Novartis AG

Good morning and good afternoon and welcome to the Novartis conference call and live webcast. Please note that during the presentation, all participants will be in listen-only mode and the conference is being recorded. After the presentation, there will be an opportunity to ask questions by pressing star 1 and 1 at any time during the conference. Please limit yourself to one question and return to the queue for any follow-up. A recording of the conference call, including the Q&A session, will be available on our website shortly after the call ends. With that, I would like to hand over to Mr. Samir Shah, Global Head of Investor Relations. Please go ahead, sir.

Thank you very much and good morning and good afternoon, everybody. And thank you for taking the time to join us on the first of our two conference calls today. And this obviously relates to the ESMO presentation relating to Plavictor. Before we start, just a safe harbor statement. The information presented today contains forward-looking statements that involve known and unknown risks, uncertainties and other factors. These may cause the actual results to be materially different from any future results, performance or achievements expressed or implied by such statements. For a description of some of these factors, Please refer to the company's Form 20F and its most recent quarterly results on Form 6K that, respectively, were filed with and furnished to the U.S. Securities and Exchange Commission. The participants, which you'll see in the slide deck, which is available on Novartis' website, the participants today will be Sriram Aradia. He's actually the Global Head of Development and Chief Medical Officer for Novartis. together with Jeff Lagos, who's actually our global head of oncology development. And with that, I'd like to hand it across to Shreya.

Thank you, Sameer. Good morning and good afternoon, everyone, and thank you for joining our call. As Novartis has become a focused pure play medicines company, oncology is a key therapeutic area for us, and within it, prostate cancer is a really important indication. If we go to the next slide, We, with 1.4 million prostate cancer cases worldwide, this being the second most common cancer in men, and a 30% five-year survival, we believe that there is still a significant need for developing therapies that have better efficacy and tolerability for these patients. On the next slide, you all know the results that we had from our phase three vision study where we convincingly showed a benefit on both the risk of progression as well as the risk of death with Pluvicto in a metastatic, castrate-resistant prostate cancer post-axane setting, as published in the New England Journal. Next slide. Emboldened by those results and the subsequent performance of Pluvicto, where it is now approved in 37 countries, and more than 7,400 patients have been treated with Pluvicto in that setting, we designed an ambitious program, on the next slide, to explore the role for Pluvicto in additional indications in this important disease. Today we will discuss the results of PSMA4, and you're all aware that in addition we are looking at PSMA addition as well as PSMA delay castration as two additional important trials that Novartis is now evaluating. Next slide. We were excited to present our data yesterday where PSMA4 demonstrated both a robust efficacy and a favorable safety profile. I'm sure that you all have a lot of interest in these results, and I'm delighted to hand over to Jeff Lagos, my colleague, for a detailed review of the data of PSMA-4. Jeff, let me hand it over to you.

Thank you, Sriram, and good morning, good afternoon, everyone. It's truly my honor and pleasure to be here following yesterday's presentation of the PSMA-4 results that we're highlighting during the ESMO Presidential Session by Dr. Sartor. Hopefully, I'll be able to provide some additional detail and context around yesterday's presentation. Let me start on slide 11 with a brief overview of the PSMA4 study design. The study population was patients with progressive metastatic castrate-resistant prostate cancer who had previously progressed on a prior second-generation androgen pathway inhibitor, which I'll subsequently refer to as an ARPI, and also were candidates for a switch in their ARPI. I'd like to underscore the importance regarding the inclusion criteria that patients were required to be eligible for a switch in ARPI. Specifically, if the treating physician believed that the patient needed or should receive chemotherapy as its next line of treatment, it's likely that this patient would not have enrolled or participated in the PSMA-4 clinical trial. Over the period of July 2021 to May of 2022, 468 patients were randomized one-to-one to receive lutetium PSMA617, which I'll subsequently refer to as Plavicto, or a change in their ARPI. If we move to slide 12, the PSMA4 trial was thoughtfully designed based on a very well-established set of data for Plavicto, and leveraged several key insights around the regional differences in clinical practice and the remaining global unmet medical needs in search of new, safer, and highly effective therapies for patients in this particular disease setting. Specifically, the dosing regimen that was chosen was based on Plavicto's low kidney absorption and an already proven safety profile in the sicker post-taxane setting, and the currently approved dosing regimen of 7.4 gigabecquerels administered every six weeks for six cycles was maintained in the PSMA-4 trial, an earlier line of treatment. With respect to the choice of comparator, here are some key data and insights found in a meta-analysis of more than 2,500 patients with metastatic castrate-resistant prostate cancer where approximately 25% of patients had died without receiving any subsequent therapy beyond their first-line ARPI. Although the standards of care may differ by geography or the type of institution and clinical prognosis, a large majority of patients are often unwilling or ineligible to receive taxane-based chemotherapy, and therefore a switch in ARPI was chosen as the comparator arm of choice in hopes to potentially provide a new safe and effective therapeutic option that would also allow patients the ability to delay, reduce, or eliminate the debilitating need for chemotherapy. Based on the strong overall survival benefit observed in the vision study that has led to approval in 37 markets, there was a high potential for loss of equipoise and an increased risk of patient dropout in the control arm to go seek PSMA 617 through alternative mechanisms. Therefore, we employed a physician-recommended patient-centric design to allow patients on the control arm the option to cross over to receive Plavicto, but only and only after blinded independent central confirmation of radiographic progression. I'd like to reiterate that crossover to Plavicto was entirely an option for patients in treatment. The protocol did not mandate which subsequent therapy that the patient should receive, but rather the treating physician would decide whether other available standards of care, including a taxane or Plavicto crossover, was the most appropriate therapy for his or her clinical judgment to be administered to the patient. These key design features were essential to ensure not only the integrity of the overall trial by eliminating any bias to the primary endpoint of radiographic progression-free survival, but also important to reduce the likelihood of any patient dropout. And in fact, only one patient had withdrawn consent from the entire study or was lost to follow-up in the PSMA-4 study. And just as a reminder, this trial was largely conducted in the midst of COVID. If we move to slide 13, so as a reminder, the primary endpoint for the PSMA-4 study was radiographic progression-free survival via a blinded independent central review. The study was powered at 95% for a hazard ratio of 0.56 after 156 radiographic progression-free survival events, using an overall one-sided alpha of 2.5%. OS was a key secondary endpoint, and we employed a four-look design that was planned for OS using a hierarchical testing procedure that would only be performed if radiographic progression-free survival was significant. The first look at survival was at the time of the RPFS primary analysis, but that was limited by a very low information fraction and short study follow-up of just over seven months. The updated analysis that I will share with you today was presented by Dr. Sartor at yesterday's ESMO presidential session and is based on a 45% information fraction for OS, corresponding to 135 deaths. Other secondary endpoints are also included on this slide. Due to the anticipated crossover rate, the protocol had also pre-specified that the primary methodology for overall survival was to use a rank-preserved structural failure time crossover adjusted analysis. If we go to slide 14, overall, here are the patient demographics and baseline clinical characteristics, which are broadly similar between treatment arms and representative of the intended treatment patient population. Minor differences across treatment arms were observed and included a slightly worse prognosis population for Plavicto, based on a higher percentage of patients with higher Gleason scores and baseline PSA values. If we move to slide 15, as you can see on the left-hand portion of the slide, Plavicto demonstrated a clinically meaningful and highly statistically significant improvement in radiographic progression-free survival at both the primary endpoint as well as the updated analysis. If you look at the Kaplan-Meier curve, the curves separate early, remain separated throughout the entire duration of follow-up, with Plavicto reducing the risk of disease progression or death by nearly 60%, corresponding to a median radiographic progression-free survival twice as long of the ARPI arm, respectively at 12 months versus 5.6 months. If we move to slide 16, This benefit in radiographic progression-free survival was consistent across the pre-specified subgroups, regardless of baseline clinical characteristics, well-known prognostic factors, which androgen receptor pathway inhibitor was previously received, and in what setting it was given in. As you can see on the far right-hand portion of the slide, the majority of the 95% confidence intervals exclude unity. with the exception of a very few small subgroups where there's less than 10 patients and the confidence intervals remain wide. If we move to slide 17, please. PSA response rates are commonly used as additional outcome measures in the metastatic castrate-resistant prostate cancer setting. Here on the waterfall plots, you could see that the confirmed PSA50 response was two and a half times more frequent on the Plavicto arm compared to patients who had received a second treatment with the androgen receptor pathway inhibitor at a 57.6% confirmed decrease in PSA greater than 50%. If we move to slide 18, other clinically relevant, especially those for patients, include symptomatic skeletal events as these are often morbidities related to bone metastases and unfortunately are a very burdensome and common problem for patients with metastatic castrate-resistant prostate cancer. A symptomatic skeletal event is defined as a bone fracture, spinal cord compression, tumor-related surgical intervention, thus requiring radiation therapy to relieve bone pain, or death if that was a preceding event. As you can see on the slide, Plavicto more than half the number of symptomatic skeletal events, as well as prolonged the time without a symptomatic skeletal event, thus demonstrating an overall 65% reduction in the risk for patients having a symptomatic skeletal event when treated with Plavicto. If we move to slide 19. In order to evaluate the direct effect of Plavicto on tumor size beyond just bone metastases, objective response rate was assessed in patients with soft tissue disease using standard RESIST 1.1 criteria. Plavicto demonstrated a confirmed response rate in 51% of his patients compared to 15% of patients treating with an ARPI switch, and these responses were quite durable at 13.6 months. It's also quite noteworthy that more than 20% of patients treated with Plavicto achieved a complete response. And this data highlights the potential for even greater eradication of cancer cells when Plavicto is used in earlier disease settings, especially relative to the data that was observed in vision. If we move to slide 20. So following the reduction in risk of symptomatic skeletal events, coupled with a very impressive objective response rate of 51%, including 20% complete response, it's not surprising that Plavicto also delayed the time to worsening on two separate health-related quality-of-life measures that overall assess the physical, social, emotional, and functional health of the patients, as well as deterioration in pain and pain scores for patients. Taken together, all of the efficacy data shared over the past six slides demonstrate that Plavicto provides a direct anti-tumor benefit across a range of clinically meaningful endpoints and is also accompanied by patients reporting an improved quality of life compared to daily oral ARPI. The interpretation of this data is neither confounded nor complicated due to additional subsequent therapies, that patients received after confirmed disease progression. If we move to slide 21, for the remaining secondary endpoint, overall survival is a very important parameter for any cancer trial. And it is defined as the time from randomization to death due to any cause and includes the results or includes the effects that are attributed to both the primary treatment assignment that patients are randomized to as well as any subsequent treatment administered during this overall time period. Therefore, it's important to note that the interpretation of overall survival cannot be done in isolation, and it can also be impacted or confounded by crossover. Specifically, in PSMA4, if you look at the consort diagram on the left-hand side of the slide, it is noteworthy that of the 146 patients who discontinued an ARPI, following blinded independent central confirmation of radiographic progression, 123 of these patients, or 84%, had crossed over to receive Plavicto. So to try to put this in better perspective, with such a high rate of crossover, you can think of this OS analysis as almost comparing Plavicto to Plavicto, just at different times of starting Plavicto therapy. If you look on the right-hand side of the slide, at the time of the second interim analysis, a total of 134 deaths were observed, which corresponded to a 45% information fraction. Although we could have never predicted that nearly all patients who progressed on an ARPI would cross over to Plavicto, because this was completely optional and physician choice, the statistical analysis plan had pre-specified that the RPSFT methodology as the primary overall survival measure that does adjust or account for crossover. Using the most appropriate statistical methodology for crossover, the observed hazard ratio for overall survival was 0.8, but based on the low information fraction, the 95% confidence interval remains wide, ranging from 0.48 to 1.33. In analyzing overall survival using a traditional unadjusted intent to treat analysis, which also includes patients who die for any reason, and specifically three patients who are randomized to receive Plavicto had died before ever receiving their first single dose of Plavicto. And this analysis also includes one patient who died from COVID-19, which was unrelated to disease. The observed hazard ratio was 1.16, also with corresponding wide 95% confidence intervals that range from 0.83 to 1.64. So if we move to slide 22, I'd like to use this slide to hopefully better visualize the impact that Plevicto has on patients who were initially randomized to receive an ARPI switch. If we take a look at the SWMRS plot that compare the radiographic progression-free survival times shown in gray, plus the overall survival time up to the point of data cutoff from the time of radiographic progression-free survival highlighted in orange, you actually see there is a difference in patients who did or did not receive Plavicto as a crossover treatment at the time of blinded independent central confirmation. What is consistent and common that you see across both plots is a very large proportion of patients did have rapid disease progression. However, if you look at both the shape of the plots as well as the total area under the curve in orange, it is quite clear that Plavicto increases both the number of patients that were alive as well as the length of time that they are surviving. and the estimated 12-month survival rate is actually 92% for patients that had crossed over to receive Plavicto. In contrast, if I draw your attention specifically to the lower plot, this provides additional evidence that unfortunately a reasonable number of patients die without ever receiving subsequent therapy as highlighted earlier in terms of the unmet medical need that we are trying to advance. The estimated 12-month survival rate for patients that had not received Plavicto as part of crossover is approximately one-third lower for this group. One of the key takeaways from this swimmer's plot for me is that it's quite evident that the difference in patient outcomes apparently appears to be attributed to Plavicto in terms of crossover in this trial. and thus provides further or additional evidence that Pluvicto is a highly effective treatment for patients even when administered after a second ARPI. If we move to slide 23, I think another important component that needs to be assessed when you're trying to interpret the overall survival hazard ratio or an estimated landmark survival based on the swimmer's plot, it's important to also look at how patients were treated after radiographic progression-free survival, and to see if there was any observed difference between treatment arms. As you could see from the table, the Plavicto crossover rate occurred in 84.2% of patients who were initially randomized to an ARPI switch. As a reminder to what I talked about in the methodology, crossover was optional and required that two conditions must be met. Condition number one is that blinded independent confirmation of radiographic progression occurs to minimize any investigator or patient bias to which treatment they were received. And then secondly, the crossover has to be recommended by the treating physician as the most appropriate next treatment amongst all available standards of care, including taxane-based chemotherapy. If you look on the right-hand slide, these are patients who were initially randomized to a subsequent ARPI, and in addition to the 84% crossover, another six patients had also received PSMA RLT directed therapy outside of the study. Please note that the chart only highlights five. There is a sixth patient that was excluded from the chart. There are also two kind of key important takeaways from this trial. I think importantly, it shows that other than Plavicto, as well as these patients who received PSMA-directed therapy outside of the trial, it's noteworthy that additional 30 patients were required to receive concurrent radiation, primarily due to extensive bone metastases on the ARPI arm, and then subsequently, it actually highlights that other than these two therapies, all other available standards of care were routinely used in a similar proportion of patients across treatment arms. What this table also highlights is that it makes it very difficult to isolate the true effect of Plavicto because so many patients on the control arm had received either Plavicto, other types of PSMA-directed radioligant therapy, or concurrent radiation because of symptomatic bone metastases or pain. If we move to slide 24, at the time of the updated data cutoff, the median follow-up time was 15.9 months, which represents a sufficient follow-up time so that all randomized patients had adequate time to complete their intended course of therapy. As of the data cutoff, 63% of patients had received the full six cycles of Plavicto, and 75% received at least five doses. So this represents a very mature follow-up to assess the overall safety of Plavicto relative to an ARPI change. As you can see from the overall safety table, Plavicto had a lower rate of grade three or higher adverse events, very low rates of dose adjustment at 3.5%, and a similar 5% rate of discontinuation due to an ARPI. If we go to slide 25, the majority of adverse events were low-grade and consistent with the known safety profile of Plavicto based on the previous established vision trial in a post-taxane setting. Xerostomia, or dry mouth, is the most common adverse event observed However, only 1% of patients had reported a grade three or higher adverse event, and this actually only led to discontinuation in one patient, suggesting that xerostomia or dry mouth is quite manageable and allows patients to live and resume a normal daily quality of life. Anemia was the only grade three adverse event that was reported in more than 5% of patients, but did occur at a similar 6% rate across treatment arms. If we move to slide 26, please. Overall, we have accumulated more than 2,000 patient years of safety data across the vision, PSMA-4, and post-marketing setting, which overall support the favorable safety and well-tolerated profile of Plavicto. If you look at the exposure adjusted safety by indirect cross-trial comparison between both PSMA-4 and vision, It's noteworthy that there is a much lower incident rate per unit time for grade three or higher adverse events, as well as for severe adverse events. An important takeaway from this slide is that the overall safety profile relative to the vision patient population supports the broad clinical development plan where we are continuing to evaluate Plevicto in even earlier lines of therapy and earlier stages of disease. If we move to slide 27. So in conclusion, Plavicto demonstrated a clinically meaningful and highly statistically significant improvement in the primary endpoint of radiographic progression-free survival. Plavicto also demonstrated robust efficacy against important secondary endpoints, such as PSA50 response, time to symptomatic skeletal event, objective response rate, and overall health-related quality of life. I'd like to reiterate that the clinical benefit observed for the primary endpoint and all of these secondary endpoints are based on mature or final analysis, which provide further support for the robust efficacy of Plavicto. Since all of these are direct measures of Plavicto randomized against a switch or a second treatment with an ARPI, The interpretation of this data is not impacted by any subsequent therapy, nor is it confounded by the results of crossover. The overall safety of Plavicto is favorable compared to an ARPI switch, with lower reported rates of grade three or higher adverse events, lower rate of severe adverse events, less frequent dose adjustments, and the overall low rate of discontinuations. The data in PSMA4 in a much healthier population also compares favorably to the sicker post-taxane population with lower incident rates of high-grade adverse events based on a cumulative data set of more than 2,000 patient years. If we just move to the last slide, slide 28. So overall, PSMA4 was a very well-designed and well-controlled study. The physician recommended patient-centric crossover design that allowed patients on the control arm the option to cross over to receive Plavicto, but only after central confirmation of radiographic progression-free survival, enabled a very robust and independent assessment of the primary endpoint, and likely reduced any risk of patient dropout due to physician decision. The high rate of crossover further reiterates the unmet medical need that both patients, physicians, and investigators are seeking for safer and more tolerable and highly effective therapies. These key design features were essential to ensure the integrity of the trial by eliminating any bias to the primary endpoint as well as reduce the likelihood of patient dropout with only one patient withdrawing consent during the PSMA-4 study. However, I would fully acknowledge that the challenges that this crossover design and the fact that almost all patients had received Plavicto following radiographic central confirmation of progression does impact our ability to reliably assess endpoints such as overall survival since the randomized treatment assignment is no longer isolated. And especially at the time of this data cutoff, the follow-up does remain short at 15.9 months, and only 135 or 134 deaths have occurred. So specifically, if we look at the conclusions, at the time of the interim analysis, there remains only 45% information fraction. There was a very high crossover rate of 84%, plus patients who received PSMA4-directed therapy in another setting, does confound our ability to interpret the overall survival analysis at this point in time. The PSMA-4 trial is ongoing, and it will continue to the next interim analysis, where we'd expect approximately another 90 to 100 additional deaths, which would correspond to a 75% information fraction. And our regulatory submissions to health authorities will follow in 2024 after we reach our next interim analysis of 75%. Thank you very much, and I will now turn it back over for our Q&A.

Thank you. As a reminder, to ask a question, you will need to press star 1 and 1 on your telephone and wait for your name to be announced. To withdraw your question, please press star 1 and 1 again. Please limit yourself to one question and return to the queue for any follow-ups. Please go ahead. Our first question comes from the line of Graham Parry from Bank of America. Please go ahead. Your line is open.

Great. Thanks for taking my question, and thanks for the presentation today, the data as well. The main question, I think, is just what is it that the FDA actually needs to see on overall survival to accept a file, just given it is so confounded? So do they need to see now some statistically significant and clinically meaningful benefit on the crossover-adjusted analysis, so the 0.8 hazard ratio that you've seen there sort of moving into statistical significance? Do they need to see that the ITT analysis hazard ratio falls below 1, so evidence of no harm, which is I think what was referred to previously by yourself and Vaz on causes being sort of what they're the hurdle was here, or is it some sort of merged analysis that looks like what you have today, but just with more events? So, just precisely, what is it they're looking for? And importantly, when do you expect that data to be available for filing? Thank you.

Thank you for the question, Graham. And I think with respect to the first question around what is the FDA looking for, it's there is no absolute definition and or number which they are seeking. And if I just draw your attention back to the FDA industry investigator workshop this summer, you know, the FDA highlighted the principles of which they are seeking in order to assess overall survival or in order to establish no detriment. And what they clearly highlight is a few key important principles that I think are quite important here. So I think firstly, beyond the trial itself, is has the investigational agent demonstrated overall survival in any setting? And for Plobicto, the answer is yes. We had the overall survival benefit in the vision trial, which was not impacted by a crossover. Subsequently, the FDA also looks at, are there any other confounding factors that need to be taken into account when interpreting the overall survival data? And I think in this particular situation, the incredibly high rate of crossover is something that's very important and impactful in trying to understand overall survival. But unfortunately, at this point in time, what I think remains true is that our data does remain immature. So I think having more mature data will help with a much more reliable assessment of the overall survival results. With respect to the analyses that the FDA will look at is they obviously will take into account the totality of the data as well as looking at both the unadjusted and adjusted analyses for overall survival. Now for your second question with respect to timing, I have highlighted that the next interim analysis will occur at 75% information fraction. We are continuing to track these events closely, but for any time to event endpoint, we obviously need a little more time to get a precise estimate as to when exactly those events are going to occur. And what we plan to do is update everyone in the new year, you know, at the time of the annual results, once we'll have greater confidence around the exact timing of that data.

Thank you. Thank you. We'll now move on to our next question. Please stand by. Our next question comes from the line of Gary Steventon from BNP Paribas Exxon. Please go ahead. Your line is open.

Great. Thanks very much for taking the question. Just on biomarkers and PSMA uptake, are you able to share the proportion of patients in the trial that had SUV mean levels of 10 or greater on PSMA PET and when we can expect to see that data cut. And then just linked to that quickly, how practical do you think that biomarker is? Thank you.

No, thanks for the question, Gary. And maybe I'll start with the inclusion criteria, which is standard across all PLEVICTO trials where we do require at least one PSMA-positive lesion using our Gallium 6811 diagnostic. And in this particular trial, what was notable is of the patients who were screened for PSMA expression, 92.1 percent of patients met that eligibility criteria. a very high proportion of patients, even greater than what you would see in the literature, which reports about 80%. With respect to your second question, we have done subsequent analyses from the VISION trial and do show that SUV max or SUV mean does play an important role in the predictive outcome for patients. And without getting into specific R-squared correlation values, usually the higher the expression, the better the outcome We are obviously, we have collected that data from the PSMA-4 trial as well. We are currently analyzing it. We expect that to be presented at a future data congress.

Thank you. Thank you. We'll now move on to our next question. Our next question comes from the line of Andrew Bourne from Citi. Please go ahead. Your line is open.

Thank you. Assuming that PSMA4 gets added to the label, could you clarify the impact on the market potential? I get that some patients, maybe 15%, may progress very rapidly and you'll be able to capture those. But I'm more interested in the ability to use it across multiple lines of therapy. Could you talk to that? And although it's not on label, How many of the existing patients are seeing more than the labeled six cycles of therapy? Thank you.

Thanks for the question, Andrew. And maybe just thinking about, you know, how and where the drug has already been studied or used. So from the vision trial, we have established a very clear benefit risk with respect to usage in a post-taxane setting. And it is our belief by moving this into the pre-taxane setting that this represents about two to three times an increase in the number of patients that can become eligible for treatment. One of the reasons why we believe this to be true is, as mentioned earlier, about 25% of patients who receive first-line androgen pathway inhibitor never receive a subsequent treatment for their disease and often go and die without any further therapies. If you look at patients who receive a second line of therapy in the metastatic castrate-resistant prostate cancer setting, approximately another 25% of patients have a second line of treatment that then ultimately never see a third line of treatment. So moving this into earlier lines of therapy become... become quite important to increase the patient eligibility. With respect to the number of doses, the approved dosing regimen allows up to six cycles of Plavicto. Based on the strong efficacy as well as the safety of Plavicto, there is merit in actually studying potential re-challenge, re-treatment, or subsequent lines of therapy in these settings. but that data is not yet available.

Thank you. We'll now move on to our next question. Our next question comes from the line of Peter Welford from Jefferies. Please go ahead. Your line is open.

Oh, hi. I just wanted to return to the survival analysis here. And I guess there's sort of two parts to this, which is one, given that presumably a lot of patients who did cross over are also likely to still have not yet completed their course of Plavicto. I guess, how do you assess necessarily that the overall survival for the all-comers population isn't in fact going to worsen? And I guess related to that, do you have any data in terms of the number of cycles crossover patients received of Flavicto, i.e. up to that six, versus on the other hand, as you said, I think 75% managed to receive at least five if they're originally assigned to Flavicto. Thank you.

No, thanks for your question, Peter. And I think your question, you know, reiterates or highlights the need to accumulate additional events and to have further follow-up so that we could adequately assess you know, how patients did after crossover, as well as what the impact of crossover is on a larger proportion of patients, especially with respect to the overall survival analysis. So we continue to look forward to the interim analysis three to better address the questions that you've just raised.

Thank you. We'll now move on to our next question. Please be reminded to limit yourself to one question and return to the queue for any follow-ups. Our next question comes from the line of Mark Purcell from Morgan Stanley. Please go ahead. Your line is open.

Yeah, thank you very much for taking my question. I was just going to ask, in terms of the patients that are most appropriate for Plavicto therapy, the discussion yesterday sort of highlighted different patient subgroups. One was already mentioned, PSMA PET-HI, which the discussion felt was the most appropriate patient group for the use of Plavicto. But then you've got some germline somatic mutations, then lots of P10 and P53 and things like that. how would you help us to think about which patients are likely to be the most appropriate, and then vote for treatment with Plovictor, that is. And then given your comments around the sort of challenges of sequential therapy, the sort of 25% not receiving therapy in a subsequent line, how are you thinking about the potential for combination therapy, which would maybe circumvent some of these patient subgroup considerations? Thank you.

Yeah, thanks, Mark. And I think some very important questions around, you know, sort of clinical practice and optimal patient benefits. And, you know, if I think about how we are looking to help, you know, answer those questions, we have a very large body of clinical data already established, as well as a substantial amount of post-marketing evidence. that all collectively will help inform which baseline disease characteristics, prognostic factors, genetic or molecular alterations, and or SUV uptake, mean or max, are most clinically relevant predictors of long-term benefit. In addition to that, we'll also use all of these baseline indicators biopsies and or samples to be able to better inform potential mechanisms of resistance to identify those patients who are most sensitive or responsive to Blavicto versus those that may be more resistant, and that will ultimately inform or guide optimal-based combination therapy. So collectively all of this data will be quite helpful in assessing that and as you've seen from Sri Ram's presentation, we have a large body of evidence that continues to accumulate and two additional trials that are ongoing or soon to start in an earlier line of therapy in combination with an ARPI and then also in an earlier stage of disease, local regional disease in patients that have oligometastatic disease. And with respect to kind of all of the questions around sequencing, I would just reiterate maybe that my comment that I made to Andrew's question as well is, you know, we have already demonstrated the benefit in a post-taxane setting. I believe this data corroborates that benefit at least in terms of the endpoints that are mature, final, you know, and or not confounded by crossover. And we also have data from a Phase II study that had actually shown the benefit over ataxane, where we actually had higher improvements in PSA response of 66 versus 37 percent, a resist objective response rate of 49 versus 24 percent, progression-free survival of 0.63, and then a much lower rate of grade 3, grade 4 toxicities versus taxane-based chemotherapy at one-third versus 53%. So I think there's already a larger body of data than maybe some folks would appreciate with respect to when and where and which patients this drug could be used in. Thank you, Jeff. You're welcome, Mark.

Thank you. Please be reminded to limit yourself to one question. We'll now move on to our next question. Our next question comes from the line of Simon Baker from Redburn Atlantic. Please go ahead.

Thank you for taking my questions and for doing the presentation. Just looking at the subgroup analysis, the result looks very robust across the subgroups. that you presented. One you didn't present was on ECOG stage, so I'm just going to hand in data on that. And while saying that the result is consistent, it does appear that patients who are older and patients who are European seem to do even better. I just wonder if you had any thoughts on why that might be. Thanks so much.

Yeah, thanks for your question, Simon. And I think with respect to to your first one around overall subgroups. I know Oliver or Dr. Sartor had presented a larger amount of subgroups at yesterday's ESMO presentation. And if you look at ECOG status, you know, and or baseline LDH levels, right, the benefit was also clear for both. You know, in addition to that, we have looked across geographies. And other than kind of the Asian countries where we had a very small percentage of patients. I think in general, all data would suggest very clear clinical benefit. I would always caution when trying to interpret, you know, kind of smaller numbers across subgroups and saying that one region had done, you know, better than the other. And I think with respect to region here, I think both 0.52 and 0.40 are quite clinically meaningful in terms of European patients versus North American patients. Thanks so much. You're welcome. Next question, please.

Thank you. Our next question comes from the line of Mike Nedelkovich from TD Cohen. Please go ahead.

Thanks for the question. My understanding had been that it was pre-agreed on some level with the FDA that the overall survival endpoint needed to show only no detriment Am I misunderstanding that, or has there been some change? Thanks for your clarification.

Thanks, Mike. I think clearly you are referring to the guidance that we had previously shared externally, and I think the definition of no detriment continues to evolve using these real-world And I think in particular what is clear is you cannot look at a single data point estimate and ignore the other facts of the ongoing clinical trial, especially something like this where the crossover rate is as high as 84%. So I think during the FDA workshop this summer, they were actually wrestling through exactly what that definition would look like. And you also see, if you take a look at that data, There are some definitions around hazard ratios, confidence intervals. I think for here, the most important part is the totality of the data and the fact that we need additional maturity in order to be able to reliably assess the overall survival.

Next question, please. Thank you. Our next question comes from the line of Richard Vosser from JP Morgan. Please go ahead.

Hi, thanks for taking my question. Just a question on the other ongoing trials, particularly the PSVA addition trial, but others as well. How are patients crossing... How is crossover treated in those trials? I think the control arm is allowed to cross over as well, so how would that... be interpreted in terms of those trials, and how will we think about in terms of the submission timing given the OS issues we've seen here in the PSMA4 trial? Thanks very much.

No, thanks, Richard. And maybe before I address the question, maybe I'll comment about a very interesting scientific hypothesis that actually is driving the rationale for the PSMA addition trial. We know very well from our translational data as well as the literature that hormonal blockade does influence PSMA expression. So in this particular trial, it's reasonable to believe that, you know, hormonal blockade using an androgen receptor pathway inhibitor in a hormone-sensitive prostate cancer setting could influence the expression of the PSMA receptor and then make these patients even more eligible for benefit from Plavicto. So interesting scientific hypothesis that we are testing there. With respect to your question specifically, crossover is also an option in the PSMA addition trial. However, the kinetics are much different. So if you think about what had occurred in PSMA4, the times of radiographic progression in the control arm happened very, very quickly, right? 5.6 months, you know, on average, which means patients, some patients or 50% of the patients were progressing even before that 5.6 months and then crossing over to Plovetco almost immediately. Now, in contrast, in PSMA addition, because this is a much healthier population, the majority of patients will have completed their course of Plavicto or have been on hormonal therapy for potentially a few years, you know, before their disease would progress on average. So the median progression-free survival times are much longer in that particular setting. So there will be longer windows between the time a patient could progress and then ultimately receive subsequent therapy. So I think that was one more important notable difference. And I think on your last question with respect to the overall survival events, you know, we have also built in a multi, you know, look analysis at survival into that trial, and we have done the appropriate power calculations and the number of events that would be expected at the time of the primary readout as well as at subsequent follow-up points in time. Excellent. Thanks.

Thank you. Due to time constraints, this concludes our question and answer session. So I'll hand the call back to Samir for closing remarks.

Thank you very much. I just want to say thank you for participating in this call. And we look forward to the next call within a few minutes. Thank you.

This concludes today's conference call. Thank you for participating. You may now disconnect. Speakers, please stand by.