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

Thank you for standing by, and welcome to the Arvinas ASCO GU data conference call. [Operator Instructions] As a reminder, today's conference call is being recorded. I would now like to 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 the data, which can be accessed in the Investors 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&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 2 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. And 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 3, 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. So let me just set the stage for what we'll be talking about today. Importantly, we now have additional data that confirms the intriguing signal of efficacy we reported on earlier in the trial in the molecularly defined subgroup in patients with tumors harboring and AR H878X (sic) [ T878X ] and/or a T875Y (sic) [ H875Y ] mutation, which we'll call 878/875 throughout the rest of this presentation for conciseness. We saw a 46% PSA50 rate in all patients harboring these 878/875 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 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 7 resistant valuable patients in this subgroup, we saw 2 confirmed durable partial responses with tumor size reductions in 6 of the 7 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 878/875 mutation. This is despite all patients having received at least one prior NHA, mainly with 2 and a significant number having always previously received chemotherapy. This suggests that there may be an opportunity for bavdegalutamide beyond only tumors with 878/875 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. And 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. And 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 2 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. And now I'll turn it over to Ron to walk you through the full data. Ron?

Thanks, John. So before walking through the new data, I'll briefly summarize the treatment landscape for advanced prostate cancer as shown on Slide 4. 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 castrate resistant. Fortunately, novel hormonal agents or NHAs, such as enzalutamide and abiraterone, first introduced approximately 10 years ago, are able to overcome castrate 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 are now -- 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 5. 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 878/875 tumor mutations appear to be particularly responsive to bavdegalutamide despite the extensive AR-independent resistance expected in these patients. At that time, 2 of 5 patients with these tumor mutations have 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 878 and 875 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 milligrams administered orally once a day. The ARDENT Phase II expansion cohort was designed to answer 3 questions as outlined on the left of Slide 6. Number one, is the safety and tolerability of bavdegalutamide acceptable for use in a post-NHA-casterate-resistant patient population. Number two is the efficacy signal sufficiently robust in tumors with 878/875 tumor mutations to support the potential for accelerated approval. Number three, there's 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 1 of 4 subgroups. For the first 3 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 1 included patients selected for 878/875 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 878/875 L702H or AR-V7. And subgroup 3 included patients with tumors with L702H mutations or AR-V7 splice variants. This subgroup also included co-occurring 878/875. Patients in these biomarker-defined subgroups received 1 or 2 prior NHA therapies and could have received as many as 2 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 7, you can see a summary of the baseline characteristics for patients enrolled across the Phase I dose escalation trial in the Phase II ARDENT expansion cohort. And 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 castrate-resistant prostate cancer and a significant proportion were extensively pretreated. Notably, approximately half of all patients received 2 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 castrate-resistant patient population. On Slide 9, you can see that bavdegalutamide has a manageable safety profile at the recommended dose of 420 milligrams taken orally once daily across Phase I with ARDENT expansion cohort. The adverse events, which were predominantly gastrointestinal in nature were mostly Grade I and II in severity, led to discontinuations of less than 10%. Additionally, only 8% of patients required a dose reduction. We're also no grade IV or grade V 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 878/875 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 4 ARDENT subgroups. As you can see, PSA50 responses were seen across all subgroups, most notably, in patients with 878/875 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. 6 of 8 or 75% of patients with 878/875 tumor mutations and no 702H and AR-V7 had PSA50 responses. This finding combined with the PSA50 responses in other patients with 878/875 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 variant of AR that bavdegalutamide does not degrade preclinically. 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 878/875 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 for 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 878/875 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 878 and 875 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 878/875 tumor mutations remained on treatment for a minimum of 6 months, including 8 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 2 to 3 months. Importantly, the significant PSA50 response rate observed in patients with tumors harboring 878/875 mutations is beginning to translate into tumor regressions by CT or MRI as shown on Slide 14. Slide 14 summarizes the tumor response data amongst the 7 patients with 878/875 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 9 months and is continuing treatment. The 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 when patients with BRCA 1 and 2 had a median duration of response of 6 months by investigator assessment. While the number of patients with confirmed RECIST responses is, of course, limited at this time, the long duration of benefit in these 2 patients is extremely promising and further reinforces our confidence in a regulatory path for this patient population. Last point to make here, 3 of the 7 RECIST evaluable patients one of the partial responders in two patients with stable disease are still being treated with bavdegalutamide. Therefore, that tumor response cannot be determined yet for these patients. In total, tumor reductions were observed in 6 of 7 patients who are evaluable for tumor resistant response. Slide 15 summarizes how we think about the opportunity for bavdegalutamide in the 878/875 population. We are very excited by the results in patients with 878/875 mutant tumors, given the 46% PSA50 rate, durable responses in 2 of 7 patients valuable for RECIST and tumor reductions in 7 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 the 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 take -- 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 our precision medicine approach where the right treatment is paired with the right patient based on deeper understanding of which biological factors predict for a response is a very positive thing. According to the literature, approximately 10% of metastatic castrate-resistant patients have tumors with 878/875 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 castrate sensitive space will greatly increase the number of patients that enter metastatic castrate-resistant prostate cancer with these mutations, 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 to progress through multiple different anticancer agents are more likely to have higher levels of treatment resistance due to an accumulation of tumor mutations and resistant tumor growth. 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 showed the frequency of selected driver mutations associated with AR independent resistance, for example, p53. The blue bar show the frequency of these mutations amongst the more pretreated patients across the first 3 subgroups and the orange bar showed the mutation frequency within a less pretreated fourth subgroup. The bottom bar showed that molecular profile between these groups relative to the antigen receptor, also including the frequency of 878/875 tumor mutations. Once again, the frequency and AR alterations were similar between the more pretreated group in the blue and the less retreated 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 served in the more heavily pretreated group in blue, although there's a small numerical difference that we saw with the last 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 castrate-resistant prostate cancer who have progressed on or after an NHA. Based on a recent precedent in metastatic castrate-resistant prostate cancer, we believe there can be a path forward for accelerated approval in patients with 878/875 tumor mutations in tandem with a blood-based companion diagnostic test for this molecular profile. There is a clear unmet medical need in this post-NHA setting, especially now that NHAs are becoming increasingly used as an upfront treatment in advanced castrate-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 castrate-resistant and castrate-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 combination approaches that could be attractive in 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. And with that, I will hand it back to John to conclude the presentation.

Thanks, Ron. So 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 878/875 mutation group and manageable tolerability profile gives us the confidence to map to an accelerated approval path for bavdegalutamide. The data also showed 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 setting. We also believe that moving earlier in the treatment paradigm and into the broader NHA naive population will reveal more ER mutations and further opportunity for bavdegalutamide. From an overall company perspective, we intend to initiate 3 ongoing pivotal clinical trials, one for bavdegalutamide as a precision medicine and two for ARV-471 by year-end 2022. And 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 want to give everyone an opportunity to ask a question. You are, of course, free to rejoin the queue after your first question. So operator, with that, let's begin the Q&A.

[Operator Instructions] Our first question comes from Tyler Van Buren of Cowen.

I think earlier in the presentation, you mentioned that there is potential for approval with a greater than 25% PSA50 response rate. So can you help put that threshold in the context given the TRITON2 results? And was that from a discussion with regulators? Or how did you get there?

Tyler, and great question. Ron, do you want to take that?

Yes, certainly. Yes. So 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. So you'll often see approvals in settings of unmet medical need where there really no really 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, is there are different patient populations, right? So this would be 878/875 AR mutations. Rucaparib was BRCA 1, BRCA 2. Number two is that there will be a potential difference in benefit risk also. We have similar -- 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 III/IV anemia and 10% thrombocytopenia Grade III/IV. So it's a little bit of a different risk benefit. And the way that we look at this is we're just looking at historically what happens in solid tumors.

Our next question comes from Ted Tenthoff from Piper.

I'm really impressed by the data. I just want to confirm the numbers real quick. So 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 want to go through the details of the numbers.

Yes, there was -- between the abstract and the presentation today, there was a different data cut. But in essence, the PSA50 rate is the same.

Is the same. Yes, awesome. That's really helpful. And then I just want to get a sense. I definitely see the path forward in these mutant patients and with the 878/875 mutation. What are the opportunities? Or how would you start to explore ARV-110 in earlier lines? In particular, I was in treatment, what you're saying about pre-enzalutamide or abiraterone. What would that kind of study look like?

Ron?

Yes, certainly. Yes, I mean, there are a number of different possibilities here. I think what I would say is that 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 can really be attractive. As I mentioned in the presentation, we just initiated abiraterone combination. It's using drugs that will have competing -- that can have complementary mechanisms of action. And so we're really excited by that. We're looking at other combinations. But even as a monotherapy, it's really going to be interesting to think about taking this into more naive populations and even some whitespace opportunities earlier in the disease course.

Our next question comes from Ellie Merle of UBS.

Congrats on the data. I was just wondering if you could elaborate a bit on the biology behind the sensitivity in the 878 and 875 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 decorator. And I guess what we right know and like, I guess, not yet now. And then just 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. And I guess, your thoughts on how the prevalence is evolving as you move from earlier to later lines of therapy for the 878 and 875 mutations?

Thanks. Thanks, Ellie. We have our CSO, Ian Taylor on the call. So Ian, do you want to talk about the 878/875 mutation biology, the prevalence and how we see that evolving?

Sure. So yes, 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 antagonist to agonist. What we really feel like it ties mutations. And several of our patients have multiple of these mutations, independent, based on circulating time DNA that it's a signature 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. So it's really, we think, more of a -- again, a signature of tumor dependence on them. In terms of the prevalence, yes, when you look at the literature, there's not a lot out there, but usually around 5% of the metastatic castrate-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. And so that's one reason we think that as the literature evolve and more studies are done like this, where profiling is done more routinely if those numbers will go up. And 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. And therefore, once patients entered metastatic stage, they may well have these mutations emerging where it was before they didn't because those agents were used later on. So it's hard to know because again, there's not been a lot of studies done on this. Some of these agents are still relatively new. And so -- but as time goes on, I think we're going to see more of them as use goes early and earlier.

Our next question comes from Madhu Kumar of Goldman Sachs.

So a little bit of housekeeping. The 2 RECIST response patients in the study, can you give us some clarity on what the duration of response was. And for the Phase I patient that had a RECIST response, what was the dose that was administered?

Ron, do you want to take that?

Yes, certainly. So the dose for the patient had -- in Phase I with the PR was 140 milligrams. And this is particularly a resistant patient. You asked about duration of -- did you ask duration of response or duration of treatment?

Duration of response, please?

Yes. Yes. So duration of response. We don't have the data for those patients in terms of their progression data yet. But what we know is, and since the patients have to stay on --they -- once they have radiographic progression, they come off treatment. So duration of treatment is right now a good proxy for that. So the patient that I just mentioned was on treatment for approximately just a little bit over 10 months, in fact. And then the ongoing patient that is from the Phase II has been on treatment for 9 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 disclosed today. How do you think about kind of follow-on AR drugs where they fit in the kind of treatment landscape in relief of bav based on today's results?

Can you restate the question? I'm not sure I understand.

When we think about 110 as compared to the follow-on drugs like 766, kind of the other AR degraders you have in your pipeline, where do you think each of these drugs fit in given what you now know about 110 as compared to potentially those follow-on assets?

Yes. And that's a great question. And clearly, we're very excited with the 110 data. We see this emerging profile, and we're very encouraged about the possibility of going earlier. 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. So we note with interest what the incident rate will be of L702H through this trial. And as we've said previously, we see positioning of both 766 and 110 going forward. Our game plan right now is to move 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 in compared to 110. But we really believe there's a role for both drugs in this space.

Our next question comes from Joon Lee of Truist Security.

So you're doing a combination study with abiraterone, the ZYTIGA presumably because there's an overlap with target binding sight with enzalutamide. Have you looked at XTANDI versus ZYTIGA-experienced subgroups? And if so, were there any differences in the PSA50 in those subgroups?

Great question. Ron, do you want to take that?

Yes, certainly. I mean, of course, the numbers are small in terms of breakdowns, I would tell you that most patients in the 878/875 gotten both. So that's important to know. And when we look at the data, there's -- essentially, we're seeing activity in both settings. So at this stage, there's -- it's hard to say whether there's any difference. And importantly, we're seeing activity in both settings.

So then there's a follow-up question, sorry, which is if the binding sites are the same between XTANDI and 110, how was 110 actually working in those who progressed on XTANDI?

Well, I mean, that really takes you into the novelty and uniqueness of PROTACs. We are not inhibitors. We're degraders. We can bind to the same binding site as something like enzalutamide. But because of the unique nature of the proximity-based approach to degradation, we don't have the issue 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. We're in a highly resistant setting. We were showing really positive results because we are degrader and we're not an occupancy-driven inhibitor. 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. And then -- but by binding and degrading it, it doesn't matter if there's another agonist around the receptors are not there to respond to it. So that is the difference of biology of degrading versus simply inhibiting or antagonizing.

Our next question comes from Tazeen Ahmad of Bank of America.

It's very clear that you've got a very strong signal on these 878/875 patients. But as it relates to 110 specifically, how are you right now thinking about the potential beyond that group of patients? And do you have any idea of what might be driving the resistance to 110.

Yes. And I think Ron can talk to has been in the presentation, we talked 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 878/875 signal is real and strong and reproducible. The ARDENT trial will set up in such a way that we want to find out whether or not there was a moving target in terms of the mutation profile if you get into [indiscernible] treated patients. And 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 878/875. That means that whole post-NHA population of patients really is opened up to bavdegalutamide because of the 875/878 signal right across the board. But in terms of the theory that we could move into a more AR-dependent population, that still in play. It's just that means we have to go earlier into any chain naive population. And 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. And there's -- we see that -- 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 post-NHA and we're fortunate enough that we have identified a precision, possibility of identifying which patients are the most responsive. So that's a good thing. It's a good thing for patients who are progressing on these drugs much earlier in their disease course. Number two is, as John said, the next -- the other opportunities that could open up in other settings is to go into earlier settings. This is where combinations are going to be attractive, as I mentioned earlier, Abiraterone, as an example. But there are other combinations and also looking at even some opportunities that are so white space. So I think we're looking forward to starting to test this in other settings now.

Okay. And just maybe as a quick follow-up. For the NHA naive patients, you said that you're going to be studying them, are those studies at to start this year?

Well, right now...

Sorry, John.

No Ron, please answer, please.

I'm just saying that we're right now in 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.

Our next question comes from Zegbeh Jallah of ROTH Capital Partners.

I think the first one, I just wanted to clarify, is the logistics around testing for 878 or 875, how that's done clinically. And then if you just put a dollar amount on what you think the market opportunity is in that setting? And then the last one here is just about the combo study. We're 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. Yes, I mean, we haven't obviously gone out talking too much about the market size and dollars. But clearly, the profile of 110 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 110. So we're actually excited about the potential there and the opportunity that will be there. And of course, if we can move into the pre-NHA setting, obviously, that's an even bigger opportunity, a bigger set of patients. So all of this is open to 110, nothing has been closed out. This 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. And we certainly got that with the 878/875 data. And the other piece again is a hypothesis that then gets challenged and allows you to go in a different direction. And 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. So that's why we're so excited about the data. It's given as absolute clarity has given us direction in both sets of patient population, and that's what we're going to prosecute on. And 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.

And then Ron, I think the last bit was just about logistically about testing 878 and 875, just meaning new bottlenecks in the clinical path towards getting to those patients?

Yes, I can cover that. Yes. So the good news is that the technology has gotten us to a place where we are 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 doing -- determining the molecular profile by circulating tumor DNA. And so there have been some precedent as of recent, in companion diagnostics based on blood-based assays using circling tumor DNA. Number two is that we wouldn't be the first in the prostate cancer space. The PARP inhibitors approved 1.5 years ago, where [indiscernible] about and then [indiscernible] are using -- 1 of the 2 has a blood-based assay. So they've gotten a start. And also just the field is starting to use commercially available circulating tumor DNA assays. There's the guardian test, for example, where patients are getting sequencing profile even without the purpose of companion diagnostics. So the field is already kind of right for this, and I think that we would also take the opportunity to really increase the awareness around this thing, and it's coming at the right time in the field.

[Operator Instructions] Our next question comes from Alethia Young of Cantor.

Congrats on this interesting data. Can you talk a little bit more about kind of maybe potential sample size in the pivotal study? And kind of how kind of you're thinking about how long it might take to potentially enroll and I understand it's a little bit premature, but just anything more that you can provide about thinking about details around the specific study that's important?

Thanks. Yes, 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 we've talked about before, there is a precedent with the drug rucaparib, which is a sort of a similar -- it's a useful analog for us because it was a precision medicine approach. It was using RECIST response as a surrogate. So that essentially gives us the road map. And I think your other question was around enrollment. Of course, we can't provide those details at this time. What I will say though is that the -- 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 we would be leading in this area. So there wouldn't be competition for selecting patients for 878/875. We think that there's going to be enough enthusiasm around this to help support doing this trial.

Our next question comes from Brad Canino of Stifel.

And thanks for the details around this complicated data set. In the 878/875 population, you spoke to 28 patients on Slide 12 with that 46% PSA50. But that includes 6 patients that are less pretreated of which 4 had a PSA50 decline. So 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. And then 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 110. And we see a smaller PSA50 benefit there in that mix group in purple in Slide 11.

Ron, do you want to take that? I mean clearly, the data set we've got is actually encouraging that allows us to think of bavdegalutamide in this broader post-NHA population in its entirety. But Ron, do you want to talk to that?

Yes. Yes. I mean, I think ultimately, the patient population is going to be a conversation with the agency will come in with what we think is reasonable based on medical needs and so on. So -- 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 point in fact, is that when we looked at prior chemotherapy, the PSA50 activity prior chemotherapy versus no prior chemotherapy, we did not see any difference. Any meaningful difference, of course, is small numbers, but 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 cabozantinib, abiraterone, enzalutamide, first-generation AR inhibitor, bicalutamide and Provenge. So this is -- so we don't -- we haven't yet seen that this is something that would have a different activity unless we treated based on the data we have today.

Our next question comes from Michael Schmidt of Guggenheim.

I just had one more bigger picture question on the sort of the ultimate market positioning of 110 as a monotherapy in the mutation-positive patients. I guess you just mentioned, I think the initial accelerated approval study is presumably going to 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? And also 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 the first line CRPC setting?

Thanks, Michael. Great question. And Ron can clearly give you a nice comprehensive answer. But from my perspective, we see a significant opportunity, obviously, in this post-NHA setting now. And you could call back second line, third line plus, but that broader population post-NHA, chasing down the 875/878 signal. And that's clearly the direction we're going to go down there. And then as I said earlier, still a significant opportunity going into that NHA-naive population where we hope to see more AR-driven disease. But Ron, do you want to talk to any of that plus the evolving prostate cancer therapy world right now?

Yes, certainly. I mean, I think the point -- and one thing that we've been talking about internally is could -- there's maybe the possibility that we're going to 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. So I think that's certainly something we're thinking about. And we're also interested in generating some real-world evidence to understand that portion to help to see if there's there a bigger opportunity beyond this first -- this fast-to-market scenario? I think -- and then your other question was just in terms of development landscape, you specifically mentioned the PROPEL study. So this is the olaparib plus abiraterone versus [indiscernible]. Yes, we're interested in seeing those data. It doesn't -- 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. So it's still the need for treatments after NHA is the same exact issue, right? But of course, among combination approaches, PARP inhibitors are something that we're interested in. And so for that reason, we're actually more interested as a competitor because it won't be. It's more about is this a good partner for us.

Our next question comes from Yigal Nochomovitz of Citigroup.

I have 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 PSA50 declines were confirmed with the second reading? Or does it mean that the patients only need to cross the PSA50 threshold onetime to get counted as a PSA50 responder?

Yes. Great clarification question. Ron, you could take that.

Yes, Yigal, the 46% represents any patients that had at least one declined below 50%. It's basically the typical waterfall plot definition, right? However, importantly, of the 13 PSA50 responses for all those patients who are valuable for confirmation, which is basically at least one month of therapy, we had all but one who were confirmed responses. So the great majority of these were actually confirmed PSA responses by the Prostate Cancer Working Group.

Our next question comes from Etzer Darout of BMO Capital Markets.

Great. Thank you for this update this morning. I guess you touched on this a little bit earlier. But looking back at Slide 19, is it that the AR independent mechanisms are maybe more prevalent than we assume 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 in like castration sensitive or even sort of non-metastatic settings. And then ultimately, the potential even for ARV-110 tend to be used sort of earlier in that setting in the mutation population.

Yes. Thank you for the question, and Ron can talk to that. But yes, we think that whole slide, which was really the kind of about half or us showing that the mutation profile, both from an AR-dependent on AR-independent scenario looks similar between the more and less pretreated. That was surprising, but very interesting data, as I said before, it gives us a lot of clarity over what we do next, which is the 878/875 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 as John said, it's -- 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 to take that. I mean for us, we learned about 878/875 from that signal, but we also learned that we need to get into NHA naive patients. And the biological question that you're asking is a very good one. I'm not sure if we have any better answer.

Our next question comes from Mark Breidenbach of Oppenheimer.

Congrats on the 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 7 RECIST evaluable patients correlates with their PSA decline. That would be helpful.

Ron, any commentary there?

Yes. 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 -- had mentioned the patient who had a confirmed PR in Phase I, it's the yellow bar in the RECIST waterfall. And 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 as for single anecdote. In terms of the bigger picture, 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 Taxol profound with the lab work and then the VISION study with the [indiscernible] agent. And one thing that we have seen, just looking across these big trials is that the PSA50 response rate pretty well matches to resist response rate in these trials. So it's a good proxy that -- and we didn't really talk about this in the presentation, but that also gives us the encouragement that what we're seeing in -- I mean, the RECIST data, we don't have a lot. We're encouraged by it, and certainly very encouraged by it. But the PSA50 data and this sort of proxy factor make just reinforce the confidence that we have for the path forward.

Thank you. And this does conclude our Q&A session. I'd like to turn the call back over to John for any closing remarks.

Well, yes. Well, thank you again for joining us this morning and for all those very engaging questions. And 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.