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

Ladies and gentlemen, thank you for standing by, and welcome to the ARV-471 and ARV-110 Program Update. [Operator Instructions] I would now like to hand the conference over to your speaker today, Mr. Randy Teel, Vice President of Corporate Development. Please go ahead, sir.

Thank you very much. Good morning, everyone, and thank you for joining us today for an update on our clinical trials for our PROTAC protein degraders, ARV-471 and ARV-110. You can access the relevant press release, 8-K filing and the slides for today's presentation in the Investors and Media section of our website at www.arvinas.com. This webcast will contain audio and corresponding slides. With me today are President and Chief Executive Officer, John Houston; Chief Medical Officer, Ron Peck; and Chief Scientific Officer, Ian Taylor. As we begin the call, I'd like to remind you today that today's discussion will contain forward-looking statements that involve risks and uncertainties. These risks and uncertainties are outlined on Page 2 of today's presentation document, 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. With that, I will now turn the call over to our President and CEO, John Houston.

Thank you, Randy, and good morning, everyone. I'm John Houston, CEO and President of Arvinas. It's my great pleasure to provide an update today on the progress we made here to bring 2 novel medicines to patients in significant need. Specifically, we'll be updating you on our 2 lead programs, ARV-471, our estrogen receptor PROTAC degrader for patients with locally advanced or metastatic ER-positive, HER2-negative breast cancer; and ARV-110, our androgen receptor PROTAC degrader for men with metastatic prostate cancer. Now even during the unique circumstances of a global pandemic, both trials have progressed effectively and with minimal disruption. And for that, we thank our patients, the clinical sites and the study staff and investigators running our trials as well as the countless healthcare workers focused on providing care during these incredibly uncertain times. Thank you so much. Now here is the agenda for this morning, and I'll be supported through this update by our CMO, Ron Peck; and our CSO, Ian Taylor. But I'd like to start by reminding you of why we believe there is a significant opportunity for both ARV-471 and ARV-110 as first and/or best-in-class hormone-directed therapies in breast and prostate cancer. In the case of ARV-471, in a late-line setting of patients with refractory disease, the drug has shown an excellent tolerability profile, demonstrated robust ER degradation and provided significant clinical benefit for patients. Even though we have not yet completed dose escalation, 471 is showing that it has the potential to have the best overall profile of any ER-targeting therapy out there. And the profile we see emerging for this drug gives us confidence that it could become the endocrine backbone of choice in a new standard of care for ER-positive HER2-negative breast cancer patients. This would represent an addressable patient population of over 200,000 per year in the U.S.A. As for ARV-110, as our trial has progressed, we have learned a lot more about the patient population we're in and the promising profile of our drug. Our trial is being run in a late-line patient population, in fact one of the latest line patient populations ever tested for an androgen-directed therapy with a median of 5 lines of therapy prior to receiving ARV-110. And despite this, 110 is showing tumor responses and obvious clinical benefit. During the trial, we executed an extensive molecular profiling of patient tumors to better understand the number and type of AR dependent and AR nondependent mechanisms that are present in these tumors. And excitingly, the PSA response activity we see tracks of a clearly defined molecular profile. We believe the robustness of these molecular signatures and the safety profile of ARV-110 will allow us to take 2 potential paths to registration, one of which will be focused on third line plus patients whose tumors have this molecular defined signature and the other in a much earlier, broader first-line, second-line patient population. The opportunity in this space is significant, and we believe the ARV-110 asset affords us a fast-to-market strategy in the molecularly defined subset of patients and a more traditional approval path in a broader prostate cancer population, establishing 110 as the ER targeting agent of choice. This latter population represents approximately 250,000 patients per year in the U.S.A. alone. Now in both programs, we're starting in very late-line patients, but our plan is to move to earlier lines of therapy for our regulatory studies and it's clear that both drugs have safety profiles that should allow us to do that. Both 471 and 110 are surprisingly positive efficacy for the late line they've been tested in. And we expect to see even better efficacy when we go to earlier lines of therapy. So let's dive deeper into both programs and share some of the exciting data we've generated so far. We'll start with the first significant clinical data disclosure for ARV-471 with Slide 7. Here, we show the key points that are emerging from the ongoing dose escalation phase. As I just mentioned, there is tremendous unmet need in breast cancer, and ARV-471 has so far shown potentially best-in-class safety and tolerability with clear suitability for adjuvant and metastatic breast cancer therapy settings. We are also seeing robust ER degradation at all those levels in both wild-type and ESR 1 mutant tumors. And this degradation appears to be better than that seen with fulvestrant and the other SERDs we compare it to. Excitingly, ARV-471 has also shown a robust signal of efficacy despite the expectation for high ER independence in this population. In fact, to be eligible for the trial, patients had to have disease which progressed after treatment with a CDK4/6 inhibitor. This means 100% of our patients were post this treatment. However, even in this difficult setting, we have seen 1 confirmed partial response and 2 unconfirmed partial responses. And so far, we have a clinical benefit rate of 42%. Now this is obviously very encouraging and exciting to see when we're still at the dose escalation phase of the trial. And we believe this is tracking to have the best-in-class profile for any ER-targeting therapy. So let's discuss how we're planning to position ARV-471 as the endocrine backbone of choice for ER-positive HER2-negative breast cancer treatment. And to do that, I'd like to introduce our Chief Medical Officer, Ron Peck, and he'll take you through the plan and our 471 data. Thank you. Over to you, Ron.

Thanks, John. I'd like to start by reminding everyone about the major toll that breast cancer has on the state of public health. Breast cancer is the second most prevalent cancer in women and 1 in every 8 women will be diagnosed with breast cancer at some point in their lifetime. And each year, over 200,000 women in the U.S. are treated for breast cancer. Also, 1% of new breast cancers are diagnosed in men. It's worth noting that 80% of all breast cancers express the estrogen receptor. The foundational therapy for ER-positive breast cancer are treatments collectively known as endocrine therapies that directly or indirectly target ER. While existing endocrine therapies are reasonably effective, they do have important limitations. Despite this, no new endocrine therapies have been approved since the ER degrader fulvestrant was approved nearly 20 years ago. Recently, the combination of targeted therapies with existing endocrine treatments have become commonplace in the management of advanced ER-positive breast cancer. This is particularly notable for CDK4/6 inhibitors, which have become firmly established as the standard of care for the initial treatment of advanced ER-positive breast cancer. Despite these advances, breast cancer remains a major public health issue due to the shortcomings of current therapies that we believe can be addressed by more effective targeting of the estrogen receptor. Unlike fulvestrant, ARV-471 is an oral therapy, and we believe it is much more potent and effective degrader of ER than fulvestrant. We believe that with this profile, 471 has the opportunity to become the future standard of care in ER-positive breast cancer, first for patients with metastatic disease and eventually for patients with early-stage breast cancer. Before taking you through the exciting data on 471, I'll briefly describe the design of the first-in-human trial, as shown on Slide 9. We employed a traditional 3 + 3 dose escalation design, and the primary endpoints and secondary endpoints are typical for oncology Phase I trials. The inclusion criteria for the trial are shown on Slide 10. and as John said, a very important aspect of the eligibility is the requirement that all patients must have received prior CDK4/6 inhibitor therapy unlike trials that have recently been reported among the third class of investigational agents. This criterion was required by the FDA and reflects the place that CDK4/6 inhibitors now have in the management of ER-positive breast cancer. The other requirements are listed on the left side of the slide. The critical point here is that tumors that progress on CDK4/6 inhibitors display a high level of ER-independent resistance. Specifically, recent molecular profiling studies show that nearly 70% of patients treated with these agents develop mutations across multiple pathways that invariably lead to complete resistance to treatments that target the estrogen receptor. This translates into extremely poor outcomes for patients in this situation. In a subset analysis of the SOLAR1 trial, women who are treated with fulvestrant following CDK4/6 therapy had a median progression-free survival of only 1.8 months, and the estimated clinical benefit rate was less than 20%. These results are dramatically worse than the outcomes with fulvestrant in earlier settings. The baseline characteristics of the 21 patients treated to date with ARV-471 are shown on Slide 11 and underscore the extensive amount of prior therapy that these patients received. Most notably, patients had a median of 5 prior lines of therapy and 100% of the patients were previously treated with at least 1 CDK4/6 inhibitor. Additionally, over 70% of patients also received the ER degrader, fulvestrant, and nearly 40% were previously treated with chemotherapy. Turning now to safety. 471 was remarkably well tolerated across all dose levels, all the way up to the most recently completed dose level of 360 milligrams. Importantly, no grade 3 or 4 toxicities were reported. In fact, the adverse events reported to date have largely been grade 1 in severity. With respect to pharmacokinetics, as shown on Slide 13, 471 demonstrated dose proportional increases in exposure that far exceeded levels that were efficacious in preclinical breast cancer models, represented by the orange line towards the bottom of the graph. 471 had a half-life of 28 hours that supports daily dosing. Notably, this high level of drug exposure translated into significant ER degradation in biopsy specimens. On Slide 14, you see stained biopsy samples from a patient who was treated at the second dose level, 60 milligrams. On the left is the patient's pretreatment biopsy. On the right is the biopsy that was obtained just 40 days after starting 471. The reagents used to evaluate the biopsy specimens stain estrogen receptor protein red. What jumps out, of course, is all the red in the pretreatment biopsy and the absolute absence of any red markings in the on-treatment biopsy. Now when looking at the ER degradation results for the 5 patients with a valuable paired biopsy that have thus far been analyzed, we see that 471 significantly degraded ER up to 90%. The average degradation in these 5 patients was 62%, which is better than the 40% to 50% degradation achieved with the highest dose, 500 milligrams, of fulvestrant. What is also exciting is that in 3 of 5 patients, ER was brought down to the lower limit of detection, representing complete or near complete elimination of ER in the tumor. As a final point, ER degradation was seen regardless of whether ER was mutated or not, consistent with our preclinical data. We are thrilled with these results, particularly the fact that 471 achieved this robust result in just the first 3 dose levels. We fully expect that we will see even greater degradation at higher doses. Most importantly, this ER degradation effect has already translated into treatment benefit, as I will go through in the following slides. We have seen a confirmed partial response in a patient who received 471 at a dose of 120 milligrams, who has been treated with most of the standard treatments available for ER-positive breast cancer as well as 2 different investigational ER therapies. The patient's tumor was found to have a mutation in ESR1 gene. On the far left is a summary of the various treatments that the patient had received prior to enrollment, and you can see again that this patient was heavily pretreated. Next over, we see the patient's CAT scan at baseline, which shows a very large mass towards the front of her liver and another nodule towards the back. After 4 cycles of 471, the patient had a substantial reduction of both lesions. This response was especially remarkable given the very low expectation for responses in patients who have high level of ER-independent resistance after progressing on CDK4/6 inhibitor therapy. Slide 17 shows another example of a patient who benefited from 471 after progressing through most available treatments for ER-positive breast cancer. This is a patient who had chest wall recurrence, which is particularly devastating complication of advanced breast cancer. These lesions often break through the skin, get infected and in the case of this patient can cause bleeding. The picture on the left shows the 2 chest wall lesions just below her right collar bone, one of which was bleeding before the patient started 471. After 4 months of 471 at a dose of 180 milligrams, the patient's bleeding stopped, and we can see that the 2 lesions significantly flattened, which really excited the treating physician. Stepping back to look at the response data across all patients with at least 1 baseline measurable tumor and at least 1 on-treatment scan, we can see clear evidence that 471 is an active therapy. In the waterfall plot on Slide 18, each bar represents a patient and the color indicates dose. Bars that fall below 0% indicate that the patient had a tumor reduction by CAT scan, MRI or clinical measurements, and prior therapy is listed below the graph. In addition to the 1 confirmed partial response, there were 3 more patients who had greater than 30% reduction in tumor size, which is the cutoff for RECIST response. Of the 3 patients, 2 had unconfirmed partial responses and provided further evidence of the efficacy achieved with 471. Turning to Slide 19, we look at another strong indicator of 471's efficacy in this population, which is the clinical benefit response rate of 42%, which is far better than the less than 20% clinical benefit response rate seen with fulvestrant in a similar population, as I mentioned earlier. Notably, 3 of the 5 patients who experienced clinical benefit have previously progressed on the ER degrader, fulvestrant, and a fourth patient progressed while receiving an investigational SERD. CBR takes into account duration of tumor control since it's defined as the summation of confirmed RECIST responses plus stable disease that is of at least 24 weeks duration, as shown by the black vertical line. As a result, our analysis excludes patients who have had less than 24 weeks of follow-up and therefore, excludes patients who are treated at doses above 180 milligrams. What was truly remarkable to us is that we are seeing this level of efficacy in just the first 4 dose levels and before we have even determined a recommended Phase II dose. To put these compelling results into context, we compared the emerging 471 profile to the results seen with the selective estrogen receptor degraders, or SERDs, at a similar stage of development. Across all key parameters, 471 clearly stands out from the pack. Going from left to right, we first see that the 471 trial enrolled the most resistant patients by virtue of the fact that 100% of our patients in this trial have previously received a CDK4/6 inhibitor. Second, efficacy based on CBR rate is at the top of the range. This is especially notable since expectations were particularly low in this highly resistant patient population. Third, as the only PROTAC in development for ER-positive breast cancer, we are also thrilled to know how that -- we now have evidence that 471 accomplishes what it was designed to do, and that is to degrade ER to a greater extent than fulvestrant in just the first 3 dose levels of our trial and more than has been reported in the dose escalation portions of the SERD trials that have presented any data in this regard. Lastly, when comparing key safety findings across these agents using a 5% cutoff, the safety profile for 471 clearly differentiates from most of the agents in the SERD class, particularly with respect to diarrhea as well as bradycardia and visual disturbances, which are particularly troublesome adverse events reported with some of these treatments. A good safety profile is essential for drugs targeting ER since patients with ER-positive breast cancer may receive treatments for years, especially in the upfront metastatic setting, and this is even more critical in the adjuvant setting where patients may receive up to 10 years of treatment. So to sum up, 471 has a profile that puts it on the path towards being a best-in-class ER-directed therapy. With this exciting profile, we are committed to developing 471 to its fullest extent to address the medical needs of those with ER-positive breast cancer across the entire disease spectrum. Slide 21 shows how we are moving 471 forward in development. We will be initiating a single agent Phase II expansion cohort that will begin in the first half of 2021, and we'll more fully characterize the efficacy and safety in second and third-line patients. In addition, we are currently initiating a Phase Ib safety cohort for the combination of 471 with palbociclib. This trial will position us to conduct a future Phase III study in front-line ER-positive HER2-negative breast cancer. We also have plans in the second half of 2021 to evaluate combinations with standard of care targeting agents used in second and third-line patients that would position us to conduct Phase III studies in this high unmet medical need population. To address the need for better treatments in early-stage breast cancer, we plan to initiate a window of opportunity study in the second half of 2021 that would compare 471 alone or in combination with the CDK4/6 inhibitor with control therapy. The goal here is to understand the potential of 471 to improve outcomes in patients who have undergone surgically resected breast cancer but still face an unacceptable risk of occurrence and death despite current treatment. We are excited to begin the next chapter in the development of 471 so that we can move this potential best-in-class ER-directed therapy 1 step closer to patients. And with that, I'll hand it back to John to provide his perspective on 471 before moving on to the update for 110.

Thanks, Ron. As you've just seen, we believe ARV-471 is well positioned to become a best-in-class ER-targeting therapy. This is supported by its overall profile, including a strong efficacy signal in a mostly ER-independent population, an outstanding safety profile and clear ER degradation that is already better than fulvestrant and the SERDs that we are aware of. The development path is clear, and we are aggressively moving forward with both monotherapy and combination therapy trials, including the Phase Ib with palbociclib that will begin shortly. And we are well positioned to seize the opportunity to address a large unmet need for the hundreds of thousands of patients who could benefit from ARV-471. So with that, let us now turn to ARV-110. We shared an interim update for ARV-110 earlier this year, and we've made a lot of progress since then. Slide 24 summarizes the highlights for 110, which is targeting prostate cancer, an area that has still significant remaining unmet need. ARV-110 continues to have a good safety profile, and we are currently dosing at 700 mg. Because of our growing knowledge of the very late-line patient population in our dose escalation phase, our expectations of seeing significant PSA50 responses were lower to less than 10%. However, we have seen continued signals of efficacy, including tumor and PSA50 responses averaging 14% overall. And today, we will talk more about the promising activity we've seen in both molecularly designed and wild-type tumors. In particular, the 40% PSA50 rate, we are seeing in patients that have tumors harboring a specific molecular signature. And we've built these learnings into our strategy for Phase II and beyond. The ongoing Phase II expansion study of ARV-110, called ARDENT, is designed to confirm the potential for accelerated approval while also exploring the possibilities for ARV-110 in earlier line prostate cancer. To walk you through these opportunities and the latest data for 110, I'm going to turn over to our CSO, Ian Taylor. Ian?

Thanks, John. I'll begin on Slide 25 with an overview of the current treatment paradigm in the U.S. for prostate cancer which has been evolving. Patients with prostate cancer often progress through multiple stages of the disease, starting with castrate sensitive and eventually reaching metastatic castrate resistant, or MCRPC. Androgen deprivation therapy has a long history of use in prostate cancer, and therapies like chemotherapy are used predominantly in MCRPC. Second-generation AR therapy such as enzalutamide are also used in MCRPC, but have gained approval in earlier lines of therapy in recent years. And this has created unmet need in MCRPC where patients need non-chemotherapy options and novel therapeutic approaches. It's important to remember that our Phase I trial of ARV-110 is in very late-line MCRPC patients, later than any other trials of AR therapies that we've seen. So what does that mean? Well, enzalutamide and other AR-directed therapies rapidly decline in efficacy when used in series. They start with a robust 90% PSA80 response rate in the castrate sensitive setting. But by the time patients get to third-line MCRPC, the PSA50 rate drops to 8% to 15%. In the late lines in which ARV-110 is starting, nobody exactly knows what efficacy should be expected of an AR-directed therapy, but certainly, it's fair to say that it's under 10%. Our overall strategy is to develop ARV-110 in earlier lines than we're exploring now. That's where our Phase II is focused, and I'll discuss that today. So ultimately, ARV-110 could follow the second-generation of AR therapies and expand into much earlier lines of therapy with the opportunity to benefit more patients is even greater. With that in mind, let's review our Phase I patient population, as shown on Slide 27. In short, we believe this is the most advanced and refractory population ever studied in a clinical trial of an AR-directed therapy. Specifically, patients have had a median of 5 prior lines of therapy, 82% have been treated with abiraterone and enzalutamide, 76% were previously treated with chemotherapy. And via our circulating tumor DNA molecular profiling, we have discovered that nearly 85% have at least 1 non-AR gene mutation and up to as many as 6 out of only 70 genes in the foundation medicine panel that we've used. Therefore, and we'll come back to this, the literature and our investigators tell us that with this level of tumor heterogeneity in prior treatment, there is likely a low dependence on AR in these tumors and existing AR-directed therapies have largely ceased being effective. As you've heard, we've initiated the ARDENT Phase II. And today, we can specify that we selected 420 milligrams oral once daily as the dose. As a preview for what I'll discuss in the remainder of my time, the Phase I learnings that inform the Phase II design are shown on Slide 28 and include: clear antitumor activity that has been seen in heavily pretreated patients with limited treatment options; PSA reductions that are associated with plasma exposure; AR molecular profiling has identified a mutation bearing late-line population, which may have greatest response to ARV-110. Importantly, we see activity in patients with wild-type AR, which supports broader use of ARV-110. And 110 is well tolerated, allowing continued dose escalation up to the current dose of 700 mg daily and supports early use -- use in earlier lines of therapy. A key piece of data supporting the selection of the 420 mg dose is the pharmacokinetics. On the graph on Slide 29, increasing plasma exposures go from bottom to top. And just to give you a preview on the next slide, they'll go from left to right. As shown on the right side of the graph, 420 mg is the first dose in which plasma exposures are consistently above the minimum level associated with preclinical efficacy, but 420 also exceeds the AUC associated with efficacy in the enzalutamide-resistant Xenograft model, which we've always thought would be an important target since this is essentially the patient population in the Phase I trial. So we are really happy to be able to consistently achieve these higher exposures at 420 mg. And we believe that achieving this threshold is important because we have observed an exposure activity relationship. In Slide 30, we are presenting best PSA change broken out by the preclinical exposure thresholds, again, with increasing exposure levels going from left to right. So starting at the left section of the graph. Below the minimum preclinical threshold, as expected, very little PSA reduction is observed. Moving 1 panel to the right, as exposures move above the minimum preclinical efficacy threshold, we see significant PSA reductions, including the 2 deep PSA50 responses we disclosed at ASCO at the 140 mg dose level. And on the right, when exposures surpassed a higher threshold, 2 additional patients achieved PSA50 response, which is great. You see that a significant number of patients have shown a 30% or greater PSA reduction, which is noteworthy, and we believe this trend clearly supports the selection of the 420 mg Phase II dose. But there's a third dimension to ARV-110's activity profile that we are seeing in this very late-line population, and that is tumor heterogeneity. The figure on the left side of Slide 31 depicts what is well known, the tumors become more genetically heterogeneous with time and particularly with an increasing number of treatments. As we've noted, the patients in our Phase I trial have had many prior therapies. And we are seeing signs with this genetic context could be an important determinant of response. As a reminder, our Phase I profiling showed that 84% of patients had at least 1 non-AR gene mutation. And as you will see, many had far more than that, up to 6 in a panel of just 70 genes analyzed. So it is likely that many of these tumors are AR-independent with a lower likelihood, therefore, of showing a PSA response. To illustrate this in more detail in the graph on Slide 32, we are showing the best PSA change, including the 4 PSA50 responses to date for all the patients with exposures above the minimum preclinical efficacy threshold, along with our AR mutation status, including ARV-7 and the number of non-AR genes altered. As you see in the bottom row of the table, the vast majority of these patients have at least 1 non-AR gene mutation, and some of these genes had multiple distinct mutations. So clearly, a very heterogeneous set of tumors, which again is expected for very late-line patients. But despite that heterogeneity, we are seeing PSA declines in most of these patients, which is very encouraging. The PSA50 rate is 14%, which is above the single-digit response rates that I noted previously would be expected in these very late-line patients. In the next 2 slides, we're going to focus on 2 populations in particular. Patients with wild-type AR-expressing tumors and highlighted here, those with T878 and/or H875 AR mutations, which together make up 71% of the patients in this exposure-defined group. At ASCO, we showed that the 2 PSA50 responses were in patients with tumors that had both T878 and H875 mutations, which confer resistance to second-generation AR therapies by making the androgen receptor more promiscuous. Since then, we've enrolled 3 additional patients with that mutation profile, and there are a few interesting observations on Slide 33. First, the graph shows 4 of 5 patients had PSA reductions, including the 2 deep PSA responses, one of which also had a RECIST response. Second, as you can see in the top row of the table, each have multiple AR mutations present, at least one of which is T878 or H875. In the middle of the graph, you see 2 patients that had PSA declines over 30%, despite having multiple mutated non-AR genes present as well as the L702H AR mutation, which, as you will remember, 110 does not degrade. And one of those patients also expressed at the ARV-7 splice variant, which is also not degraded by 110. Lastly, as you can see at the bottom of the table, 3 of the patients, including one who did not quite reach PSA50, were on treatment for over 6 months, which is also the median for the subset. We find this very encouraging when comparing to recent trials such as CARD and PROfound, in which the enza and abi control arm patients, who were in earlier lines than our patients, had median progression-free survival of between 3 and 4 months. So looking at the bullet points on the right, the important takeaway is that the presence of multiple AR mutations could be a signature that these tumors retain a significant level of AR dependence, such that a clinically relevant PSA reduction in durable time on treatment can be achieved by ARV-110, even in the context of high tumor heterogeneity and in setting where abi and enza have already failed. Therefore, patients with tumors with T878 and/or H875 mutations are being enriched for in ARDENT, and we believe they could be the basis of a potential accelerated approval, which is an exciting prospect. In the graph on Slide 34, we highlight the patients with tumors expressing wild-type AR, which, in most cases, also have other non-AR mutations present, as shown in the table. Importantly, there are 2 PSA50 responses in this heterogeneous population, one at 420 mg and one at 700 mg for a PSA50 response rate of 13%, which again is above the single-digit response rates that I've highlighted previously. The key point is that these responses demonstrated ARV-110 has a much broader activity profile than just the mutation-bearing population and also supports going into earlier lines of therapy where tumors will be less heterogeneous. Turning to Slide 35. This table summarizes the parameters behind the selection of the 420 mg oral once-daily dose for the ARDENT Phase II expansion. While the 420 mg dose has a strong profile, including no treatment-related adverse events above the grade 2 level, we are leaving open the possibility of initiating another Phase II expansion with a second dose. Now for more detail on the Phase II expansion, we'll turn to Slide 36. In designing the ARDENT Phase II expansion, we built in several features that are described in the top box. First, we want to establish efficacy in the populations where we've seen signals in the Phase I, especially in the T878, H875 patients I discussed a few moments ago. And we also want to continue to explore earlier more AR-dependent populations. We are not excluding any patients. Each are being placed in the 4 subgroups shown on the lower left for statistical analysis purposes, with a total of about 100 patients. So as summarized on the right, the Phase II expansion supports our overall two-pronged approach, which first includes the potential for an accelerated approval in late-line molecularly defined patients. T878, H875 is the primary focus, but there may be other subgroups as well, which is why we're not excluding any patients. The second prong is the potential for use in earlier line MCRPC patients whose tumors are expected to be more driven by AR. Slide 37 shows how our two-pronged registrational strategy aligned with the evolving treatment paradigm in prostate cancer, which I spoke about earlier. Pursuing a potential accelerated approval in molecularly defined late-line patients is on the right of the page. Accelerated approvals require confirmatory studies, which we would plan to do in first or second-line MCRPC patients, broadening the label. The signals we've seen in AR wild-type patients as well as the known benefits of PROTAC degraders over inhibitors, gives us confidence that 110 can be successful in this setting. Eventually, we would look to take 110 even earlier into the castrate-sensitive space following the lead of enzalutamide and other inhibitors. We believe ARV-110 will outperform AR inhibitors in every stage of prostate cancer. Now I'll pass the presentation back to our CEO, John Houston.

Thanks, Ian. As you could tell, we're really excited about ARV-110 and its significant potential. We believe our results are particularly compelling, driving tumor responses in patients who have difficult-to-treat heterogeneous disease, which most physicians would not expect to respond to androgen therapy. We believe the data in this very late-line population support 110 as a potential best-in-class therapy and strong potential for eventual approval for use in earlier lines of prostate cancer therapy. As highlighted earlier, the development path is two-pronged and contemplates both an accelerated approval in a molecularly defined patient group and a traditional approval across a broad patient population. And of course, the unmet need is enormous. There are drugs that work in prostate cancer, but patients progress on all of them, opening the door for a safe, differentiated therapy with a new mechanism of action. We believe the drug with that profile is ARV-110. So naturally, we are very pleased with the considerable progress we've made with our clinical programs to date. This adds to the strong track record of execution and delivery at Arvinas, along with our history of technology breakthroughs and industry first, all achieved since the company was founded in 2013. It's also clear that this is an increasingly competitive space as many others now see the exciting potential of protein degradation as a therapeutic approach. And to that point, we have certainly not been resting on our laurels as we've been moving forward on all fronts, adding further innovation to our industry-leading protein degradation platform and building out our pipeline. Our PROTAC discovery engine has allowed us to create a diverse and innovative pipeline of protein degraders in oncology, immuno-oncology and neuroscience. And beyond the clinical assets, we have over 20 different programs moving forward with the aim of generating 5 new INDs over the next 3 years. This is truly an incredibly exciting time for this unique platform and for Arvinas, in particular, as we continue to lead a new wave of therapeutics into patients with significant unmet need. And we hope to tell you more about these programs in the coming months and years. But on Slide 41, I want to go through some of the significant milestones we have coming up over the next several years. First of all, 2021 will be a truly milestone packed year. For 110, we will share completed Phase I data as well as interim data for the ARDENT Phase II trial and initiate a combination trial. That will not disclose the combo partner yet, so more to come on that later, but we think there's a significant opportunity there. For 471, we'll also share completed Phase I data as well as safety data from the palbociclib combo trial and will also initiate Phase II. Our next-generation ER degrader, ARV-766, should also have its first-in-human trial start in 2021. And in 2022, we should be positioned to share the ARDENT Phase II data for ARV-110 to also set a clear path to registration. The combo trial will have a planned readout by then as well. For 471, we will have interim data from the Phase II trial, providing information that we'll use to set a registrational path. And if ARV-766 progresses as planned, it will also transition to Phase II. And we expect 3 INDs in that year, too. So it's going to be quite a busy and exciting journey. And finally, to close, I want to talk about where we see ourselves 4 years from now, which is shown on Slide 42. And our 2024 vision is quite simple. We want to be on the verge of bringing our novel therapies to the market for the many patients that have tremendous unmet need. This builds on our history of execution and delivery. And we set ambitious goals in the past and achieved them, and we've proved that PROTACs can be drugs. So by 2024, we want to show, in registrational studies, that PROTACs are really benefiting patients. And as I said before, we are building a sustainable pipeline that will be delivering new INDs and at least 1 clinical candidate per year. That will generate even more significant milestones over the next few years as we continue to build out Arvinas as a fully integrated biotech as our climb to the top continues. And with that, we're happy to take any questions. Thank you.

[Operator Instructions] Our first question comes from Ted Tenthoff with Piper Sandler.

Great. Congratulations on the very thorough update, really exciting. I wanted to get a sense -- I was intrigued by the activity in the castrate-resistant prostate cancer mutation status. Do you know ballpark what T878 or H875 represent in terms of a population and/or maybe in a broader view, what you think would be degradable mutation percentages for 110?

Thanks, Ed. Great question. And certainly, Ian can give you a very detailed view there. But just at a high level, clearly, we had a lot of good preclinical data with 110 showing a whole array of different point mutations in the androgen receptor that were degraded, including 878, 875 and 877 and many others. Now in the literature, when you can extract the information from the literature, it looks like in the range of 4% to 10% in patient populations have these combinations of mutations. But clearly, in our trial, it's more than that. And I recognize the fact that it's still relatively small numbers, but we were up around 20% in this patient population, where we're seeing these combination mutations. And I think that is reflective, to Ian's point, of a very heterogeneous late-stage patient population where we're seeing more mutations. We end up seeing more of these specific mutations. So that bodes well for -- if we're in that late-line patient population and moving forward with the approval path. As we go earlier, we'll be just the fact that the ER degrader is a really good degrader and we should be fairly good head-to-head with other drugs.

And just to make sure I understand it, what is the difference in profile with the follow-on candidate 766?

Yes. The 766 is a very nice follow-on drug and has somewhat different drug properties. The most specific thing that we put into 766 that 110 didn't have was its ability to degrade the point mutation L702H. So has that added in. So we'll be positioning 766 in the clinic, see how well it does in the clinic as well and we're going to move forward with the strategy to see how we can complement 110 going forward. But that's a specific thing. It can degrade more of the point mutations.

Our next question comes from Terence Flynn with Goldman Sachs.

I guess just on the -- a couple of questions on 471. Any more detail you can share about kind of the time course of tumor shrinkage that you might be seeing in terms of how quickly that comes on? And then is there a fast-to-market strategy for the drug? I know you mentioned your thoughts on the initial Phase III program, but is there a way to move that drug forward to the market quicker? And then the last question is just how much paired biopsy data will we ultimately see from this trial?

Great. Thanks. Great question. And I will ask Ron to answer a few of those. But in terms of the paired biopsies, going into the trial, we're hoping to hit maybe around 25% of the patients with paired biopsies, and we're almost exactly on that mark. So we're pretty pleased with that. We've got more paired biopsies in the hopper going forward. So I'd expect us to have more seasonally more as we go pause. So that's good. In terms of the fast-to-market strategy and the tumor size changes, Ron, why don't you tackle those 2 because I know you've been thinking about same of that fast-to-market potential and also the data around tumor shrinkage.

Yes, certainly, I'll take the second one first. So time to response, with the patients that we've seen so far, we've already -- we've seen changes with the first on-treatment scans. So that's -- the scans are every 8 weeks. And so what we're seeing is generally that there's a change that's noted in the first scan and then it might take a second on-study scan to get to that peak response. But I would say, in general, it's probably -- what we're seeing here is pretty consistent with other therapies that tackle breast cancer, and it's also a disease where you might see some later responses too. So that's time to response. And then in terms of the registrational path, well, I think the fortunate thing for us, number one, is that we are seeing, obviously, very interesting activity in a population that, frankly, we were not expecting a lot because of the resistance. And so this makes us think more about how can we get this to market in a later line setting. We had always thought that this drug would work, especially well, of course, in the early line, but -- and I think while there isn't a lot of precedent -- of any precedent for getting hormonal -- there's actually no precedent for getting hormonal therapies approved based on accelerated approval, like a single-arm trial, however, when we're in this setting where, as I mentioned, existing endocrine therapies have really essentially no activity here and patients progress very rapidly, then we have at least enough to talk to the agency if these types of data hold up. I think more realistically, it would look like potentially doing that registrational trial in a late-line setting. But the study would likely not go -- it would be fairly short study, I believe, because again, the population with existing therapy does so poorly that the endpoints would be coming in earlier. So I think that there could be a pretty, pretty quick way to do this even if it's through the context of a Phase III.

Our next question comes from Alethia Young with Cantor Fitzgerald.

Congrats on this very, very good data update. Good way to start off on Monday. 2 questions. Just 1 is a big picture. I mean, we all know there's a lot of SERDs, but between the degradation you're seeing in a very tough to treat population of safety, I just wanted you to talk a little bit about what you think about the true kind of commercial potential may be as you move into earlier lines of therapy with CDK4/6 in light of the fact there are some companies ahead of you guys. I get that question a lot. And then the second question, I'm just curious, in some of these populations in 110 where you saw mutational activity, but where you might have not expected to see degradation. Why you think that's the case? And also, I guess, just internal perspective on even must be seeing AR degradation of a pretty meaningful amount even though it wasn't measured here.

Thanks, Alethia. That's great questions. In terms of the opportunity in the ER space, it's obviously very, very significant. Clearly, there's a whole bit of activity with other SERDs. And we knew as we moved into that space with our degrader that we would have to be able to hit our mark pretty well. We had to show and we have done that the ER degradation data, pre and post-treatment would prove the mechanism of 471 that we'd have to show degradation at all those levels and the paired biopsies and show in ESR1 mutant and wild-type tumors as well. So I think we're actually starting to show that the compound that we have here is a significantly good one in terms of the mechanism and the safety and the clinical benefit were also exceptional. So we think the profile itself will drive it to best-in-class. We do have to be fairly aggressive in our clinical trial plan, which we will be and moving forward with our combination studies. So I think what you'll see from us is that the acceleration of activities to really position 471 in a significant way and for it to be best-in-class and with that will come a significant financial opportunity, obviously. In terms of the question around AR, Ian, do you want to talk about AR degradation and what we're seeing there? Clearly, the ability to get biopsies in the prostate cancer trial will be more difficult and a lot of the mets are on the bone. So it's much more difficult to actually get. So Ian, do you want to talk about what we've seen so far?

Sure, sure. Yes. So since the ASCO update, we've only actually gotten 1 additional paired biopsy that we've been able to evaluate, which, again, continues to be a low rate, just as we expected. That was at a 420 mg dose. The degradation was about on the same level that we showed at the 280 mg dose at the ASCO presentation. So again, similar range. That particular patient was on the lower end of the exposure range. So again, not too surprising that we saw that level of degradation. But it's really hard to evaluate degradation, unfortunately, in this population. We get so few paired biopsies. And as we've talked about before, the circulating tumor cells that we've built into the trial to sort of as a backup for that, just haven't really panned out. Most patients are getting very few CTCs. Those CTCs rarely expressing AR that we can detect. So we have to continue to work on that. But -- so showing degradation in this population has been difficult for sure.

Our next question comes from George Farmer with BMO Capital Markets.

Congratulations on the great data. Perhaps I missed this, perhaps -- can you correlate the ER degradation profiles that you saw with the response in the waterfall plot? I don't know if I caught that, number one. Number two, you did have 1 patient on the -- that you label that is stable disease, but it looked like the target lesion decreased by over 50% -- by 56%, I think. And then finally, as you think about combining with CD4/CDCK46 inhibitors with this drug, have you thought about different ways of sequencing? I mean the data that we have now is in combination with fulvestrant, which appears to have a very different profile. I mean maybe your drug would work differently with the CDK4/6 inhibitors in the clinic, if that's possible or worthy of thinking of that. Could you comment on that?

Yes, great question, George, and I'll answer the last one and then turn to Ron. Yes, clearly, we're obviously with the combination trial with palbo, we'll be seeing how well 471 works in conjunction with palbo. There's also potential other partner combos that could be looked at as well with the 471, and we'll be exploring those. And ultimately, going earlier in the treatment paradigm would be an attractive way forward as well. Yes, we're going to be exploring all aspects of that over the coming year and beyond. And we do think 471 will either in monotherapy be very exciting or in partnership with a number of different compounds. Ron, do you want to talk about ER degradation as it relates to response rate and also that 1 patient stable disease with 56% response?

Yes, certainly. I'll start with the second one. So that patient, it was a situation where the patient started to have regression with the first unsteady scan. I think it was around 25% or so. So it didn't cross the RECIST line. In the second follow-up, that's when the patient went down greater than 50%, but at the same time they had progression in another site of disease. So by RECIST that stable disease. Nonetheless, in this resistant population and potentially at a dose that might be lower than what a recommended dose is, this is just clearly a sign. And interestingly, back to your first question, this is one of the patients that we had biopsies from and did have ER degradation. So that's 1 example of the correlation. I'll also point out that in the CBR analysis, so just to back up, we had 5 patients with CBR, and 2 of the patients had biopsies that showed degradation. So yes, it's small numbers, but this is, let's say, beginning of -- at least the anecdotal correlation that we can -- once we get more data, we can have more robust analysis showing the correlation with outcome.

Our next question comes from Michael Schmidt with Guggenheim.

Really nice data. I had a couple more on the -- on 471, I was just wondering if you could comment maybe on the sort of the kinetics of ER degradation and response? Is that something that happens basically instantly? Or is it a trajectory over time where we could maybe expect more response deepening as more ERs degraded longitudinally? And then on 110, I was wondering if you could comment some more on the 878 and 875 mutations and whether those have been observed in other studies as well? And I guess, what is really ongoing with those patients that might explain why they could respond better? And how should we think about a regulatory bar potentially in that setting? Is the PARP inhibitors is that a good analog, for example, in this context?

Yes. Great -- some great questions there. Why don't we start with the ER -- I started to answer some of that on the 878, 875 mutations and talking about some of the publications that are out there, about the rate of the mutations appear there. And we're clearly seeing more of these mutations in our late-stage trial than has been published. You could talk about that a little bit more, but maybe start off with the regulatory path for ER. Ron, do you want to talk about the regulatory path that we lead out there in terms of the fast track approval -- fast approach to approval?

Yes, certainly. And Michael, you pointed out the PARP approval, the one precedent that was the approval for rucaparib back in May. And so that -- it really gives us a head start because the agency is clearly open to this. In that case, it was approved based on a RECIST response. Their response rate by independent review was about 44%. On the flip side, they have -- as you may know, rucaparib has some adverse events that put a frame around the benefit/risk picture. They have a significant number of patients who have liver enzymes. I think they had about 1/3 of patients having grade 3 anemia. So it's all about benefit/risk. The way that we're looking at this is that while that 44% is one data point, if you look at the recent publications from the FDA, where they've really cataloged the response rates and other characteristics of the accelerated approvals that they've given across different drugs across different solid tumors, you'll see that it gets quite low, especially with the immunotherapies. What we're thinking is that somewhere around 30% may be a bar. It's going to be highly dependent on duration of response. In other words, if duration of response is clearly outstanding, then that bar goes down just like with immunotherapies. It could be down to the 20s or even lower. We're thinking more realistically. It won't be -- that will have -- it may be around probably the high 20s to 30 would be a starting point for thinking about that. But the good thing is that we're in a good starting position based on the data that we have right now for 878, 875.

Thanks, Ron. And Ian, anything you want to add color to in terms of the specific point mutations?

Yes. Again, I think we're viewing those hypotheses -- we're reviewing those as a signature of AR dependence. There's 110 degrades those mutations just equally well as wild type. But in those particular tumors, there's multiple AR mutations and therefore, something about those tumors, they just keep wanting to mutate AR. They want to stay dependent on AR. Those are mutations that make them more promiscuous to other ligands. So there's really nothing per se about the mutations other than a signature that those tumors, they could have chosen to mutate other genes as well and they have. But for some reason, they've mutated AR twice, and in some cases, 3 times and in another case, 4 times, 4 different mutations. So that really caught our attention to say, okay, it's hard to pick out AR dependent tumors, but maybe this is the way to do it. And I think our PSA reductions are showing that or at least hypothesized amount.

And then just touching on that. The first question you asked, which is the kinetics of ER degradation. Clearly, we have lots of information about the kinetics of degradation preclinically. And we know the profile of 471 incredibly well based on that degradation and how quickly we see degradation and the profound nature of how it stays down on continued dosing. Now in the setting in the clinic, it's almost impossible to show kinetics. You've got a paired biopsy. You're getting some biopsy at baseline, then you're taking a 1 point in time further on. But we will keep tracking as best we can, the paired biopsies, the dose they are -- the dose they are at and also the time the biopsy was done. But all we can do is say that the data we had preclinically that showed superb kinetics as it relates to degradation and tumor effect. And the data so far is telling as that must be playing out in the clinic as well.

Okay. And if I may just ask 1 quick follow-up. I guess with 2 drugs now in moving into mid-stage clinical trials, pursuing very large potential market opportunities, how do you think about those from a partnering perspective? Do you feel like you would want to keep those in-house for the foreseeable future? Or is it -- is there maybe an opportunity to leverage a larger pharmaceutical company to really maximize the scope of development for either of those 2 agents?

Yes. Clearly, our focus over the last 2 or 3 years has been getting to this point, which is showing that we have 2 compounds that are active in the clinic and providing benefit. We have a good layout plan for the next year in terms of getting Phase II started for 110 and initiated for 471. But we know that we're moving into fairly large areas of development. And obviously, the idea of a strategic partner would make sense at some point. So we're not saying that, that's not something we'll be looking at in the future. There's anything that would allow our program to move faster and more comprehensively and get into more patients, that's something we would look at for sure.

Our next question comes from Yigal Nochomovitz with Citigroup.

Congrats on the very impressive data. I was just curious with respect to the ARV-471 degradation. It looks like you're practically maxing out the degradation even at the 30 mg dose. So I'm just wondering, do you see evidence of a dose response with the degradation? Or you think that even with the low dose of 30 milligrams, you can -- you're really getting really most of the AR degraded?

Yes. Thanks, Yigal. A great question. Yes. I mean, it's early days yet for those types of analysis. We've only got those 5 paired biopsies, a range of different doses. And it's clear that even at the 30 mg dose, we're getting significant degradation. That's very encouraging. It could be that the you get threshold and you're getting significant degradation. Our belief is that as we increase our exposure in those, we'll have a very consistent ER degradation right across all the biopsies that we see. So we're still pursuing -- let's get to the recommended Phase II dose. Let's get the maximum exposure we can. And of course, with these biopsies, you're going to get variation. It's a needle biopsy. You never know if it's going to a highly vascularized and non-vascularized part of the tumor, so you don't know how well your drug is penetrating. So we'll need more biopsies at different doses as we go up to allow ourselves to answer those types of questions. But yes, I'm very encouraged by what we're seeing already, even at this early stage.

Great. And then with regard to the plans for the combo study for 471 in the second and third-line setting that you're planning to start in the second half of next year, can you just offer your perspectives on what combos you might be considering?

Yes. Certainly, for 471, we'll be initiating fairly shortly with palbociclib. And Ron mentioned, there's a potential range of other compounds that we can look at. I mean, Ron, do you want to just -- very briefly just touch on some of your thinking there? Obviously, we're just at the early stages of thinking about the different combos, but...

Yes, certainly. Yes, essentially, what we're doing is really thinking about the endgame here, right? So we want to determine a combination that makes sense for this -- for 471 and would support a registrational strategy. So I mean, I think the drugs that we're -- we've been putting a lot of thought into are alpelisib, the PI3 kinase inhibitor from Novartis and everolimus which has an indication in combination with exemestane. So these are the ones that we're thinking about the most.

Okay. And then just 1 final question on ARV-110. On Slide 30, where you show the PSA changes broken out by exposure, could you just give us a little bit more detail as to how well those correlate with dose? For example, on the right with the highest exposure levels, is it fair to assume that those are all the 420-milligram patients or not necessarily? And similarly, for the left side, is it mainly the 35 and the 70 in the gray?

The simple answer is yes. We are trying to find different ways of showing the data because clearly where we're seeing an exposure activity relationship starting to build up with these PSA30 and above in the higher exposures. When we -- and we'll show this at some point in the future. But when you look at it from a dose point of view, yes, the higher doses are shifted to the right, the lower doses are to the left, which is gratifying.

Our next question comes from Zegbeh Jallah with ROTH.

Congrats on the update. I think early line use of these drugs could indeed be a huge market opportunity. So just my modeling, just kind of curious by the front-line setting, you think you'll be pursuing a combo strategy or a single-agent strategy or is that still being determined?

Yes. I think -- thank you very much for the question. I think for both compounds, there's no reason for us not to think about pursuing a monotherapy at the same time as doing the combination studies. Clearly, with the AR program at the late-stage patient population, a monotherapy approach would be fine. And the activity we're seeing there supports that. But we are excited about doing combination studies because I think that's really what's needed for this type of patient population. And similarly, with 471, I think we're going to show good monotherapy activity with 471. But clearly, the standard of care in this space is combination therapy. So we want to show that 471 will be the backbone partner of choice for any one of these different combinations. And I think that's really how we're positioned 471 of the best-in-class opportunity.

And then specifically for 110, will you be waiting for data from ARDENT before initiating the combo study? And again, also for 110, any thoughts on what conditions or treatment might lead to an emergence for loss of 878 or the 875 mutation?

Could you repeat that last question? Sorry...

Yes. I just wanted to know if you've been looking at what conditions or treatments might lead to an emergence or a loss of the 878 or 875 mutations.

That's an interesting question. I mean I'll ask Ian to cover that. But in terms of the data and when the data will be coming out. So we're hoping we'll have the full Phase II readout of ARDENT at some point in 2022, and we'll also have our combination study data at that time as well. So whether one is just before the other, we don't know yet. We'll be initiating the combo study relatively soon. So we're trying to time the data to be more or less simultaneous or near as we can. But yes, they'll both be 2022. Ian, do you want to talk about the idea of emergence of these mutations and how they might be impacted?

Sure. Yes. All the mutations that we show and that exist are resistance mechanisms to abiraterone and enzalutamide. The T878 and H875 particularly skewed toward emerging with abiraterone treatment. And as I mentioned, the way it works is they're in the ligand binding domain and they make the androgen receptor more promiscuous to other ligands. And so that's how they work. In terms of them disappearing, of course, we hope -- we see 110 can degrade them, and that's what we expect is that even though these mutations are no longer responsive to inhibitors or to abi, they can be degraded by 110. And so that's how they'll disappear in the long run.

And just another follow-up here. Basically, based on what you're always talking about, are the mutations going to affect the dose response? Because in that case, then we'll need multiple patients with the same mutations to kind of look at the dose response there? And then final one for me is just any learnings from what you've seen here, that can kind of help accelerate the planned clinical trials as well as some of your early stage efforts.

Yes. Ian, do you want to cover the -- again, the -- I mean, I think you laid out nicely in the presentation. It's a combination of dose exposure and the molecular profile in this late-stage patient population.

Right. Yes. No, exactly. The number of patients, yes, we have 8 so far that have the mutations. As long as we're above the minimum preclinical efficacious threshold, the exposure threshold, we're seeing some level of PSA response, including PSA50 responses at 140 mg. So there is some exposure/dose relationship with the mutations as well. You have to be above the minimum. Other than that, it's, again, more of a signature of sensitivity that the tumor has, just because they have multiple of these mutations are showing us, this could be a signature that these tumors are particularly dependent on AR, and therefore, 110 is working. And that's perfectly set up accelerated approval path with a molecular defined population. It will require a companion diagnostic, which we're planning for. But we can pick these patients out and go really fast.

And then just the last one here. Because you presented the pipeline expansion, I feel like the market didn't really appreciate that expansion. But now that you have some of this data, I thought that some of the stuff that you're doing with your early-stage pipeline might be more appreciating. And so I was just kind of wondering how you plan to kind of accelerate development there.

Yes. No, we're very excited by the rest of our pipeline. And you're right, we want to certainly draw the connection between the evidence we have with our 2 lead programs that PROTACs work and they act as normal drugs and we're seeing efficacy. And that would also give confidence that we will be able to deliver the same type of approach with the rest of our pipeline. So with that 766 is up next, hopefully be in the clinic in the first half of the year. We have BCL6, which we talked about, which we're aiming for an IND in 2022, KRAS for the IND in 2023 and Tau an IND in 2022. And we have a number of other programs earlier making HPK1 and also Huntington. I just -- I get very excited when I look at the pipeline, see the huge amount of activity that's going into moving forward and the great degraders we're seeing. So the next year to 2 years is going to be incredibly productive as we bridge the pipeline that we have into the clinic. And yes -- so yes, a lot more to come and we'll be talking about that over the next year.

Our next question comes from Mark Breidenbach with Oppenheimer.

Congrats on these really nice data. Just a quick one for me on 110 actually. I was hoping you could comment on the time to PSA50 response and the durability of the responses you've seen so far? And I'm also wondering if the 1 patient who had a previously reported RECIST response, is that still ongoing?

Yes. Great question. And Ron, you've been the closest, obviously to the clinical data. Do you want to talk to that?

Yes, certainly. Yes, the patient with the RECIST response was able to stay on therapy for quite some time. I -- it was certainly several months, that's for sure. I think that patient just recently came off. But -- and if you remember, this is a patient who had extensive prior therapy. They had chemotherapy, they had enzalutamide, apparatarone and a number of other standard treatments. So this patient was pretty much at the end of the line. So he did stay on for therapy for quite some time before coming off. And then I think your question otherwise was around time to response. Now that we have more experience, it's actually been a little bit variable in terms of when patients develop response. I think your other -- and I think that's pretty standard for any type of cancer therapy. It doesn't really, for us, to tell us on anything in particular about this. It's probably more just about biology and getting enough critical mass of the drug into the patient and let it do its thing. And then I think in general, yes, I mean, in terms of durations of response beyond that 1 patient, we've -- Ian presented a slide that looked at the 878, 875 mutation, it has the waterfall plot. But there on the bottom was the time on therapy. And as Ian presented, for that particular group, you can see that these patients are actually staying on treatment for quite some time and actually beyond what we would expect from historical data when you look at the control arms for CARD and PROfound. So we -- this all tells us that we've got something here.

And just to jump in that the patient on the far right on that waterfall, it's the RECIST response, you can see that treatment duration on that graph on Slide 33.

And that's all the time we have for questions. I'd like to turn the call back to Mr. John Houston for closing remarks.

Thank you, and thank you all for joining our call and hearing about the progress we've made with ARV-471 and ARV-110. As you can tell, it's an exciting time coming up for the company over the next year, and we'll certainly keep you all updated on our progress as we move forward. Thanks for your time, and have a good day. Bye-bye.

Ladies and gentlemen, this concludes today's conference call. Thank you for participating. You may now disconnect.