Welcome, everyone, on this third day of IGCS. I think we can all agree it's been a fantastic meeting. And I'm so excited to be together with all of us again here in New York City, re-engage with our international colleagues. It's been fantastic. I'm Dr. Kathleen Moore. I'll be moderating this session. And as you can tell, I've caught a germ. So hopefully my voice will hang in through this whole session. But fortunately, I'm not doing a lot of the talking today, unusually. So I get to sit back and listen to my esteemed panel educate today on platinum-sensitive ovarian cancer. So thank you for joining us. As you can see, the title is on the screen, Platinum-Sensitive Ovarian Cancer Unmet Medical Needs Beyond PARP Inhibitors, really something that's right in front of us right now. The GOG Foundation and GOG partners would very much like to thank Mursana Therapeutics for supporting this important symposium. I've introduced myself. Let me introduce you to our panel. Starting on the far my right is Dr. Ramesh Iskander, who's an associate professor of gynecologic oncology and the co-director of the International Patient Program at UC San Diego. He also serves as associate clinical trial advisor for the GOG partners. There we go. Then to my immediate right is my good friend and colleague, Dr. Ramesh is my friend, too. I didn't mean to say that. He's my lesser friend. No, I'm just kidding. Everyone's my friend. I'm going to stop going off script. Dr. Catherine Fah is an associate professor in the Department of Obstetrics and Gynecology at the University of California, San Francisco, and director of translational and basic research for the Division of Gynecology. She's the principal investigator for GOG 3059, NGOT OB 66, as well as multiple grants from federal and foundation sources. And finally, also my friend, Dr. Antonio Gonzalez-Martin is the director of Cancer Center Universidad de Navarra. Did I do pretty good? Okay. There's more Spanish. In Madrid. He is also the associate professor of medicine at Francisco de Vitoria University in Madrid and collaborator professor at the Universidad de Navarra. He serves as chairman of GEICO and is currently a delegate in gynecologic cancer inner group. So here are speaker disclosures. I'll leave those up for a moment. And here's an overview of our session. So our learning objectives for this symposium are to identify opportunities beyond PARP inhibitors for patients with platinum-sensitive ovarian cancer. Oops. I'm failing. Understand emerging data and what could be next beyond PARP inhibitors. Discuss unmet medical needs and platinum-sensitive ovarian cancer post-standard of care and raise awareness for ongoing clinical trials with a focus on antibody drug conjugates. Throughout this session, we'll incorporate a few audience response questions. So if you could please pull out your phones. We're going to try this again. It was a little glitchy yesterday, but hopefully it works better today. Scan the QR code and you can walk up if you need to to get that scanned. On the screen to assess the web-based tool and participate in our audience response questions, those are actually really important for us to get a sense of what people are doing currently in the field. Let me put this back up there for a second just so you can grab that QR code for another couple seconds. The GOG staff throughout the room have flyers available with instructions on how to access the audience response system via your smartphone. So if you need someone, just flag us down. So with that, without further ado, let's get started. And we're going to begin with a presentation from Dr. Ramesh Eskandar titled PARP Inhibitors and Frontline Maintenance, the Evolving Treatment Paradigm. Dr. Eskandar. Thank you, Dr. Moore, and thank you for turning out. I know it's afternoon and the last day of an excellent meeting, so we really appreciate your attendance. And this is a topic that many of you have heard about throughout the IGCS meeting, but I do believe that there's an opportunity to continue to learn and to be able to conceptualize essentially treatment strategies. This schematic highlights what we would imagine really is the historical landscape of treatment or the treatment course for patients that are diagnosed with a high-grade epithelial ovarian cancer. We understand that patients with advanced stage disease are first triaged to either primary cytoreductive surgery or neoadjuvant chemotherapy, the backbone of which has remained unchanged for over two decades essentially and that's intravenous carboplatin and paclitaxel. More recently with incorporation of bevacizumab maintenance. And again, this is a schematic that doesn't take into account the evolution of PARP inhibitors, which we're going to be discussing throughout this presentation. Thankfully, the vast majority of these patients achieve a response to therapy, although unfortunately approximately 80% of which will develop recurrent disease that's going to necessitate subsequent lines of therapy. And historically, we've really dichotomized these patients into two cohorts. We used to use the term platinum sensitive quite frequently. We still do, I would say. And that's defined pragmatically as patients who are progressing more than six months after their prior platinum exposure. We've also evolved to include platinum is an option for those patients because we've realized that we're extending beyond just the historical categorization of a defined six month interval as we discuss drug development and advances in therapeutic treatment strategies. And the other cohort is for those who are platinum resistant who progress less than six months after prior platinum exposure or for those patients where platinum is no longer an option. The ICON-8 trial is likely familiar to many of you in the audience. This trial was designed and conducted to try to determine whether or not incorporation of weekly paclitaxel was beneficial over the Q3 week regimen. And they also looked at a combined weekly regimen of both carboplatin and paclitaxel. And you see here from the Kaplan-Meier progression free survival curves, they are essentially completely overlapping. But what this did give us is it gave us an understanding of what the progression free survival median may be in these patients as a baseline, 17 to 21 months. You can see that the hazard ratios are very close to one, suggesting no difference. And this really was a study that was prompted by the Japanese GOG study that suggested that weekly paclitaxel may have a survival advantage. Again, speaking to the importance of diverse patient populations enrolled on trial because the results may be impacted by the heterogeneity of the patients being treated. We then conducted GOG-218 and ICON-7 which were analogous but not identical clinical trials in the United States. And in the EU. And these studies looked at chemotherapy backbone with bevacizumab and bevacizumab maintenance, essentially versus a comparator of chemotherapy, placebo and placebo maintenance. We know GOG-218 had a third arm that had chemotherapy, bevacizumab and a placebo maintenance. And what we saw was a statistically significant, significant, excuse me, and meaningful improvement in the median progression free survival reported on these trials of approximately three months. But I will say that if you look at the package insert and the ultimate approval in the United States of bevacizumab in this indication on GOG-218, the reported progression free survival advantage based on radiographic imaging assessments of progression and removing those that progress based on CA-125 was over six months. It was 12 months in the chemotherapy placebo with placebo maintenance and 18.2 months in the chemotherapy bevacizumab, bevacizumab, bevacizumab maintenance cohort. And the hazard ratio for that population was 0.62. And I want you to remember that hazard ratio because that is a meaningful reduction in the risk of disease progression or death in these patient populations. The final overall survival was updated and published by Dr. Tiwari and colleagues on behalf of the GOG-218 team. And you can see that there was no significant difference in overall survival in the protocol specified population. They did perform an exploratory analysis in the quote-unquote higher risk patient population, although I will just make the disclaimer that there is no low risk stage three or stage four ovarian cancer patient. That being said, in the higher risk subsets, there was a signal that there may be a survival advantage with incorporation of bevacizumab to chemotherapy and as maintenance versus a placebo arm. But we do know that we've evolved pretty substantially from the era in which GOG-218 and ICON-7 were completed. Gone from disease homogeneity to what I call molecular granularity and thankfully we're doing that across our gynecologic malignancies. This is a paper that was published by Panos that really highlighted molecular signatures as they are relevant to the development of effective treatment strategies in epithelial ovarian cancer. And we've taken from this that we have about 15% of patients with high-grade serous ovarian cancer that have a germline BRCA1 or BRCA2 mutation. We have approximately another 5% of patients that have a somatic BRCA1 or BRCA2 mutation accounting for about one in five of our newly diagnosed epithelial ovarian cancer patients. But now we've moved beyond that. We've understood the relevance of the homologous recombination deficiency test positive patient cohorts and we see that if we incorporate both the HRD test positive and the BRCA patients we're capturing about one in two, anywhere from about 40 to 50% for a high-grade epithelial ovarian cancer patient population and the clinical implications will be self-evident of that in the slides that we will be reviewing. This is an image that really reviews the pivotal trials and milestones in the frontline maintenance strategy. Again, we've talked about GOG218 leading to the incorporation of Bevacizumab as a maintenance in conjunction with cytotoxic chemotherapy. You have then the incorporation of Olaparib in the BRCA mutated patient population as a maintenance treatment. And what was remarkable about this is it was presented, if I remember correctly, in October of 2018 and the FDA approval in the United States was in December, two months after the publication and presentation. And that really has dramatically changed the management of our BRCA mutated ovarian cancer patients, as we'll discuss. And then subsequent to that, the platinum-sensitive maintenance strategies were interdigitated here. But again, in the frontline, we're talking about the PRIMA trial with Naraparib, the PAOLA1 clinical trial, which was a combination of Olaparib plus Bevacizumab, and then the VILIA trial, which was Voliparib. And what was unique about the VILIA trial, you may recall, is that it was the one study where the PARP inhibitor, excuse me, was given in conjunction with the chemotherapy and then as a maintenance. And that's a little bit different because when you give chemotherapy first, you're able to assess for a quote, unquote, potentially a platinum response or a platinum sensitivity. That's very different than when you give the PARP with the chemo a priori. And then subsequently, we know that we've had Naraparib approval and Olaparib plus Bevacizumab approvals that we'll review. These Kaplan-Meier curves really should be burned on the back of our corneas, and that's because we recognize that there is a significant and meaningful clinical benefit with PARP inhibitor maintenance therapy in the BRCA-mutated homologous or combination deficiency test-positive patient population. Just by eyeballing these curves, you can see that the curves diverge and they stay separated for the duration in which they're being followed. And when we look at the hazard ratio, we see remarkable consistency. There is a 60 to 70% reduction in the risk of disease, progression, and death across these trials. PRIMA, SOLA-1, Athena Mono, which was presented once again here at IGCS by Dr. Monk, PRIME, which was uniquely a Chinese population, and then the PAOLA-1 clinical trial looking at olaparib and Bev versus Bevacizumab. And I will mention, it's important to note briefly, guys, that PAOLA-1 was the only trial that truly had a quote-unquote active placebo because it was placebo plus Bevacizumab and not truly placebo alone. If we look at the BRCA-wild type, BRCA-wild type patients, homologous or combination deficiency test-positive, you can see that there continues to be a statistically significant and meaningful benefit, but it was slightly more modest than the prior slides. And again, here it's quite consistent, approximately a 40 to 60% reduction in the risk of disease, progression, or death. And the hazard ratios matter and the morphology of these curves matter, and we clearly see a benefit that's resulted in incorporation and ultimate FDA approvals in these spaces. And then we talk about the homologous or combination proficient patient population where there is, I would venture to say, that there is a bit more debate as to whether or not there's utility, but I will just say again, if you look at the hazard ratios, aside from the PRIME study, which did have what appeared to be a remarkably stronger reduction in the risk of disease, progression, or death, the hazard ratios here are very similar to the hazard ratios that I showed you in the GOG218 of 0.62. Here we're talking about 0.65 for Prima and Athena Mono. The PAOLA-1 trial, again, has a Bevacizumab comparator arm, and that was a trial that had a hazard ratio of 0.92. And thankfully, we've now seen the updated data for the overall survival. This is the updated seven-year overall survival for the SOLA-1 trial. This data was remarkable in that despite 44% crossover, some people said, well, maybe we don't have to give it initially because some of these BRCA mutation patients may be cured. Well, we clearly see here in the updated overall survival data that initial treatment with maintenance PARP in these patients is essential because we may be identifying and eliciting cures. 67% of patients were without evidence of death on the arm that received Olaparib versus 46% in the cohort that received placebo, again, despite 44% crossover. And when we look at the PAOLA-1 overall survival data in the homologous recombination deficient cohort on the right, HRD positive, you can see that there's an improvement of 17% in the five-year OS rate. And I like simple math. There's a 17-month improvement in the median overall survival at five years, which again is a remarkable and meaningful progression in therapeutic treatment options for these patients. On the left side, the ITT population was more modest, 51 to 56 months. And then we can further subdivide it into additional subgroups, including the BRCA mutated cohort, the HRD positive but BRCA wild-type cohort or excluding BRCA mutation, and on the very right, the HRD test negative population. And we can see that the HRD test, the relevance of that assay and understanding efficacy is useful to us. We also know that the importance of BRCA mutation, but again, it doesn't speak against the potential relevance in an all-comer population based on the images that I showed you two slides ago. And I don't know if you attended the master session for ovarian cancer yesterday, but we had a panel of experts, brilliant minds on the stage, discussing the recent implications of the withdrawals. This slide really summarizes those prior indications for which withdrawals were initiated. And that's based on subset analysis that were not intended and were not hypothesis-tested, but rather more hypothesis-generating than anything else. But we do know that the treatment indications that emerged from ARIEL4, SOLO3, and QUADRO were voluntarily withdrawn, certainly impacting treatment landscape in those settings. So in summary, we understand the relevance of maintenance therapy in the frontline for patients with epithelial ovarian cancer. Bevacizumab and PARP have shown progression-free survival prolongation that is statistically significant and meaningful. The greatest benefit of particular maintenance therapy is in the BRCA mutated or homologous recombination deficiency test positive population which accounts for up to 50% of these patient cohorts based on the data that we've shared. There has been no overall survival benefit with PARP maintenance or treatment in the recurrent disease setting. Again, recurrent is the key word here. And the recent OS data have shown benefit associated with PARP in the frontline setting. And that overall survival benefit is dramatic and profound in the BRCA mutated and also significant and provocative in the HRD test positive patient cohorts. So I'd like to thank you guys very much for your time and I'll transfer back to Dr. Moore for the audience response. Hopefully we'll have lots of questions. But let's turn to some audience response. So hopefully some of you got the app to work on your phone. We'll see if it's a little less glitchy than yesterday. So let's go to that. So here's audience response question one. What is your preferred strategy for treating, here we say homologous recombination proficient or homologous recombination deficiency test negative tumors in the frontline setting? Platinum-based chemo with no maintenance, platinum-based chemo followed by PARPy, platinum-based chemo followed by or with Bev plus PARPy, and platinum-based chemo with Bev and Bev maintenance or other. Go ahead and vote. I think that this should come up. Do we have the audience response? There we go. Oh, good. It's working today. All right. Perfect. So much more fun. All right. Let's give it another couple seconds here and let people kind of weigh in on what they think. We're staying pretty stable. Okay. So it looks like about 29%, about 30% are not going to use maintenance, so close monitoring. About 12% are going to follow with a PARP inhibitor. 12% are going to try to use Bev and PARP-E. And almost 50% are going to use Bevacizumab and Bevacizumab maintenance for this bollux recombination deficient group. We're a little ahead of schedule, so I could ask our panel, what do you think of these results? Dr. Gonzales-Martin, what do you think? What's your practice and what do you think? So it's an interesting result of this pooling. First of all, I think that the combination of Bev and PARP-E, according to the data presented by Ramez, right now is not a good option. That is the first impression here. I would say that no maintenance nowadays is not an option, at least in my institution, because we know that this population that we call HRP are people, are patients with the worst prognosis. Some sort of maintenance therapy should be discussed with the patients. We realize that nothing is perfect, that both PARP inhibitors and Bevacizumab can improve the median progression-free survival for a while. That is not the context of the BRCA-mutated patients in which the maintenance therapy can cure patients, but it's a benefit for them to keep the disease without progression. I miss one option, that is that what I usually do is to select the therapy depending on the quality of the response to platinum. In those patients that do have a good response to platinum, by resist, killing biomarker, or whatever, I would prefer the Neuroparif in this case, because it's the only option approved in our country for this HRP population, and if not, I prefer to use Bevacizumab. That is what we are doing right now. Yeah. Dr. Faux, what do you think of your thoughts on this? Then we'll move on to your talk. I think the range of responses is really reflective of the current question and the situation. I think it exactly depends on the patient. So I definitely counsel my patients on these options. And depending on how they responded, if they have ascites, sort of taking all that into account, maintenance regimen is certainly an option that we discuss. Yeah. Any last thoughts, Dr. Eskander, before we move over to the postpartum world? Nothing to add. Yeah. I think we have to acknowledge a little bit that at a global conference like this, a lot of countries don't have front-line bevacizumab to use, and some of them don't even have PARP inhibitor to use. And so post-monitoring is an appropriate selection. So there are sort of equity issues with kind of these questions sometimes as well. So with that, let's move on to our next speaker. Let me advance the slides. I'm happy to introduce Dr. Catherine Fu to present post-PARP inhibitor data and platinum-sensitive recurrent disease. Thank you very much for that introduction, and thank you all again for being here. So we're going to think about our last patient who had front-line treatment, had perhaps PARP inhibitor as maintenance therapy, and develops platinum-sensitive recurrent disease. So what are some considerations for resistance? And so we'll start first with the slide on mechanisms for platinum resistance. We've been through a lot of this through the meeting for the last few days, and this really highlights the array of different mechanisms. And it could be as straightforward as decreased platinum accumulation. The tumor cell accumulates less platinum, and therefore they're more resistant. But more likely we find that our tumor cells are able to repair themselves again. They are able to restore their DNA repair mechanisms, such as some oxygen combination repair that you see there. And another mechanism to highlight that Liz Swisher and others and colleagues have published recently was the idea of the BRCA1 promoter methylation. And about 10, Dr. Rasmus showed that 10 to 20% of ovarian cancer tumors do have this BRCA1 promoter methylation. And this idea that there's a reversal of the BRCA1 promoter methylation that can then, the tumor cell regains the BRCA1 function, and then also then becomes more platinum resistant. And we always talk about what are some PARP inhibitor resistant mechanisms. And this is a table taken from Elizabeth Lee and Ursula Machelonis in their review article. You can see that there's four main mechanisms. And so the first, thinking about altered PARP1. So there's mutations in PARP1 that can then actually lead to the PARP inhibitor binding to be a little bit more difficult. And that could be a mechanism for PARP inhibitor resistance. The restoration and modular combination. You can see the specific alterations are many. And we do talk about BRCA reversion mutations. And that can be commonly seen. And so this is an idea about, you know, restoring the tumor cells able to recover their BRCA or their BRAF51, a way to repair themselves through modular combination. And that then restores their ability to become more resistant to PARP. What about replication fork stability? So part of the PARP inhibitor cytotoxicity is able to actually act on the replication fork. So the idea that replication fork reversal and restarts are actually really important to how PARP inhibitors work. So the tumor cells can actually stabilize the replication fork by depleting chromatin remodelers or other, you know, sort of upregulating other RTK pathways, for example. This actually then leads for them to, you know, induce their PARP inhibitor resistance by stabilizing replication forks. What about PARP inhibitor efflux? This overexpression, the MDR1 efflux pump. There was a study that showed for those patients that had PARP inhibitor resistant tumors in ovarian cancer, about 8% had this overexpression of MDR1 efflux pump. And what does that mean? It means that, for example, they're able to pump out the PARP inhibitor. And there is perhaps an idea that either paclitaxel or doxorubicin is a substrate for MDR1. So perhaps, you know, technically, the idea that if a patient's treated with either of these prior, they could actually overexpress the MDR1 and then lead to more PARP inhibitor resistance. So what are these overlapping mechanisms? You know, you can see similarities between the two. And this is a figure taken from Amit Oza and colleagues. That really highlights sort of the three main ones we think about in terms of reactivation, the modest combination repair, the loss of 52BP1, so they're able to repair, the cells are able to repair themselves through a BRCA1 independent function, and then the replication for protection that we just discussed. But, you know, one piece that we don't, you know, we haven't really focused on is the tumor microenvironment. You know, of course, immunosuppressive microenvironment, the desmoplastic stroma, you know, how can the targeted therapies kind of, you know, integrate and be able to acquire and become more sensitive and not really become as resistant with the microenvironment? And this is the table that highlights some proteins that are involved. And we talk about these sort of general mechanisms, but there's actually mechanisms, you know, that have been explored and tried to really understand, you know, how can we actively target these? But truly, as you look at this, there's so many different mechanisms for resistance. So one question that, you know, we've been talking about today is, you know, what about PARP inhibitors? So let's say your patient received a PARP inhibitor for maintenance, and, you know, what is the response again? And so this is a Rayo NGOT-OV38, which many of you know this trial, and really looked at patients with relapsed epithelial ovarian cancer. And they had one prior course of PARP inhibitor maintenance therapy and really looked at the BRCA mutated cohort and the BRCA non-mutated cohort. And both received Olaparib versus placebo in a two-to-one fashion, the primary endpoint of PFS. And this is the Kappa-Myocard looking at the BRCA mutated cohort. And you can see that, you know, this group of patients, there was a significant improvement in PFS for those who had the Olaparib maintenance. And the tail that you can see of the Olaparib, 20% of these patients had this really long tail of response. And this cohort also are, they had five lines, you know, 50% had five more lines of therapy. So really a cohort that is really heavily pretreated. And when we look at the non-BRCA mutated, irrespective of HRD status, you see that the confidence interval crosses one. And so the differences in terms of the PFS is a little bit less clear than the BRCA mutated cohort. So then let's think about your patient had received PARP inhibitor. And then, you know, trying to ask the question, well, what would the response to platinum be then? So we looked at Arraya, we looked at PARP after PARP. And what about PARP and now platinum? And so I think some of you have been here, have heard about the post and read it too, the post hoc analysis looking at SOLO2 that tried to answer this question. And as a reminder, SOLO2 is for patients relapsed, high-grade ovarian cancer, BRCA mutated. And really the idea was to maintenance of Olaparib, you know, after response to the most recent platinum agent. And you can see the progression-free survival differences are so great, 19 months versus 5.5 months, for those Olaparib maintenance. And so then we're looking at, you know, what happens to those patients that actually had a racist progression and was treated with treatment. And, you know, what was their response to platinum? And this is when we actually look at those patients that those who actually had placebo in gray responded better to the next platinum chemotherapy compared to those that had seen Olaparib as maintenance. And you can see the numbers there. And then Peter Rose and his group actually looked at this as well in a single institution retrospective study and found similar findings, that those patients that had no prior PARP and saw the line there had responded better to platinum-based chemotherapy compared to those that did have prior PARP with the dotted line there. So then this leads us to ask, well, how can we overcome PARP inhibitor resistance, platinum resistance, and, you know, just globally thinking about it in two different categories. You know, targeting resistance-causing mechanisms or targeting acquired vulnerabilities. And then this next slide is, you know, quite busy, but really kind of focuses on the different mechanisms of what might be needed to actually target this PARP inhibitor resistance. So the first idea in letter A is, you know, knowing that, you know, HR division tumors usually have high genomic instability and thought to present an increased number of new antigens on their surfaces, you know, how can we optimize the immune system to target PARP inhibitor resistance? And as you know, this is very much an ongoing question. In letter B, we look at C-gastine. So PARP inhibitor has been shown to induce PD-L1 expression, upregulate C-gastine pathway. Is there a way to, you know, further enhance this C-gastine signaling to boost recruitment and to activate CD8 T-cells? And what about receptor tyrosine kinases? So they've been shown, you know, to be upregulated, perhaps in PARP inhibitor resistance, EGFR, VEGF receptor, IGF1R, AXL. You know, could we target these RTKs and then actually, you know, inhibit reactivation of a model's combination by these tumor cells and then therefore, you know, actually target the PARP inhibitor resistance? And letter D looks at NAD synthesis, how that might actually further enhance the cytotoxicity of PARP inhibitors, the indirect inhibition of parlation. And then what about suppressing replication fork protection? We talked about that again, where the tumor cells are able to, you know, stabilize replication fork and that actually causes a PARP inhibitor resistance. And inhibiting microhomology-mediated end joining. So this is actually a mechanism that does mediate BRCA reversion mutations. Perhaps, can we target this with inhibitors of Poltheta and that might help decrease BRCA reversion mutations and therefore, a PARP inhibitor resistance. And target ATM, RNF168, promote homologous combination absence of BRCA1. So next three slides are just tables to summarize, you know, what we've been really talking about. Highlighting, again, these DNA damage repair pathways, the key genes that are involved, and these alterations that occur for therapeutic resistance. And this, again, is to highlight that there is just, you know, so many different types of mechanisms to think about to really be able to hopefully overcome this. And again, this is what we've gone through before. And to highlight, you know, there's other, the non-homologous end joining pathway that 52BP1 is part of. You know, the loss of this can actually also initiate homologous combination in a BRCA independent manner. And these are the trials. There are many trials ongoing, you know, really trying to target platinum and PARP inhibitor resistance and study populations for those who had had, you know, recurrent setting, platinum-resistant, prior PARP inhibitor, you know, really combining all these different agents that we had just described about that hopefully are biologically rational in this setting. So in summary, developing mechanisms of resistance that develop against PARP inhibitors and platinum-based chemotherapy, we've been through several of them. Additional sequencing studies in terms of PARP and the resistance are needed. And when do you give what, when? You know, is it chemo? What type of chemotherapy? In terms of the mechanisms that we described. And there are retrospective and post-hoc analyses, data that highlight PARP exposure or PARP inhibitors can decrease response to second-line, third-line platinum-based chemotherapy. And we've been talking about novel strategies to hopefully overcome PARP inhibitor resistance that are currently under investigation. Thank you. Thank you. Thank you so much. That was fantastic. So let's do the audience response question first, and then we'll have some discussion. So here's the question for you. What treatment strategy do you believe holds the most promise post-PARP inhibition as a tumor becomes resistant to PARP inhibitors? The straight-up non-platinum-based chemotherapy, A, B, immune checkpoint inhibitors, C, antibody drug conjugates, D, resensitization to other PARP inhibitors, either a combination or single agent, or other option? So go ahead and vote. Yeah, I think let's respond to that. So why don't we start with Dr. Eskander. What's your pick, and how do you view the audience responses here? I'm excited to see these numbers because I think it means that the people in the room are informed of the evolution of drug discovery and efficacy in this space. Antibody drug conjugates are emerging as therapeutic treatment strategies, and I think for me what it's most reflective of is our understanding that we have to continue to be smart and think critically about the diseases, and they're not all the same. And with A, antibody drug conjugates, we're starting to think about targets, and targets are differentially expressed, and we have to enrich for those patients. And I think the more we're able to do that, the more likely we're going to be effective at identifying therapeutic treatment strategies that are going to work. And I think immunotherapy, I'm happy actually to see that it's at 6%. I was worried it might be higher, but we were all biased towards thinking it was going to work, and we've seen clearly to date that we need to do better in the ovarian cancer arena. And so it's refreshing actually to see this, and I would agree that I'm most excited about that space as well. Yeah, I wanted to just point out, we did build in time for this for audience questions, so there's a microphone right in the middle. So if you have a question for the panel on this topic or the prior topic, please feel free to come up, and I'll recognize you. We really wanted this to be interactive kind of right in the center there. So I'll watch for folks that come up and have a question, but we wanted to sort of just discuss this because this really is one of the many kind of high unmet needs currently facing us. We have hopefully cured four women with front line ovarian cancer. I think we can say we're pretty confident about that for BRCA-associated cancers. But as Dr. Letterman pointed out in his ESMO discussion of that, while we celebrate the 45% who are disease-free and recurrence-free at seven years, we have to do better for the 55% who have recurred, some of whom recurred on PARP, some after, and then that number is going to be a lot higher amongst those who are BRCA-wild type if they've progressed on a PARP. So what do we do in the subsequent lines of therapy, and how do we individualize? I'm going to ask the panel, when you think about this concept of resensitizing to PARP, there's a myriad of combinations that we're studying right now. We heard Dr. Constantinopoulos and others talk about PI3 kinase plus PARP. We've heard Dr. Shannon Weston talk about we want kinase and PARP. Stephanie LaRue, we want a gemcitabine. Dr. LaRue's also done a laparosciderative, so this sort of VEGF antangiogenic PARP combination. PARP plus something, PARP plus something. Does that make sense to you? You know, is that really going to be actionable for our patients moving forward? Is that a maintenance strategy in the next slide, or do we just need to be moving away from trying to keep pairing something with PARP? What's the value? I'll start with what you said. That's a great question, Jetty. Honestly, I think that we need to have more science, more knowledge about what are the mechanisms of resistance to the PARP inhibitor to think about the resensitization to PARP inhibitor treatment. Obviously, all those options are considering that all patients can be restored, that sensitivity in the same way. I'm not sure that that is the reality. So I think that for that 55% of patients that still relapse on PARP with the BRCA mutation, we need to perform much more research at the moment of the relapse or even before just to understand what is the reason for that progression. I cannot figure out one of those options as the best one without more predictive biomarkers, I would say. I think I've had this conversation with Katie and Catherine. When I think about the reversal of resistance, I think about when I was a fellow and we talked a lot about reversal of platinum resistance. And we spent a long time thinking about how can we reverse platinum resistance, and then suddenly the narrative behind PARP inhibitors and BRCA mutations emerged and we redirected our attention justifiably and we've made dramatic gains. So when I think about this, I think, should we focus our efforts in reversal of resistance after a resistance mechanism has been deployed evolutionarily by these cancer cells, or is it about understanding effective combinations that are tolerable that we can then put together, use earlier to try to reduce the evolution of the resistance with selection pressure? And I don't know the answer to that, because we need a lot of information to better define this. But in my mind, that's how I think about it. And I think part of the idea of resistance is acquired or innate resistance. So I think in the population solo one, for example, for those that should have responded, was that acquired or was that innate? And so I think that's where these multiple rational approaches are needed, because resistance on its own is a very complicated and really trying to understand, for that particular patient and tumor, what is the resistance? How is it best targeted? Do you have a question? Please. Yes, thank you. I'm Afshin Bahadur from San Diego. Along with what just Ramez actually commented on, my question is about the HRP population of patients that are about 50% of what we know in terms of doing the HR diagnostic early on in the disease process. Now that we know that there is this compromised platinum sensitivity for recurrent disease, what does the panel think about the concept of treating the HRP population with PARP inhibitors and potentially opening up this phenomenon of platinum resistance or chemo resistance down the line for treatment of recurrent disease? How does that change your approach in terms of offering PARP inhibitors in the HR-proficient patient group? So that's an excellent question. I would differentiate what we know about the context of the relapse setting and the first line. All the data that we have seen about the potential impact in overall survival of patients that have been exposed at least twice to platinum and once to PARP inhibitor. So that could generate the hypothesis that we actually have much more metonyms of resistance in that population, even RACM reversion, but many other metonyms of resistance. And that could explain why chemotherapy after PARP inhibitor in that specific context may not work so well. Anyhow, that's analysis of subgroup of patients in exploratory analysis. The situation in the first line, I think, is completely different. Our patient that have received only once the platinum and only once the PARP inhibitor, we don't have enough information about the response to platinum in that setting. I think that both TENAMONO and PRIMA study will provide that sort of information in the future because we are capturing also the treatment at progression. And we will have at least some idea of how is the response to platinum and other chemotherapies in the relapse setting. In the meantime, we will have other trials that could give some sort of information. For instance, the ANITA study that we have closed, and we are very close to having the number of events. It's a trial of platinum followed by neuroperative in second or third line, but we allow patients that receive PARP inhibitor in the first line. So we will have another piece of information there to know what's happened with patient that have already received PARP inhibitor in first line and then are treated with platinum. So we don't have enough data to answer your question, but I would be very cautious about the interpretation of the things that happen in the late relapse of patients and move that to the first line of the patients. The other comment, and this came up in the symposium, or not symposium, sorry, the master session yesterday, and Dr. Gonzalez mentioned it just a moment ago, is the patient evaluation is also relevant to the decision. So not all HRD test negative or HRP patients in my mind are the same. There are some patients that have a dramatic response to platinum. I look at the score for my assay that I'm using to evaluate HRD test results because we all recognize that they had to assign, there's an arbitrary cutoff. And whether you're using LOH alone or an HRD assay that's looking at the three components, you're gonna make a decision based on that score. So if someone has, just as an example, I have a patient who has a foundation and their LOH was 15%. That's not technically LOH high. That's gonna be read as LOH low. But is that patient who had an excellent platinum response truly not gonna respond? So I think we need more information for all the reasons that were mentioned. And I think we also need to be thoughtful about patient selection even amongst that 50% so that we don't inadvertently lump someone in who may still derive a meaningful benefit because we see in all of those survival curves for HRP patients, there are long tails. So there are patients in the HRP that still derive a very meaningful benefit and I don't wanna miss that person. But I will tell you, I struggle with it just the same way. I will do one last question and then we'll ask it and then maybe we'll see if people change their minds after Dr. Gonzalez-Martin's talk. But you just brought up the point. So an HRD test negative, there is this long tail. But for the most part, the patients kind of have a modest benefit. I think we can agree on that. And in the master session yesterday, Drs. Monk and Colbin brought up the elephant in the room, at least in the United States, that we're worried we're gonna lose that indication with an upcoming ODAC. So we're worried. So let's say we do. So all the discussion that you just brought up, these PARP combinations, PARP plus whatever, you've done extensive preclinical work with PARP plus Axel-Gas-6 that needs to move into the clinic. Is that the strategy for that patient population? Say we lose the monotherapy PARP, we still need a maintenance for that group of tubers who have a poor prognosis. I think we can agree on that. The assay's imperfect, but it identifies a group of tubers that do not do as well. So is our strategy there a PARP combination to help them respond better or a completely different asset like an antibody drug conjugate? What do you think our best frontline maintenance strategy is, because we're likely gonna be facing that and we're gonna have to do some trials. What do you think, Dr. Fook? Oh gosh, that would be a great question to know the answer for, without having multiple trials for it. I still keep thinking about how each patient, although we have been really great at sort of separating and identifying patients based on their mutation status, I mean the tumors based on mutation status, I think that there will be some patients where having a PARP inhibitor combination with another drug first line maintenance for the HRD test negative will be helpful. And I do think that there are gonna be some patients that will really be better with another form, ADC or something else. So I think the field will be moving towards not just multiple combinations, but how do you obviously identify the patients that best respond to that combination. So I think the ovarian cancer is complicated enough that it probably will deserve and need that these multiple approaches. So I'm wondering if we are in the position to start to design trials for the HRP population. That's my thought now, because probably we need that sort of trials, but we will need also to identify much better what is really HRP or what is HRD. We are facing that all the tests that we are using right now are not perfect. Even without perfect test, what I think is we need to start to think about trials for this specific population. Probably we need to demonstrate some sort of activity in other setting and the EPICO trial is a good example of a combination of anti-PA3K plus olaparib. And if we see some sort of signal in that platinum resistant setting, probably it's time to move immediately to the first line setting in this HRP. But again, my question is, are we ready to perform, to design trials for the HRP? I think so, but we have to do that. Yep. All right, let's turn to, if we could get Dr. Gonzalez-Martin's slides up, please. We'll turn to the last talk of the day on antibody drug conjugates. Thank you. Thank you very much for inviting me to talk about this new class of compounds that we expect could potentially change also the landscape of ovarian cancer patients, the treatment of our patients as PARP inhibitor has changed already. So let me present you the ADC. This is the anatomy of the antibody drug conjugate. It consists of an antibody specific for a tumor antigen with a drug payload, which is usually highly potent anti-tumor agent. And don't forget the linker. The linker is very important for the ADC because it is responsible of an efficient release of the payload at the tumor site. And even more importantly, it is responsible to keep stable the payload in the ADC in the circulation. How ADC works, and this cartoon is showing nicely the metonyms of action of an ADC. The first step is the binding of the ADC to the target antigen at the surface of the cell. The second step is the internalization of this complex of the tumor antigen and the ADC in the cell through the endolysosomal compartment. And then the payload is released in the lysosome. That payload enters the cytoplamps and exerts its action. Usually it's an anti-microtubule drug, but also anti-DNA drug can also be used. And this finally led to the cancer cell death. There are three important things that we have to understand and to realize about the ADCs. The first is that this is a perfect way for optimizing the therapeutic index of some sort of drugs that are highly toxic. They are highly potent, but at the same time are highly toxic. In the left side of the slide, you can see what could be the therapeutic index of this sort of drug. And the therapeutic index is very narrow because with a small dose you will have higher toxicity. But the ADC allows you to integrate the drug directly in the tumor cells, protecting the normal cells around. And that expand clearly the therapeutic index of this sort of new, of cytotoxic highly potent agents. The second concept you have to know about the ADCs is the drug to antibody ratio, what is called DARD. This is the average number of drugs that conjugate to the antibody. Normally, the number of drugs that are conjugated with antibody are three to four, because when you increase the number of payloads in an antibody, that antibody lose its property and it's detrimental for the activity of the ADC. Actually, this is an important way to improve the activity and the performance of the ADCs. And the third concept that you have to manage when talking about ADCs are to understand what are the potential mechanisms of toxicity. And roughly we can divide these mechanisms in three. One is those that are target independent toxicity, when the ADC is taken into the normal immune cells for any mechanisms, non-specific endocytosis, macropinocytosis, micropinocytosis, or whatever. Second mechanism is on target, but of tumor toxicity, the target antigen is also expressed in normal cells, and then the ADC integrate the payload in a normal cell. And the third effect that is very important to understand with ADCs is what is called bystander effect, that is off-target and off-tissue effect or toxicity. And when I say effect or toxicity, it's depend on the cells surrounding, the cell that received the ADC. If the neighboring cells are tumor cells, that is a positive effect of the bystander effect. But if the neighboring cells are normal cells, that is a detrimental effect of our payload, a detrimental effect of this bystander effect. So thinking in these concepts of the ADC, it comes to your mind immediately that there are two ways to improve the performance of an ADC. One is the increasing the drug-to-antibody rate, because if you have more payloads, probably the antibody-drug conjugate will have more efficacy. And the second option is to try to control that bystander effect in order to protect the normal cells from that payload that can go through the membrane of the tumor cells to the neighboring cells. In this table, we try to show you the four of the most relevant ADCs that are under development in the clinic for gynecological tumors. The upifetamab risolutin, mirvetuximab soraptansin, STR0-002, and disotumab betadine. You have to realize that the target is different for these different ADCs. One of the important targets nowadays is the folate receptor alpha, as you probably know very well. The linker is also different, and we will show you later the importance of the linker for upifetamab risolutin, which is a polymer-escafol conjugated. That influenced the drug-antibody ratio. Again, I will show you later some things about that. And also it's different, the payload of the different ADCs, and that could also influence the bystander effect. And we will come back later on these different concepts. So now it's time to show you what are the recent achievements, ongoing trials with these ADCs. Let's start with mirvetuximab soraptansin. It's a drug very well known by our chair, Dr. Katimur, that was very much involved in its development from the beginning. And we have seen this year, in many meetings since SGO, the data of the Soraya study. The Soraya study using mirvetuximab, I remember you, it's a folate receptor alpha ADC with DN4 as a payload. This study included 106 patients. It's a single-arm study with registrational purposes. It, in this trial, included patients with platinum-resistant ovarian cancer with up to three prior lines of therapy, in which prior bevacizumab was mandatory. Importantly, there was a patient selection. And this is a key point for the development of the ADCs, that is a lesson that was very well learned by the mirvetuximab development program. And for this new era of the development of this ADC, they have to include patients with high expression of folate receptor defined by more than 75% of positive cells with a immunochemistry staining of at least two plus. In this study, mirvetuximab was given every three weeks, six milligrams per kilo, and the primary endpoint was overall response rate. And here are the results. This is a promycin drug with a 30% blinded independent central review responses and a median progression-free survival of the patients of around five months, which is also very promising for these patients with platinum-resistant disease and up to three prior lines of therapy. In terms of safety, 9% of the patient discontinue this drug due to treatment-related adverse events. I could say that most of the side effects are mild, grade one or grade two. The most frequent are the bladder lesion and the keropathy. There are some grade three toxicities related to this high toxicity and also to nitropenia and diarrhea, but this is very low, around 2%. This drug is also under exploration in a phase three trial called Mirasol, which has been already completed the recruitment. This is a very nice cooperation between GOG and ENGORD. This is a phase three study that included patients with platinum-resistant ovarian cancer, one to three prior lines of therapy, in which Bevacizumab was allowed before, as well as the PARP inhibitors. Again, there was a selection of patients in the high rate expression of folic receptor alpha according to the criteria that I have already mentioned, and the randomization was one-to-one between Mirvetoximab or investigator choice. We are looking forward to see the results of this validation study for Mirvetoximab. But this concept is so interesting that we have started to move to earlier lines or earlier context of the disease, and this is the case of the GLORIOSA study. GLORIOSA study is a maintenance study for patients with platinum-sensitive relapse that have received two times platinum and that have respond to the second line platinum in combination with Bevacizumab. In this study, prior PARP is required in case of BRCA-mutated patients. Again, the selection is according to folic receptor alpha, and the randomization is again one-to-one between Mirvetoximab, Bevacizumab, or Bevacizumab. As I said, as maintenance for patients that are in complete response, partial response, or a stable disease after the end of chemo plus Bevacizumab. And now let's me introduce Upifetamab-Rilsodotin from now APRI for all. This is a first-in-class ADC targeting NAPI-2b. What is NAPI-2b? NAPI-2b is a sodium-dependent phosphate transported that is broadly expressed in ovarian cancer, and it is limited expressed in normal cells. It is thought that approximately two-third of patients with high-grade serous ovarian cancer have some sort of expression or high expression of this NAPI-2b antigen. When you see the anatomy of this ADC, you realize that the drug-antibody ratio is higher than was shown before. In the other ADCs, it is around four payloads per antibody. Here you can see that it is around 10 per antibody, and the reason is because of the linker. The linker is a fleximer polymer escaphol that has the ability of integrate more than four payloads without a detrimental effect in the physicochemical characteristics of this ADC. And the third characteristic of this ADC is the controller-by-standard effect. This is because of the payload. The payload is the aoristarting of FHPA. This is a drug that when it is in this formula, it can go through the one cell to the other, can pass the membrane, but when it is activated to aoristarting F, that is locked into the cell and cannot go to other cells. That is a way why this ADC can control the by-standard effect, affecting only the cells that have the drug activated inside. Well, with this drug, we have seen very nice data coming from this phase 1B study that included one to three prior lines of platinum-resistant ovarian cancer, or up to four prior lines, regardless of platinum status. All the patients were high-grade serous ovarian cancer, and for all the patients, it was taking some tissue, archival or fresh tissue, in order to develop the biomarker for this new drug. In this phase 1B study, two doses were tested, 36 milligram per square meter and 43 milligram per square meter, and the primary endpoint was the MTD and the recommended phase 2 doses. As a secondary endpoint, and I think it's one of the most important for the development of this drug, is to develop immunochemistry testing for an Api2b expression and try to correlate that with the activity of the drug. In this table, you can see summarizing the effect of this APRI in this phase 1B study. And the first idea is that this is an active drug. When you consider all the patients regardless of the dose or regardless of the expression of NAPI2B, you can see almost 25% of response rate in a population that is platinum resistant and usually heavily pretreated. But when you see what happened with the 36 milligram per square meter in the subgroup of patient that are NAPI2B positive with an expression that is at least of 75%, the response rate is 44%. It's true that it's only 16 patients, but it's a clear signal that this drug can be very active. In terms of safety, due to the properties of this ADC or due to the payload, the safety profile is completely different to other ADCs. There is no significant or no relevant ocular toxicity we haven't seen, neutropenia or peripheral neuropathy. On the other hand, fatigue and nausea are relatively frequent but low grade. Transient increment in transaminase is also seen. Obviously, this has a new profile compared with the other ADCs that have been already shown before. And this drug has been now moved to a development program in ovarian cancer. The first study that has been launched and recently closed for recruitment is the UPLIFT, which is a single arm registrational study, registrational trial in platinum-resistant ovarian cancer. In this study, we have included patients with up to four prior lines of therapy. I insist it's for platinum-resistant patients. Bevacizumab was mandatory if only one or two lines were permitted before or did before. Importantly, all the patients need to have issue for the biomarker development program. In this study, the dose was 36 milligram per square meter. This is important because with the 43 milligram per square meter in the phase one B expansion program, some patients had pneumonitis, but it seems that with 36 milligram per square meter, pneumonitis is no longer an issue. So we will see with the results of this study come up and we will have much deeper information about the activity and safety of this interesting new drug. And again, this concept is so interesting that we are moving to earlier lines of therapy. And you can see in the slide, the design of the up next study, which is a phase three study of maintenance in recurrent platinum-sensitive ovarian cancer. In this case, patients with up to four prior platinum-containing chemotherapy regimens can be included. The patient need to have a situation of non-evidence of disease, complete or partial response, or even a stable disease after the last platinum dose. And in this case, it is important to highlight two differences with the uplift. The first is that here we will include only patients with high expression of NAPI2B, which I think makes sense in order to treat the patients with the highest probability to respond to the treatment. And the second is that the dose is a bit lower than in the uplift, is 30 mg per square meter, which makes sense for a maintenance trial in which patient will be treated until progressive disease. Primary endpoint will be progression phase survival. So this is an exciting moment, I think, for the development of the ADCs in the platinum-resistant and moving to the context of maintenance in the platinum-sensitive. And I would like to summarize this talk with some take-home messages. First, the ADCs is a drug with three components. And remember that the three components are important, not only the antibody targeting the tumor antigen, but also the drug payload and the linker that plays an important role in the activity of the drug. These drugs are designed to enhance the anti-tumor activity and minimize the off-target side effects, which is important. And innovative designs, as that for APRI, can improve the efficacy and can improve the safety by many, essentially by two mechanisms. Well, one is the controller, by controlling the bystander effect. And the second is improving or incrementing the drug to antibody rate. As you have seen in my slides, UBRI and mirbetuximab are nowadays the most promising drugs with robust clinical activity in the platinum-resistant setting. I hope that these drugs will demonstrate in the trials that we are now running solid and robust activity, as well as in the context of maintenance for platinum-sensitive. And as I said at the beginning, we'll change the landscape and we'll give more opportunities to our patients. Thank you very much for your attention. Thank you. Well, great. Thank you so much for that excellent talk. We have, let's take about maybe 10 minutes for kind of discussion here. And again, if the audience has questions, there's a microphone right there. Feel free to step up and ask any of our panel about the presentations today. But it's an exciting time. You know, Dr. Gonzales-Martin, you brought up that we have two studies for randomized phase three studies for platinum-sensitive ovarian cancer, including antibody drug conjugates just launching kind of at the same time in a space where we desperately need some new studies. Unfortunately, we were all excited about Adelante and that was negative. You brought up Anita that we're kind of anxious to see the results of, but that won't be out for a bit. So this is a hole in our clinical trial pallets that we're filling, but it's a new era. These are both biomarker-selected studies. One, foliar receptor alpha, that's about 35 to 40% of high-grade serous, and the other, sodium-gated phosphate transporter, that's about, what do you think? What's the prevalence? 75. About 75% is what we're thinking to be high, so a little more common. So how are you going to, can you just take the audience through, if they have both of those open, or they're interested in opening them, how are you gonna approach screening patients, so they're kind of getting access to these with tests that are sort of proximal to them being treated? What are the differences between the two trials, and sort of how do you line patients up so they can benefit from these opportunities? So, thank you, Katie. I think that the first thought is that these ADCs will change, probably, not only the treatment, but also the diagnostic process of patients with advanced ovarian cancer, but nowadays, we are asking for the BRCA status, the HRD status, but probably in the future, we will also need to know the folate receptor alpha and the NAPI to be expression of the tumor, so the first thing that we will change is the diagnostic process. The second thing is, once you have in front of you a patient with a platinum-sensitive relapse, again, if you know, probably, it should be very good to have the data of the folate receptor alpha and the NAPI to be, because that will help you in the selection of the treatment for the trial of the patient. Otherwise, I think that you will use your standard process of making decisions for patients, at least in the European Union, the use of the basisomap is restricted to one indication in the natural history of the patient. If you have used it in the first or second line, you cannot use it in subsequent lines, so probably the up next is the best study for those patients, but if a patient is folate receptor alpha, has never received a basisomap, or has received only parapenemeter in first line, and the relapse platinum plus basisomap, and is folate receptor alpha, then the patient should go to the mirveduximab. I don't know if one study is completely exclusive of the other, because imagine a patient that is both folate receptor alpha positive and NAPI to be positive, and that you could treat in the first relapse with platinum plus or minus beban in one study, and then, at progression, respond again to platinum and put in the other study, so we don't know. Yeah, we don't really know yet the, in some sense, the overlap, they are probably a little bit distinct populations, but there's probably a little bit of kind of Venn diagram overlap in the middle, so they may be distinct populations. I think we'll see that with additional data, but I'm intrigued by your comment, so you think that the diagnostics will change. Certainly, what we have in the US, we hope to have mirveduximab approved very shortly, in which case, the companion diagnostic will roll out so we can start testing earlier. Sodium gated phosphate will still be experimental until the uplift study hopefully reads out and is positive, so that will have to be proximal to the trial, but say both of them are approved in the platinum-resistant setting, so you could test. When are you gonna test? When are you gonna set those immunohistochemical tests on your patient, ideally? So, again, ideally, I would test all the patients. Probably we need to, and in this process of development of the biomarker, it's important to know is the expression of the biomarker is stable along the history of the patient because maybe that the expression, you know probably much better than me what is the situation for folate receptor. We don't know yet for NAPI to be. We have archival and also fresh tissue, and we need some sort of correlation between the expression in both because if it is stable, then it can be done at the diagnostic at the beginning of the primary diagnosis, and that will be the easiest way to do that. Yeah. Any thoughts from Dr. Eskander? I agree. I think there's two factors that play into this. One is time is important for our patients, too, both when you're screening for clinical trial, but also when you're treating clinically, and so if, as I mentioned, the assay or the assessment is valid, in my personal opinion, it's always best to have the information up front so that I can make informed decisions prospectively rather than having to wait on data to come back and track down some tissue from a lab that we can't access anymore, et cetera. I think that it's suggestive for FR-alpha that there's stability from what I understand over time so you don't have to re-biopsy, which is good. I'm hopeful it will be the same as we explore these biomarkers so that we can have these assays, the testing algorithms, put them in place to derive the information, and then when we're seeing the patient and treating them, we're already anticipating, for example, if you have these trials open, you'll be able to say prospectively, proactively, if we have to deal with a recurrence, you're NAPI 2B high, I have this trial, and I can begin to plan rather than wait and see, which I feel puts us in a position where we're a bit vulnerable to delays and patients deciding not to enroll and compromises potentially outcome. I remember asking the same question about folate receptor alpha and NAPI 2B, whether it's stable throughout, and it does seem like it is actually for NAPI 2B, and it sounds like for folate receptor too, so this is actually really, I would say, the development of these strategies have been really well thought out because that has been a question for us, is the tumor expression at the time of diagnosis going to be the same at recurrence, and it seems like for these two, they are, and so that will actually, from a patient perspective, exactly in terms of the timing, and for us as providers, we won't feel this need of, you know, we can actually test it at the time of diagnosis, and really, I think we all would love to have the plan for our patients where we kind of know exactly the strategy. You know, what is the next step? I think that really provides an ability for all of us to understand how to handle this diagnosis. Yeah, I think that's such a good point, and things that I don't know that I'm interested in knowing as we go back to this question of how to better identify therapies for our tumors that are homologous or combination deficient test negative is sort of where these markers fall in that group. We certainly think that folate receptor alpha high is associated with poor prognosis tumors, so is it more apt to be in that HRP group, in which case, maybe you move that up front. We don't really know that yet. Like, we haven't done those sort of global studies of IHC and next-gen sequencing, but hopefully that will be coming. That's a good idea for those trainees in the room to start working on that, working on that for next year. Good little retrospective study. But sort of, so coming back to that point, you know, we're in platinum-sensitive maintenance now with these two antibody drug conjugates where PARPs have lived before. Very much differentiated safety profile between a PARP and an antibody drug conjugate. Did you have concerns about, this is sort of targeted chemo, so in the past, we've sort of said, why on earth would you use chemo as a maintenance? That's crazy town. But here we are using targeted chemo now as a maintenance. Why isn't that just crazy town for our patients? Why do we think this is a good strategy? Who wants to take that? Yeah, go ahead. Okay, thank you. I don't know whether to thank you or no thank you. So I think that the key point is not that that is chemotherapy. The key point is that that works and is safe. So it doesn't matter if it does chemotherapy or another thing. The problem with maintenance chemo is that it was not safe and it was not really good for the patients in terms of outcome. So for me, it's not a problem. I have to say that we have seen in other diseases such a huge improvement in the progression-free survival in also in bad context, for instance, that the story of the breast cancer which had to positive disease, that really it is not a matter of chemoism. The issue is we need to know very well the safety profile and to manage very well the safety profile of these drugs, because I guess that if you reach this sort of knowledge, good management of the drug, and you can keep the patient with this drug for a long time, that should not be a problem at all. We had this conversation last night with colleagues, and I said, I've never walked into a patient's room ever where I've had a conversation with them and said that you've recurred and have not seen the look of, it's devastating to patients to hear the cancer has come back. And I think that, you know, I remember there was a paper that was published when there was controversy about maintenance therapy, and if there's no overall survival advantage, should we be treating patients? And they went to patients, and they asked GYN cancer patients, what benefit, what PFS, first, do you need an OS benefit? And the patient said, no. And they said, what PFS benefit would you accept for a maintenance strategy? And if I remember correctly, it was a three-month from the patient's perspective. So I feel like it's our, if we're fortunate enough to have effective treatment strategies and these trials are positive, what appeals to me is, one, they're targeted, we're being thoughtful in selecting patients, but more importantly, if we can deliver the drug in an effective manner and it's safe and tolerable, and we don't have to continually walk into that patient's room and say, you've recurred, I think that's a benefit. And I think the patients themselves, I don't know if there's any patient advocates in there, I'd love to hear from you if you are, but the patients themselves have also spoken about this and said, we're willing, we're accepting of a therapy if it's gonna keep the cancer away. Oh, yes. Yes, wonderful. We might have a patient advocate. There we go. Perfect. Perfect. Thank you so much for these presentations and we have so much hope in everything that's in the pipeline and I'm someone who has had two recurrences, so I really appreciate you being emphatic with the patients and knowing what we feel. And if it's the same study we were talking about, I think that happened around Bevacizumab, I think, yeah, it was part of the show and I think the hub in the room was that there was a disparity between what the doctors believed and what the patients believed. We're greedy. Three months was not what we wanted. We were going for six and everything was at the last, you know, whatever the last amount was, that's what we wanted because we're greedy. But I think that patients really want to know what's best for them and so having these biomarker directed things help us prioritize, you know, and it's not like the olden days when I was diagnosed in 2004. It was, you know, it's so exciting to have so many options and I hear different things from different patients. Some people, when they're done with chemotherapy, especially now when we're saying, okay, guess what, we found out, you know, you carry mutation. You win two more years of oral, you know, therapy and, you know, they don't understand survival curves yet and so it's very daunting. They thought they were gonna be done with chemo and then other people, when you near the end of your first line treatment, are we done? You know, how do we know it's gonna really stay away? And so they feel, you know, they want to do something. They want to be active in keeping the disease at bay and, you know, they're doing things that are not evidence-based to try to do that in some places but everyone's gonna be a little bit different and I think the most important ingredient in making these decisions is the communication that you're going to have with them to help them understand about themselves and the disease that they have, the different markers and what's available and that things are evolving and so what we tell you today may be different, you know, down the road but I thank you guys so much for your work and keep doing it. Thank you. Well, honestly, we didn't plan that but patients are the center of everything that we do and why we're here and so I'm not gonna even say anything other than thank you to my panel. We're gonna end with the voice that we're here to serve and thank you for attending this hopefully informative session today. Good afternoon. Thank you.

platinum-sensitive ovarian cancer

PARP inhibitors

platinum resistance

tumor microenvironment

clinical trials

immune checkpoint inhibitors

antibody-drug conjugates

resensitization

treatment options

post-PARP inhibition

research