olaparib, and then the VISION study with the lutetium PSMA agent. One thing that we have seen just looking across these big trials is that the PSA50 response rate pretty well matches to RECIST response rate in these trials. It's a good proxy that. We didn't really talk about this in the presentation, but that also gives us, you know, the encouragement that what we're seeing at PSA. I mean, the RECIST data, we don't have a lot. We're encouraged by it. Certainly very encouraged by it. But the PSA50 data and this sort of proxy factor make it, you know, just reinforce the confidence that we have for the path forward. Thank you. This does conclude our Q&A session. I'd like to turn the call back over to John for any closing remarks. Well, yeah. Well, thank you again for joining us this morning and for all those very engaging questions. Of course, thank you for the continued interest and support of Arvinas. Have a great day. Thank you. Thank you. Ladies and gentlemen, this does conclude today's conference. Thank you all for participating. You may now disconnect. Have a great day.