I really want to take the time for joining us. I'm David O'Malley from the Ohio State University and Western Medical Center and James Comprehensive Cancer Center and honored to serve as a moderator for this afternoon's symposium. How do we define non-eligible for platinum in ovarian cancer? Impact of prior therapies and novel strategies for treatment. Thank you to Novacure and the Ju-Ju Foundation for making this symposium available to us. You will see that the participants within today's symposium produce all of the slides and this is really identifying those patients and the impact of how we're gonna really define non-eligible for platinum resistance. The learning objectives for this symposium are listed here. We're looking to increase the knowledge related to defining platinum-based therapy that is no longer an option for patients, impact of prior therapies, the mechanism of action and definition of PARP resistance, strategies for overcoming PARP resistance and the impact of PARP inhibitors on subsequent therapies, as well as outlining new novel strategies and defining new exciting treatments in this population. So really like to go through it and I was thinking with regards to the participation that we have on this panel today and not only are these my friends, they're probably the smartest people, some of the smartest people in the world that I know and who deal with ovarian cancer. It's really my honor to be moderating this session. So Dr. Bradley Monk, he's from Honor Health Research Institute, University of Arizona College of Medicine, Creighton University School of Medicine at St. Joseph's Hospital in Phoenix. I think you need one more academic affiliation. All right, Dr. Kathleen Katie Moore from the Stevenson Cancer Center where she's the Deputy Cancer Center Director. No, you are the Director of Clinical Research. That wasn't in the script. I should not go off script, sorry. Dr. Vonda Salutari, Jew Oncology Unit at Polyclinical Universidad Augustino. Jamel from Rome, Italy. I'm sure I didn't butcher that, I'm sorry. Unfortunately, Vonda's unable to make it at the last minute due to some travel changes. Dr. Isabel Rae Cucard, Professor of Medical Oncology, University Club Bernard Lyon, France. Dr. Ahmed Oza from Princess Margaret Cancer Center, Toronto, Ontario, Canada. In order to stay on schedule, we'll be strictly enforcing the time limitations for our presentation. We'll be asking for polling questions. The polling questions will be launched. We'll give about 15 seconds and look at the answers. And again, we'd like everybody to participate. So we're gonna start, see if we can figure out the polling questions here. So what is New York famous for? You read the questions and if you have trouble reading, look at the pictures, okay? So let's see if we can figure out the polling questions. All right, let's see if we can get some responses here. Again, as you grab your lunches, please feel free to come down to the front as well as to our panelists right, your left. Make yourself at home plenty of seats. Okay, next question. For ovarian cancer patients, which of the following treatment options are you aware of and select all that apply? All that apply. I don't see a lot of phones out. I need help here, guys. There's no what? There's no poll on the thing? Yeah. Okay, well then we won't do the poll. So answer verbally. No, just kidding. All right, let's think about here. We're looking at PIK3 inhibitors, PARP inhibitors, tumor treating fields, immune checkpoint inhibitors, folate receptor, alpha ADCs, and I would just put ADCs in general there. And anticoagulant, relacorlan. I don't know. Hey! Well, there you go. Two voters. One, two, three, four, eight. Now they're flying in. All right, it's working. Did something happen or did? All right. So, you know, I think as we look here and we look at this new world and you're hearing a lot of data here, I thought it was a really good session this morning and good, some really hypothesis generating ideas with regards to the impact PARP inhibitors, for example, are having on our patients. We have so many exciting new agents and areas of agents that we're really going to move forward at this time to learn more about those. So I would now like to welcome Dr. Brad Mung to the stage to do our first presentation, defining platinum-based therapy as no longer an option for patients. So welcome. Good to talk to you guys again. This is something, you know, it's a surprise that I'm very passionate about, okay? And I hope that I can sort of expand the way you look at things. I think we all sort of are confident when we treat a recurrent ovarian cancer patient, but we don't talk about some of these basic principles often enough. So I wanna talk about when platinum is not an option. My disclosures are on the website and haven't changed since this morning. So this idea of treating a patient who fails a regimen with the same regimen again is virtually unprecedented in solid tumor oncology, and we do it all the time. We treat patients with platinum over and over, paclitaxel over and over, bevacizumab over and over, and when did this start? So I don't think Maury Markman's here, but he's been one of my mentors and close friends for a long time, and it dates back that I can find the first mentioned in the literature and at least the historical opportunity by Maury Markman in the Journal of Clinical Oncology, and he says that second-line platinum works after platinum, duh, okay? And what he says was is that the longer the platinum-free interval, the better it works. I get it that that's fundamental, and he says in conclusion, secondary responses to platinum are common, okay, in previously, patients who previously responded. Immediately the next year, he coined this term, platinum-resistant, also in the Journal of Clinical Oncology while he was at Memorial with Bill Hoskins, and look at the definition of platinum-resistant recurrent ovarian cancer, those that did not respond to their last platinum. That is not what we have been taught in our fellowship, and I can tell you it's not the most common way that patients are treated. Everybody else, okay, in other words, that progresses during platinum is not an eligible patient, but everyone else that did respond is potentially platinum-sensitive, and you see the six months, he says the six months, but he never implied that you should not treat a patient less than six months with platinum. The most active agent in patients who respond to the last line of platinum is platinum, okay? And he noticed that the gynecological oncology group was studying these single agents in platinum-resistant patients who had previously responded, and now working with his colleagues at the clinic, said, look, subsequently responding to platinum calls into the question of the clinical relevance of this commonly employed definition. He never meant for us to do that, and then my other mentors, Phil Desai and Robert Nagorni, said, look, clearly the only patient that shouldn't be treated with platinum again is the patient who definitively progresses. You can even do a doublet, and this idea that a gem platinum doublet is a very good option. So this is not my idea, and I could show you all the data, but I want to tell you how you got to this idea, and then Maury Markman, again, writing with Ronnie Alvarez and the rest of my friends, sort of created this new terminology based on histology, molecular signature, treatment-free interval, and number of chemotherapy agents. And we got all of these drugs approved. I get it. It's all about platinum, and you heard that this morning in these wonderful presentations and panelists' wonderful distillation. We have many other options other than platinum, including anti-angiogenics, antibody drug conjugates, tumor-treating fields, and we've now removed these PARP later line indications, and you're familiar with that, and there's going to be an Oncology Drug Advisory Committee on November 22nd now with the NOVA data in the non-bracket patients. So we're still evolving what the best patient population is. But bevacizumab is a good medication. It's indicated in platinum-resistant recurrent ovarian cancer now for eight years. Based on the Aurelia study, which you've seen over and over again, I just want to point out to you that the median PFS in Paclitaxel Bev is 10 months. It's better than anything that we possibly could use. In fact, it even shows that the response rate is 51%, and then we use probably, I'm not sure we, maybe, I've heard, that liposomal doxorubicin is used all the time. Even in Aurelia, the response rate was only 7%, 0.9%, and patients not only respond, but I thought a lot of these are patients who had any symptoms at baseline, and if they had a greater than 15% improvement in their symptoms or in their ascites. So not only does it have a response rate and a trend towards overall survival, but it improves the quality of life. And it's safe and effective in elderly patients, not that 65 is elderly, but you can see the difference. And then if you have not seen this paper, again, Aurelia is second and third line, or sort of primary or secondary platinum resistance. And you can see that the secondary platinum resistance do better in Aurelia, and they live longer, of course, but the benefit from adding bebacizumab to chemotherapy in Aurelia was greater in the secondary platinum, okay? In the primary platinum resistance, hazard ratio is 0.55, here it's 0.30. So again, a decade ago, this was the definition, and now this is the definition now, okay? Either it's an option or it's not, and who is it not an option for? Hypersensitivity, end organ damage, or you progress on it. So these are the preferred regimens. A clinical trial is always the NCCN-recommended preferred regimen for patients who are not eligible for platinum. And second is weekly paclitaxel, period. All of these other agents, topatecan, PLD, and so on, are less active, and certainly if you wanted to do supportive care alone, that would be acceptable. This is what you get when you get liposomal doxorubicin alone, checkpoint inhibitor alone, or the combination. You get 30 to 50% come off at their first assessment. They rapidly progress, and as you know, they're at risk of dying. And also, that's interesting, okay. And we really need to enroll the most favorable patients on our clinical trials. These patients who have a good performance status and don't have a lot of ascites, smaller lesions, lower CA125s, and probably exclude primary platinum resistant in order to test, because again, if you progress early, you can't get enough doses for it to work. Okay, so thank you. The patient who's ineligible for platinum is the patient that progresses, or cannot get it because of hypersensitivity or organ damage. Thank you for having me. Thank you. where we'll have an open discussion. Hopefully, we'll have about 20, 25 minutes for an open discussion, because I really want to hear the opinions of everybody around the table. Before I go to our next presenter, do we have the polling question up? If not, we can move on. Okay, so I'd like to welcome Dr. Isabel Rae-Cricard, and she's going to tell us how to define PARP resistance and mechanisms of action of resistance. Okay, we're moving on. Here you go. Sorry. Thank you very much for your kind invitation. I just would like to come to the beginning. So, as mentioned by Brad before, we have now several indication using the PARP inhibitor. Also, we have some trouble with the use of PARP in the treatment setting. We have the maintenance therapy. And now, if you look to the patient journey with an ovarian cancer, we have finally several option where we can use PARP inhibitor, always in maintenance, but we have clearly the idea to see that we have the possibility to have progression under PARP inhibitor or progression after PARP inhibitor. And one of the big challenge now to resolve the PARP inhibitor resistance is to have to consider that PARP inhibitor duration impact on the resistance to PARP in the second line, or is there any difference when we have a PARP and we progress under PARP? And the second point that we have also to resolve is the pre-exposure to platin and the crosstalk between the resistance to platin and the resistance to PARP inhibitor. Moving to the clinical data, do we consider that PARP inhibitor can be able to increase the resistance to platin? When we look at the REL3 data and how many patient receive a platinum-based chemotherapy after PARP inhibitor or placebo, we see finally that it is quite similar, the same in both. So that means that there is no evidence that PARP inhibitor increase the risk to not receive a platinum-based chemotherapy after treatment. The second question is how is the efficacy of the platinum-based chemotherapy after that? To try to explore this question, and I'm sure that Katie will make some comment about that, we need to look at the differential time between PFS2 or TSST and PFS1 and TFST. That means that you have to look at what is the efficacy of the subsequent therapy after PARP inhibitor, and this was well represented by Rob Coleman several years ago. If we look in the data, for example, looking to the NOVA trial, we see that in both arm, the efficacy of the subsequent therapy is quite similar. There is no difference in term of efficacy of the subsequent chemotherapy, the patient receive a PARP before or the placebo. If we look in the detail, and if we look to REL3 and NOVA, in REL3 is the same. We don't see a difference in the both arm looking to the efficacy of the next subsequent therapy. Looking to the NOVA trial, I tried to look at the patient with BRCA mutation and those without BRCA mutation, and we don't see any difference in the wild-type BRCA mutated subgroup. However, in the GBRCA mutation, when you look at the efficacy of the subsequent therapy, it seems a little bit quite different. We also have the SOLO2 post-treatment and subsequent analysis we have done and now published in the Annals of Oncology, and in this post-doc analysis, we have seen that the patient receive a platinum-based chemotherapy after Olaparib, but they progress on treatment, do not have the same PFS compared to those who receive a placebo before. Also, we exclude the patient who receive PARP maintenance therapy as a subsequent therapy. Do we have to consider that it is a specific mechanism in the BRCA mutated population or just a post-doc analysis with some limitation? The question remain open today. We have also the question about the resistance post-op inhibitor, and the OREO trial explore the efficacy of hot challenge with Olaparib for patient who already receive a PARP inhibitor before. You well know these results. I don't want to move too much in the detail, but what we have observed. Also, the trial were considered to be positive in term of statistical point of view. The clinically meaningful results with only three months of benefits remain to be challenged, and when we look at the results, we observe two population. We have 50% of the patient who already progress during the two first months of maintenance therapy with PARP inhibitor, and so in this population, do we have to consider that the pre-exposure to PARP inhibitor before lead this resistance? But also, we have 20% of the patient who are not progressive after one years of PARP inhibitor challenge. So there is something that we need to move in the detail. Unfortunately, when we look at the detail and we look in the HRD versus HRP population, for example, we don't see any argument to consider what could be the base candidate, how to explain the resistance to this patient. We just look that the longer duration of the efficacy of PARP before can be something to increase the efficacy of the PARP again, and also we see that complete response, also including C.1.2.5 normalization are probably the best argument to challenge with PARP inhibitor. And finally, clinical factor are more relevant than molecular subgroup to identify the patient who continue to be sensitive to PARP inhibitor. And for this reason, I think we need to move in the detail. We also have this trial which is quite encouraging. This patient received chemotherapy, response to chemotherapy and start the maintenance with PARP inhibitor. Unfortunately, we observe an oligo metastasis progression and the patient receive a local treatment and restart the PARP after the local treatment. What it is, the duration of the efficacy of this new lines of PARP inhibitor, also the patient progress before is close to one year. It's something quite strange. It seems that there is not exactly the same mechanism of resistance when we speak about oligo progression versus systemic progression. This need to be explored in detail. If we want also to look at the patient who progress under PARP versus those who progress after PARP, we need to move to the first line. Currently, we don't have the data, but when we look at the results of the PARLA-1, looking to the PFS2-PFS1, when we look at the ITT population, we don't see any difference. So perhaps there is a difference if the patient progress under PARP or if the patient progress after PARP because in the PARLA-1, more than 50% of the patient did not progress under PARP inhibitor. And we don't have to look, we have, sorry, to look at the benefits by molecular subgroup. If we would like to understand, we need to move to biology as usual. I just mentioned this review several years ago. It's a very nice review and very easy for us clinical oncologists. This review explain and make some comments about the mechanism of resistance with PARP inhibitor. And we are not surprised to see that there is a lot of mechanism to resist to PARP inhibitor. The first one is the restoration of homologous recombination activity. More particularly, when we look at the BRCA pathway, we have the possibility to see secondary mutation and it is well described by Elizabeth Swisher several years ago when we have seen that mutation relation induced resistance to PARP inhibitor as a treatment. We also seen that in HAT51 population. We have the promoter demethylation. We know that hypermethylation is a good marker to be sensitive to PARP inhibitor, but in the relapse setting, we have observed that we can lose this methylation. There is also restoration of homologous recombination, BRCA independent, and we have the loss of 53BP1. We increase the use of non-angiogenic hand reparation. We have also the oncogenic signalling that increase the BRCA-ness of the disease. We will speak about VEGF inhibitor in the next topic. We also have the mitigation of the replication stress, where the cancer cell slows the cell cycle, and so we'd be able to stabilise the replication force and to induce resistance to PARP inhibitor. There is also alteration of the interaction drug target. We have up-regulation of drug extracellular pumps. We have the mutation of the PARP itself. We also have the loss of PARG hydrolysis. We'll be able to increase pyridation. There is also a lot of mechanism where we don't know very well how this works, as we can speak about Schlafen-11, but also EMT signature. At the end, how can we predict the resistance to PARP when we would like to include PARP inhibitor in the treatment of our patient? We have to move to look at the extreme. Amit is here to report about this nice paper. We have seen that patients with short duration of efficacy of PARP inhibitor are those who do not have any BRCA mutation or they have some amplification of CCNE. We also can look at the BRCA mutation. We always have seen in these different trials how BRCA mutation is able to improve the efficacy of PARP inhibitor compared to the other one. We have the possibility now to use the PARP or the PARP with BEV. If we move into detail, we reported this year at ASCO several data concerning the localisation of the BRCA mutation but also the type of the mutation. We have seen a decrease of sensitivity to PARP inhibitor looking to the localisation of the mutation but also the type of the mutation. This is a post hoc analysis but it is interesting to mention for the future. BRCA reversion mutation is already mentioned before and will be probably detailed later. It's something that now we need to really push in this direction. HRD test. When we look at the results by molecular subgroup, BRCA mutated, HRD positive, HRD negative, we see that the median efficacy of PARP inhibitor is not the same. It's something that we need to think in the first line setting. What about the HRR gene panel? We have already reported with the Parallel1 data that this use of gene panel unfortunately are not able to mention the sensitivity to PARP inhibitor. Only those who have a correlation between an HRR gene alteration and an HRD test positive seem to be sensitive to OLAP-ARIB. Effectively, when you move to the detail, when you look at all genes involved in the HRD pathway, you are able to see that some of them are really an HRD test positive and some of the others are really close to nothing. What about HAT51 assay? It's something that we would like to develop in the future. It's a functional test able to reveal our capability to be in HRD or in HRP population. Unfortunately, it seems not so easy to develop. The recent publication from the MITO revealed that it is efficient. But when you look at the number of patients able to be tested and report a positive or negative test, unfortunately, it's not completely easy to move in routine practice. There is also circulating tumour cell and also ctDNA. There is a several standardisation of methodology we need to improve. The threshold also needs to be developed. Currently, there is some issue to be reproducible from different data sets, but it is something that we need to develop. The last point is about the surgery. We mentioned before that oligometastatic disease is not exactly the same as systemic disease. Do we have to consider the efficacy of the surgery and the residual disease status as something able to predict the longer of the efficacy of PARP inhibitor? The question remains open. Finally, the KLIM model. This morning, we speak about this C125 kinetic. We have seen with Benoit Yu and the Velia trial that there is a correlation between Favorab, KLIM and the efficacy of Veliparib in the Velia trial. However, when we move in the molecular subgroup, we don't see exactly the same. There is some argument to consider that Favorab, KLIM is considering to be favourable of PARP inhibitor in the BRCA and the HRD population. It is the opposite in the HRD negative population. This is something that we need to understand. Finally, if I would like to summarise the resistance to PARP inhibitor, the question, and it is a provocative question, because today there is no consensus to develop, but I hope that the next year we will develop, do we have the primary refractory resistance? That means the patients are resistant to platen. We try to include PARP inhibitor and unfortunately we are not able to see response with PARP alone. In this population, probably we speak about HRD negative tumour, including CCN1 mutation, but also other tumour genes have RB1 and so on. Do we have to define a secondary resistance? That means under therapy as a maintenance. In this case, probably we will see more patients with BRCA reverse mutation, BRCA demethylation, HRP genotype, probably MDA like flux pump will be also involved in this setting. The third one that can speak about delayed resistance for the patient who did not progress under the first line, but progress when we restart the PARP inhibitor. In this case, it will be time to define time-free interval PARP inhibitor. To conclude, the resistance to platen and PARP inhibitor are major clinical challenges and need. Cross-resistance are now clearly developed. We have to remember that secondary mutation drives 26% of the resistance to PARP and there are other mechanisms not well identified right now. If we like to think of factors that can be included and influence the treatment-free interval with PARP, molecular profile, duration of the maintenance, the type of the maintenance, perhaps surgery, and new oncogenic events are probably the most important topics to address. Thank you very much for your attention. Amazing amount of information in 15 minutes and we're actually on time. Dr. Monk, Dr. Rickard, fantastic start. Now we're going to go to really our next speaker. Oh, here we go. We have an audience question. I'm going to change this a little bit. Are you using Bev in the first-line therapy? Are you using Bev in the first-line therapy for ovarian cancer? Yes. One yes. We got it. Okay. Here we go. All right. So... Hey, we're getting some... I'm going to move on. I'm trying to move on. I'm going to move on. There we go. This is... We don't think we have to worry about confidentiality here. We're only talking about information which is in the public domain. Katie... I would like to now introduce Dr. Katie Moore. And Katie is going to talk about strategies for overcoming PARP resistance. Thank you. Well, thank you for the kind invitation to speak. I will try to maintain the trend of staying on time. Here are my disclosures. And so what I'm going to talk about today is the therapeutic opportunities to really control tumors that have become what we think are PARP resistant in the recurrent setting. And we're going to talk mainly about the opportunities to prevent or overcome BRCA reversions, restoration of homologous recombination deficiency, which Dr. Rekukar just touched on. And that's either in the setting of de novo or acquired resistance. And then really focusing on probably what may be our best opportunity, which is targeting the replication fork. And I'll talk about some clinical trials, so there will be a little off-label use. Okay. I think we can all agree that PARP inhibitors have been transformative for the treatment of women with ovarian cancer in the front line. For patients with BRCA-associated cancers, here are your indications. For patients with BRCA wild-type, HRD. And even for patients, and we can argue about this, but I still believe it, for patients whose tumors are homologous recombination deficiency test negative, these are effective and safe agents, and the development has been really, truly transformational for our patients. But, you know, we are curing more patients. You saw my partner and friend, Dr. Paul DeSilvestro, present SOLO1. You heard Dr. Rekukar present PAOLA1 at ESMO with OS endpoints that would imply we are curing a higher fraction of women. And that's why we're all here, to make ourselves irrelevant. And so that's great, and we should celebrate it. But as Jonathan Letterman said, while we celebrate that, we have to remember in SOLO1, over 50% of patients still recurred. So what about them? So we still have a group of patients that we've not converted to cure, and what do we do at the time of recurrence? So here are the things we have to consider now. It's a new era for BRCA. Some of our patients are cured. Some of our patients are recurring after completion of PARP. And in SOLO1, that was about 25% of the 50% who have recurred. It's a little bit higher in higher-risk populations. About 25% in SOLO1 recurred during PARP. Very, very few, if any, within six months. But during PARP, during the two years of PARP, were about 25%. So why? Why did they recur? This is really what we have to understand. Reversion mutations, type of BRCA, restoration of homologous recombination proficiency by other means. We can do the same exercise with BRCA wild-type homologous recombination-deficient tumors. We haven't seen cure yet, although Dr. Rekukard's data at five years looks awfully similar to SOLO, but we haven't really seen any comparator yet for HRD BRCA wild-type. So more time needs to be passed before we can declare the cure fraction in this population, but there's probably some there. But then the same issues arise. And then certainly for patients who are BRCA wild-type HRD test negative, I don't know how many of these, if any, are being cured. I hate to say it out loud. Many recur during chemotherapy. I must have some timing in there. Many recur during PARP inhibitor, very few after. I think we saw that on PRIMA. And so really, why are these tumors so resistant and how can we overcome that with novel therapies is our big question. And Dr. Rekukard brought this up. Are all patients who've seen a PARP resistant to that PARP? And so, that's wrong title. So we have some data from Dr. Fresnel from SOLO2, which is exploratory. It's the best study that's been done. So I congratulate him and the study team on this, but it's the best study that's been done and unbalanced. But it did make us wonder, in this population of tumors who had progressed on a PARP inhibitor and then got a subsequent platinum, there does seem to be a difference there. And it's pretty consistent with what we saw from Dr. Weathington and Dr. Simpkins looking at a similar population who are PARP resistant, so definitely progressed on PARP, but platinum sensitive. And then here they use PARP ATR. The median progression for e-survivors are pretty similar. So we're about seven months. And then OREO, I'm going to take the opposite turn, and I'm really sorry, my title's wrong. I clearly cut and pasted my formatting. Bad Katie. This is the OREO study, and I'm going to take the opposite kind of emphasis that Dr. Rekukard did. And while 50% did progress by that first disease assessment, it worked in like 20%. And so who are these remarkable tumors and women who are in their fourth or third platinum respond and still get this benefit on a PARP? So exposure to PARP and even progression on a PARP apparently does not equal PARP resistance. And so we have to learn more about that as we're moving forward in designing trials so we can give the patients the right drug at the right time and not make dogmatic statements based on some recent withdrawals. That's all I'm going to say about that. And so we think about overcoming PARP resistance, we have to remember how PARP works. It's not just all about homologous recombination deficiency and the effect of the PARP protein in that repair of double-strand breaks, and you can see that here on the left. PARP also, and BRCA, also play a very important role in stabilizing the replication fork. And so when we develop PARP resistance on the homologous recombination deficiency side that does not necessarily equate to full resistance and lack of targeting on the replication fork side, so we can still hit a very important part of cell cycle control in these tumors that have acquired PARP resistance. And so you saw this, and this is Pilet et al, and the reference fell off, and so I was a little mad about that when I saw my slides. I did not make these figures, and it's probably the best review ever written on this topic to date, but these are sort of the three ways we can overcome homologous recombination proficiency. We either restore it through a number of ways, and we mitigate replication stress, or other. Those are the three categories. Let's start here. And so can we prevent or overcome reversion mutations? Maybe. So homologous recombination deficient cells, and you heard this morning if you heard Dr. Constantinopoulos' discussion, these homologous recombination repair deficient cells are microhomology and joining dependent. And so this is a new pathway for us. We haven't heard a lot about this, but get ready, because you're going to hear a lot about it. It may be kind of the new PARP, right? The pole theta, which mediates microhomology and joining, is essential to repair of double-strand DNA breaks and other functions for DNA repair, and is brought into the damaged DNA by the PARP protein. And so it may be another way to target and to synergize with other agents that we use, like PARP inhibitors, with carboplatin, to try and sensitize cells more to this homologous recombination deficiency pathway. So this is a pathway that we're very interested in. It's now under study. There's been beautiful review articles. This is just one by Tobolino et al, outlining, in large data sets, the mechanisms of these reversion mutations. Some of them are DNAPK results of that pathway in terms of repairing the mutation, but many are microhomology and joining mediated repair. And so these reversion mutations are occurring because of microhomology and joining. So one, we can target this potentially therapeutically just in general. Two, this actually may be responsible for a lot of the reversion mutations that we see. And so we can target this now. So this is data from Jeff Shapiro et al, many at Dana-Farber, who have studied this pathway. This is novobiacin, which actually has PULF data inhibitory capabilities, has been tested in preclinical models. And you can see in the upper right-hand side a PARP-resistant model in red, that's olaparib, and in purple is olaparib plus novobiacin. So resensitizing these models to PARP inhibition. And then RTOS has a true PULF data inhibitor now in clinical trials as monotherapy plus or minus a PARP inhibitor. So these are coming. How we use them is the next best question. And I'm just gonna tell you, if I can figure out who the 25% of my patients are in SOLID1 who progressed during PARP, I wanna maybe give them a PARP plus a PULF data. So this is coming, very exciting. How about overcoming homologous recombination proficiency? So we were really excited about this idea of inducing hypoxia to down-regulate homologous recombination proteins and resensitize or sensitize further cells to agents that target DNA damage response like PARP inhibitors. And this was shown beautifully. This is data from Tim Yapp et al at MD Anderson looking at both bevacizumab as well as tyrosine kinase inhibitors targeting VEGF or PDGFR. This led to a lot of clinical work at Avanova. Dr. Joyce Liu's work. We were all very excited about this, especially in the group of patients who were BRCA wild type because it kind of looked like we were shifting the curves up to look like a BRCA tumor with the combination of anti-angiogenics plus PARP inhibitor. So would this work in a tumor that's become PARP inhibitor resistant? Well, this was studied by Stephanie LaRue at Princess Margaret, and this is a beautiful paper. This is the EVOLVE study where she did that. She took tumors that were PARP resistant and platinum resistant, biopsied them importantly, and then used siderinib and olaparib. And the message is it didn't work. It didn't restore homologous recombination deficiency and patients really didn't benefit in large part. But the most important part of the study is this. And this is humbling. This is the biopsy results. So the mechanisms of resistance that she uncovered in these brave women who went on this study, not brave because they went on the study, but they got a biopsy and they participated in a clinical trial, are diverse and not unifocal. They have multiple lines of resistance. So how on earth are we gonna really target one thing and expect it to overcome resistances when this is the kind of chaos that these tumors present with when they're both platinum and PARP resistant? So if you haven't looked at this paper, I'd highly encourage you to because it's beautiful science and really sets our path for the challenge. So one kind of way that we're looking at is this idea of a metabolic intervention. So not focusing on a single mutation, but can we really change the landscape of the tumor? And this is work from Gerberg-Wolff and Panos Constantinopoulos and many who really have elucidated this idea that if you use a PA3 kinase inhibitor, irrespective of whether or not you have a mutation, it doesn't matter. It induces this series of events that down-regulates proteins involved in DNA damage response. So you induce this BRCA-like phenotype, again, irrespective of having a PIK3 mutation. So this is fascinating. And there's been proof of concept in ovarian cancer. So this is, again, Dr. Constantinopoulos' work in platinum-resistant BRCA wild type with a combination of PA3 kinase inhibitor and olaparib. And this is the waterfall plot. You don't see this type of a plot very often in platinum-resistant in general, much less with a PARP inhibitor. So there is definitely something here in the molecular characterization at the bottom. It's just, again, showing it does not matter if you have a PIK3 mutation. And so this has moved into a large randomized trial now. This is a randomized phase two running through the NRG. This is NRG GYO29 in platinum-resistant, PARP-resistant recurrent ovarian cancer, randomizing to physician's choice chemotherapy versus copain-lacebo-laparib with a progression-free survival endpoint open and accruing. This will be an incredibly important study for us moving forward, and we're very proud of Dr. Constantinopoulos. So moving to mitigation of replication stress, can we target the replication fork? And again, the answer is yes, and we should be looking at this very closely because we have a number of successes. Again, BRCA and PARP are important in replication fork protection. I'm at 15 minutes. Okay, I'm going to finish. Thank you. We've exploited gemcitabine-induced replication stress already with combination of gemcitabine and ATR. Again, Dr. Constantinopoulos' work, and the most exciting thing is they've proposed a biomarker selection for picking patients who actually, you know, some patients will do fine with gemcitabine alone, but some patients have such low replication stress that you have to induce it more with an ATR inhibitor, and this may translate to better outcomes, and this is also moving forward into clinical trials. We won is another big target here. I won't go into this further other than to say that we've now learned that it may be a sequence, there may be sequence importance to ATR followed by we won as a better way to use we won. This has moved in and has been shown in clinical trials, again, celebrating Dr. LaRue with we won gemcitabine versus gemcitabine randomized phase two with even with that phase two, very compelling evidence to move forward, and then I've done work with gemcitabine as well, ATR, we won, but the toxicities are somewhat daunting in talking about toxicities, but efficacy, we won, and olaparib, again, this is Shannon Weston's work with effort in PARP resistant, platinum resistant, mostly tumors, and here are your response rates for BRCA, kind of meh, but here they are in wild type, very good, and so this is exciting, but some caution because of the tox, and so how we target replication stress remains an unmet need, but exciting, and so just in conclusion, the other here is everything else, and it's antibody drug conjugates for the win, amongst other things, but I'm biased, and I'm gonna turn that over to Amanda to talk about a little bit more, and so in conclusion, we have to overcome reversion mutations, we have to understand why these tumors become resistant, and the quality of science coming forward, as I've shown you, is amazing, and you should be proud of it, and I think we're going to solve this, and thank you for asking me to speak. amount of information and science within about 15 minutes. So thank you for that. When I was introducing Dr. Vandesayuteri earlier, I said she wasn't able to make it, but I didn't say as our tech team has been working diligently to bring her to us in Zoom. So let's hope that that works. Now let's ask a similar question that we had before. Among the treatments that are currently in clinical trials, this is a little bit different, not the ones you're familiar with, but what are the ones that you think are gonna have the greatest potential to change the ovarian cancer landscape? PIK3 inhibitors, PARP inhibitors, tumor-treating fields, IO, ADCs, anti-glucocorticoid, relacolant. So I'd like to see this, if you guys could, if we could try to get this working, this would be really interesting to shape our discussion at the conclusion of Dr. Vandesayuteri's presentation. So hopefully we're getting here. So why don't we switch over to the Zoom and we're going to have Dr. Vandesayuteri talk about defining new novel strategies and exciting trials in these populations. These are my disclosure, perfect. Platinum-resistant disease is a very challenging disease to treat and many alternative experimental new trial are ongoing as novel target and novel therapeutics, cell signaling target therapy, some antigenic therapy, and some kind of new immunotherapy. In this context, there are a lot of new compounds and today we will focus on some of these. I wanted to focus firstly in cell signaling target therapy and I want to show you this compound that inhibits GAS6 and AXL. GAS6 and AXL are over-expressed in many cancer and associated with the tumor growth, metastasis, drug-resistant, and poor overall survival. And in particular, these molecules are responsible of taxon resistance. It has been shown that chemotherapy-resistant tumors express high level of AXL respect to tumor platinum-sensitive or tumor in which we do cannot see recurrence. And high level of AXL are correlated with the poor progression-free survival and overall survival. Preclinical data shows that an increase of AXL expression is associated with the drug-resistant and inactivation of AXL leads to increase paclitaxel accumulation, which is one of the mechanism for how inhibition of AXL improve the sensitivity to paclitaxel. In this context, ABV-500 is a new protein that selectively inhibits GAS6 and AXL signaling. Considering these new targets, in this moment, there is a phase three adaptive registrational trial in which patient with platinum-resistant disease up to four prior lines of chemotherapy are randomized to receive weekly paclitaxel plus ABV-500 or placebo. And this will be a very interesting trial for which we can see if these new molecules will show some interesting results. Move on. We have a new innovative strategy, the Tt-FILD. Tt-FILD, our tumor-treating field, is a new non-invasive anti-cancer treatment that utilize low-intensity alternating electric field delivery throughout transducer array placed on the skin around the tumor region. This strategy disrupts the cancer cell division and the Tt-FILD are not associated with the meaningful systemic toxicity. And it was recently shown that the Tt-FILD may be used as effective adjuvant to currently use chemotherapy agents. In this context, we recently completed the approval of this phase three trial, INNOVATE3, in which a patient with the platinum-resistant ovarian cancer recurrence were randomized to receive weekly paclitaxel plus or not the Tt-FILD. So we are waiting for exciting results because these strategies showed very interesting results in other tumors as glioblastoma and are ongoing several clinical trials also in other kinds of tumors. In other strategies is combining new molecules as corticosteroid inhibitors as relacoritant to weekly NAB-paclitaxel. Cortisol contributes to chemotherapy resistance by suppressing apoptotic pathways that cytotoxic agents utilize. Preclinical and clinical data indicate that the glucocorticoid receptor modulation with relacoritant reverse the anti-apoptotic effects of cortisol and restores the efficacy of chemotherapy. Phase one study suggested a synergy between relacoritant and NAB-paclitaxel. Recently, results of this phase two trial have been recently reported. In this study, platinum-resistant ovarian cancer patient up to four prior line of chemotherapy were randomized to receive intermittent relacoritant plus NAB-paclitaxel versus continuous relacoritant plus NAB-paclitaxel versus NAB-paclitaxel alone. The arm NAB-paclitaxel plus intermittent relacoritant met the primary endpoint with a statistical significant improvement of progression-free survival compared with NAB-paclitaxel alone with an hazard ratio of 0.66, as well as the overall survival improvement with an hazard ratio of 0.67. And this is very interesting because on this basis, phase three trial is ongoing in which patient with platinum-resistant disease are randomized to receive relacoritant plus NAB-paclitaxel versus investigator-choice chemotherapy. Moving on strategies, I think that the antibody drug coniugatis are very interesting drug to explore. This antibody binds specific target agents on tumor cells and the complex is internalized and release very powerful cytotoxic agent that disrupt tumor cells microtubules leading to apoptosis of cancer cells. These are the two compound that are actually ongoing in gynecological cancer and above all, ovarian cancer. The first compound target NAB-2B that is highly expressed in ovarian cancer cell tumors. And this is the first compound very difficult to pronunciate, upifitamab. It is the first ADC in class that is ongoing in experimentation in ovarian cancer. In this context, we can see that this ADC showed an initial good activity in ovarian cancer patient in terms of response rate and in a duration of response. For this reason, a phase two registrational trial is ongoing aimed to demonstrate the efficacy of this compound in platinum-resistant ovarian cancer patient up to four line of chemotherapy. The second ADC is nirvetuximab that targets folate receptor alpha. STORAIA trial was a phase two trial dedicated to platinum-resistant ovarian cancer patient with a high expression of folate receptor who receive up to three lines of prior chemotherapy. From patient demographic, I want to underline that 48% of patient included in STORAIA trial receive prior PARP inhibitors, and these are results. The study show an impressive overall response rate, 32.4%. And if we think about a weekly paclitaxel that is usually reporting 27% of response rate, we can understand that this compound is very, very interesting. And this compound seem very active in patient who receive prior PARP inhibitors. With a duration of response of 6.9 months. Actually, the phase three trial mirasol completed the accrual, and this phase three compared nirvetuximab with investigators choice chemotherapy in platinum-resistant patients with a high expression of folate receptor alpha. Finally, this is my last issues, is immunotherapy. There are a lot of immunotherapy and we can talk about it several times, but I want to show an interesting compound that is nemvalokin-alpha. This is a novel engineer's cytokine that selectively binds interlocking two receptors and activate preferentially anti-tumor CD8 T-cells and natural killer. ARTIS-T1 was a three-part phase one study of nemvalokin alone, and in combination with pembrolizumab in patient with advanced solid tumor resistant to platinum. My patient with platinum-resistant ovarian cancer patient had a clinically significant benefit to complete response to partial response, one stable disease for 1.5 year. On this basis, there is an exciting phase three trial in which patient with platinum-resistant disease are randomized to receive nemvalokin plus pembrolizumab versus investigator choice chemotherapy. So we can see that the scenario is very, very exciting. And I thank you for attention. I'm sorry for my pronunciation. That was wonderful. And thank you. And I know there's some people going on to the next meetings we will be done at 1.25 to allow you to make the 1.30 meetings. But the most exciting part of this symposium for me is having some of the world's experts in ovarian cancer on the stage remote to talk about really where we are in the treatment of platinum-resistant ovarian cancer. You and I got off easy here without needing to put presentation together. And I don't think I could have competed with the wonderful presentations you had today. So Amit, you've done a lot of your research on PARP resistance, really looking at. So let's start with this question. What is PARP resistance? Is it clinical? Is it molecular? Is it both? How should we be talking about this? So thank you for that question. First of all, I'd like to congratulate the four speakers. They've done an amazing job of putting the context in terms of PARP resistance and platinum. So fantastic, and hats off to you guys. I think the era of trying to define PARP resistance is just beginning. I think in terms of platinum resistance, we've been working at trying to define both functionally as well as biologically platinum resistance probably for the past five decades. And the last consensus conference is still redefining it. So I think that we've done a really good job in the last few years in terms of really looking at PARP resistance. I mean, I think that the speakers really summarized it really nicely. PARP exposure doesn't necessarily mean that it's PARP resistant. I think we need to sort of really look at that. The functional definitions and the timing really needs to be sort of clarified in terms of how much exposure to PARP inhibitors or the sequence between platinum and PARP leads to the generation of resistance. Or some of the tools that you heard about which will actually really help us a lot is the biologic and the genomic tools. Because I think that already, within a relatively short period of time, we've started linking the functional definitions of PARP resistance with the biologic definitions of PARP resistance in terms of uncovering the mechanisms of resistance. And as you heard, there are multiple different resistance mechanisms, some of which are really well defined and actually form the basis of defining potential predictive biomarkers like reversion mutations that will actually help us really start deciding which patients can we potentially re-expose to PARP inhibitors again if they've been exposed before but not resistant? Which patients can we actually look at modulating PARP resistance by adding other agents which interfere with the mechanisms of resistance that we've identified? And when can we actually go completely outside of those resistance mechanism and bypass the resistance mechanisms completely like some of the potentially disruptive technologies like antibody drug conjugates or perhaps looking at tumor-treating fields and others? So lots of work going on. And I think that we're doing a very good job in terms of trying to link the biology with the functional definitions. It's wonderful. I see Dr. Monk raising your hand. Vine, if you have a comment, can you just raise your hand and I'll make sure I recognize you, okay? I just want to caution people. The tumor heterogeneity in ovarian cancer, I think, Katie, you showed it nicely, is real. So if you show a BRCA reversion mutation in one spot, it doesn't mean it represents the entire tumor. I get it that cell-free DNA might be a representative sample but, again, you may get a clone. So I think we need to be very careful and probably PARP resistance and platinum resistance are the same, progress while getting the agent. Okay, so I'm gonna switch gears here a little bit. I'm hearing that, Isabel, you told me that we have cross-resistance between PARP and platinum. We saw in a couple of presentations that your response to platinum's not as high. So I'm not gonna give PARPs, right? I'm not gonna give PARPs because I'm worried about creating platinum resistance. Or just not give platinum. Or, you know what, you're right. If we don't give platinum, we're not gonna get platinum resistance either. Now, obviously, I'm being dramatic, right? But this is what I'm hearing. And there are some very respected individuals in our field around the world who have said that. I think that we need to keep in mind that what is the goal for us. And the goal for us is to cure our patient. And so preserving the future to anticipate something we will not completely understand is not a good way. However, when we look at the results in the relapse setting and when we suspect that possibly a progression on the PARP is not the same than after PARP, is something that we have to push to use the PARP in the first-line setting. If you cure a patient, they're never gonna become platinum resistant. And we need to start talking about curing advanced-stage ovarian cancer patients like Katie Moore did in SOLO1. It's what, Katie, 48%, 47.5% are probably cured of their disease disease-free beyond five years. So, and then the PowerWheel data that we had updated at ESMO, right? We are looking at potentially curing nearly half of a patient's advanced-stage ovarian cancer to omit a PARP inhibitor because you're worried about platinum resistant. If you cure them, you're not gonna have to worry about resistance. Other comments? So I think you're right. In terms of curing and the exposure, I think what the PALO and the SOLO-1 data also really start reminding us is that in both of those studies, there was a limited duration of exposure, that there was a duration of exposure for the platinum, a limited duration of exposure for the PARP inhibitor, and then the treatments were stopped. And the benefits really continued to benefit many women beyond stopping all of the treatment. So I think that really is beginning to sort of perhaps start telling us that exposure and duration of exposure may also be associated with increasing patterns of resistance, both to the platinum as well as continued duration of exposure to PARP inhibitors. Katie, one of the things that I've heard you say is that sort of the curves separate early in SOLO-1. Does it make any sense to only give 18 months of a lap rib in SOLO-1 because of what Ami just said? Yeah, I think that's a great question. And it might, but the truth is we don't know. And so I would not advocate for that based on lack of data. But I definitely advocate for stopping it too, which for, and I get a lot of emails from providers and actually patients nationally about that because they don't want to stop. They're scared. Appropriately so. And we just don't know, honestly. So I really come back to the fact that there's a wealth of data that's been collected, both clinical data as well as tissue and blood, from SOLO-1 and from Paola and from Prima. And there are a group of patients who are cured. And can we characterize them? There are a group of patients who recur within one year. Why? Especially with BRCA. Like, what is wrong? And I think your paper at ASCO, honestly, I don't understand how that was a poster and not an oral presentation. Because it was so important. Because I may start treating, if poltheta inhibitors come to fruition, for example, which I'm excited about them, I will say, then if I have a specific BRCA, I'm going to start paying attention to the specific type of BRCA. Which right now, I'm like, yay, you're BRCA. But maybe I'm like, oh, OK, kind of good, but meh. And you need Bev. Or you need a poltheta. Or you need something else plus the PARP. Or I'm going to do something terrible to your tumor with a PARP. I think there's just so much we don't know. And I hope that there's lots of translational work going on exploratory-wise so we can start looking at these groups of patients and making biomarker-driven studies to incorporate these new drugs. Because we're not going to be able to study poltheta as a maintenance in all comers. Like, it's just not going to be realistic. But you can study it if you know who's at highest risk. So I would stop it to, I would never extend unless I'm treating visible disease. And someday, maybe we can shorten it. But don't do that right now. So let's switch gears a little bit and move to platinum-resistant. I knew this was a hot topic. And I wanted to bring it up. So obviously, for dramatic effect, I'm talking about not giving PARPs. I believe in statin, I believe in potentially combination HRD-positive, as well as PARP in germline and somatic BRCA. So just getting the conversation going here. I don't want people to talk away that I was being serious. But Isabel, let's change gears here a little bit. The history of the Markman papers is really interesting. And I saw, I was a resident of Cleveland Clinic. And Barb and Gert, who are the chemotherapy nurses, were on the paper in 98. So Barb and Gert were wonderful. They taught me oncology, actually. So Isabel, as we look at this, as we look at this, when are you switching from platinum in the recurrent setting? Are you treating until progression? And the follow-up question is, we still have, both in Europe and in the US, these strict definitions of platinum-resistant ovarian cancer. But should that only be a regulatory and not a clinical? Or should we try to get the regulatory to look at it differently? How are you doing it? And what should we be doing from a drug development standpoint? I would say, if you are able to change the authority mind, I will really give you a champion glaze. Because right now, unfortunately, it's not the reality. I agree with you. We have identified more than 26 mechanisms of resistance to platinum, more than 10 for PARP inhibitor. We put all these patients together. And we say, it is the patient we would like to treat. For sure, it's not the same patient. And it is one of the reasons that it is some quite complex. However, I agree that for a clinical trial, we need to have a sort of homogeneous population. And the inclusion criteria will help us. But for the management in routine practice, we have to go back to other factors. And the molecular aspect, we speak about BRCA. We speak about HRD. It's not enough. It's for this reason that I put the surgery in my talk. I think that there is clinical factor. And as physician, we are able to look at it that we need to include in our decision making. And for the platinum-resistant population is the same. You perfectly mentioned the work moving to histology, looking to all other factor. This is something more important. So Dr. Monk, putting people in clinical trials is tough, man. I gotta do more work. I get the attributions. I gotta go over that. It's a lot of work. Why not just put my patient, and I give a weekly taxol after platinum GEMS are and platinum sensitive, she progresses. I go to weekly taxol. It's so much easier just to give PLD or GEM or TOPO. I mean, why would I do all that extra work to put a patient on a clinical trial? It's an interesting statement. All of us have spent much of our careers doing clinical trials. I have an epiphany here to announce. You make more money doing clinical trials than you do giving chemotherapy or surgery or radiation. The question is whether or not your institution keeps the money. So I've really been a passionate advocate to get you paid for your additional work, Dave O'Malley. Now it's up to your Ohio State whether or not they're gonna keep it or not. There is this paradigm where if you do a hysterectomy or give chemotherapy or radiation, you get paid. I invite you to change the paradigm with if you do the additional work that your institution is getting paid for from NGOT and the GOG, you get paid for your work. So the reason to do it is it's right for the patient, and we've created a mechanism for you to get paid for your additional effort. Well, I think having the opportunity to make sure that your time is attested for is important. But Katie, when we look at these response rates, weekly PAFCA tax of maybe 30%. And then after that, five, four, seven, 9%. And we saw the ADCs 35 to 40% response rate. So Katie, you lead a huge amount of the portfolio within GOG partners. Where's your bar where you're gonna say this drug should be tested in platen-resistant ovarian cancer? And how are you looking at this? Yeah, I think we're getting smarter and better with biomarker selection. But in general, in sort of a phase one expansion or phase two at the recommended phase two dose in a true tumor that's resistant to platinum, I think you're looking for a response rate that's north of 30% and a duration of response that's somewhere around six months-ish to really give you a signal that that's a drug that's gonna be clinically beneficial to our patients, number one, and will be successful in a confirmatory phase three study to meet the regulatory requirements in both Europe and the United States from a progression-free survival and overall survival standpoint, which is ultimately what's critically important. But some drugs, Vanda talked about the Axel-Gas6 drug. That doesn't have any single agent activity. It's purely meant to be a synergistic agent. So it can't go through, you can't evaluate it that way. So sometimes we just need kind of these nice, really nice, appropriately done preclinical models that work was done by Dr. Catherine Fuh. It's her career. And then you sort of roll it into these bigger studies. And then they have to win. And then you have to get probably two disease assessment improvement in time to event endpoint to be clinically relevant for our patients. So the bar is pretty high. But it's not just about platinum resistance. It's about weakly paclitaxel resistance. Because if you say that the weakly paclitaxel efficacy threshold is 30%, 30% from an ADC is not that exciting if those patients would have been eligible for weakly paclitaxel. It's pretty exciting if you don't lose your hair and you don't get neuropathy and it's biomarker directed. I'm talking about a regulatory excitement. So no question, and if we could get those drugs approved, I'm gonna use them preferentially to weakly paclitaxel, no question. But I think from a regulatory, in order to have to be better than available therapy, and weakly paclitaxel is cheaper, right? And all of these aspects, no question it causes all these problems. And probably the biggest reason for not being eligible for weakly paclitaxel is grade two neuropathy, which is a lot of patients. And obviously once the drug is approved, then obviously the aversion to alopecia is significant. I think as we look at this, so Rhonda, you did a wonderful job of going over what we have in our portfolio in the GRG and NGOT across the world. I have to admit, I'm biased here, I'm the US GRG lead for tumor treating fields. And when I first heard about this technology, I'm like, what is this hocus-pocus, right? They put electronic arrays on somebody and help deliver, but again, as you just heard Katie say, weakly paclitaxel by itself is pretty darn good. Combined with Bev is pretty good too, but we have a lot of patients who have a contraindication to Bev due to bowel involvement. In Ohio, we have a lot of undiagnosed diabetes, thus a lot of renal disease, which makes it challenging. What are some of the agents that you're most excited about seeing? We saw the survey here, so what are you looking forward to in hearing from some of those you reviewed today? Yes, I think that the blood-immune-resistant disease is more or less to talk about a multidrug-resistant disease, in my opinion. So I think that we must find something different and in this context, TPP could be something that could be different in a population in which we know that the peritoneal carcinomatosis is the most important problem that will lead our patient to die in the natural history of ovarian cancer. So TPP, that is something that controls the peritoneal disease. In our experience, in a TPP trial, we could find a control of peritoneal disease and we can change chemotherapy, so we give a kick-up, say, to the immune, but sometimes, when we have the control of the autoimmune, we can change the chemotherapy and improve the control of disease with the TPP. So I think that this kind of new strategies could be effective in the control of disease, quality of care for patients, and delay, as soon as possible, the death of disease for global abstraction. So I think that TPP can find a space if we think about ovarian cancer in this natural history. And then, I believe also in ATC, antibody drug-communicating. If we find the target, we can find something more. So I believe that the fact that the TPP is not a systemic toxicity and to ask to combine the strategy with all compounds that we have for our patients. I love it. So I think there is a microphone if anybody had a question from the audience. In the last five, six minutes here, I'm gonna start off, and I'd like everybody's final thoughts. So what I'm hearing from you all and what I'm thinking here is, platinum-resistant ovarian cancer, one of the highest unmet needs, particularly that symptomatic patient. So helping people feel better while living longer, okay? We didn't get into, but we alluded to HRD test negative. I'm not sure we're curing more patients with our current treatments in the first line. So I think, and then on that, we need to change the dialogue and start talking about curing patients with advanced stage ovarian cancer because that's really what is realistic now. Those, to me, are the three biggest unmet needs within our field, particularly as we think about from a drug development standpoint. Dr. Monk, let's all have a minute or so of final thoughts, please. Listen, if it's not bevacizumab or PARP inhibitors, it doesn't work in ovarian cancer. PROC is undefeated. Platinum-resistant recurrent ovarian cancer is undefeated for eight years. The number of agents that we've studied over eight years, I have them on my laptop, it's a big number. So I think we just have to keep trying. We have to keep trying. What you said, Katie, we have to keep learning. What you said, Isabelle, we have to study the biology. And we just have to cooperate together. So I just want to thank you. You saw this morning from my Gallup presentation. We did the best we could and we failed. And ovarian cancer has beaten us many times, but we're not gonna give up. But we're getting smarter from precision medicine, which is my fourth point. Isabelle. I agree that we need to conjugate our efforts. First, better definition of the disease, and we have now the biological tool to help us, but also to push our effort in the unmet need population. That mean you mentioned HRP population, but also resistant population. And what about patient after pump? Katie. I mean, there's so many unmet needs. So there's not just one. I just want unmet need. I'm happy to hear anything with regards to what we talked about today. Free reign. I agree with what my partners have said 100%. I would just bring it back to frontline. I feel like there's so much data in the frontline. There's four studies that are going to read out next year likely into maybe the following year. Thousands of, like 4,000 patients of data. Many of which had blocks supplied and so much biologic material. And we'll see if they're positive or negative. I lead US First with Ann and Eric, and so I'm hopeful that's positive. But the truth is that it's not gonna work for most patients. And we have to figure out sort of what we're doing to people that sort of sets them up to do well or do less well. And so I'm hopeful that we can convince all of our pharmaceutical partners to potentially collaborate more and work more once the primary endpoints are reached on some of these hard questions. Why do some women with BRCA-associated tumors progress during PARP? And how do we fix that? Do we induce reversions by doing neoadjuvant chemotherapy in BRCA-associated cancers? My good friend Michael Friedlander threw that hypothesis bomb out at me at ESMO. I kind of want to know the answer to that. There's no data. But if you knew that, you would change your surgical practice potentially. So I just think there's so much we don't know and we just keep trying to like use a hammer and a nail like the same way on every patient. And I think that era's over. So I just want to collaborate and have less people be in my recurrent phase one unit and be irrelevant at some point and do something else. I love it. Amit. So I agree with all of those sentiments. I think we need to sort of increasingly try and integrate biology with clinical data that's coming through. And there are a lot of questions that we still need to address and particularly duration of therapy and how do you actually stop treatment. I think we've talked a lot about the frontline setting and increasingly moving PARP inhibitors into the frontline setting. But there's still a lot of women who have PARP inhibitors for recurrent disease. And there is a bit of a challenge. Every day you face the challenge in terms of somebody who's actually deriving great benefit after three, four, five, six years for recurrent disease. You know that the potential for complications as well as resistance is increasing. But you dare not stop because recurrent disease is generally not curable. So how do you reach that balance? And so I think that integrating biology, understanding when resistance is actually emerging and perhaps looking at a more proactive approach to stopping and discontinuing treatment I think is a sort of huge unmet need at the moment. Lots of other unmet needs as well including having better treatments. But I think that we need to sort of really start focusing on really taking advantage of the translational approach to try and improve our precision for therapeutics. Great. And one last comment, then I'll wrap us up. Please, what was your takeaway for the audience? I think that platinum-resistant disease is more or less to talk about a multidrug-resistant disease in my opinion. So I think that we must find something different. In this context, TTP could be something that could be different in a population in which we know that the peritoneal carcinomatosis is the most important problem that will lead our patient to die in the natural history of ovarian cancer. So TTP is something that control the peritoneal disease. In our experience in innovative trial, we could find a control of peritoneal disease and we can change chemotherapy. So weekly paclitaxel at the beginning, but sometime when we have the control of the abdomen, we can change the chemotherapy and improve the control of disease with the TTP. So I think that this kind of new strategies could be effective in the control of disease, a quality of life of patient and to delay as soon as possible the die, the death of disease for bowel obstruction. So I think that the TTP can find a space if we think about ovarian cancer in this natural history. And then I believe also in ADC, antibody drug conjugated, if we find the target, we can find something more. So I believe that the fact that TTP is not a systemic toxicity, help us to combine the strategy with all compound that we have for our patients. All right, I'm gonna wrap you up then. All right, well, again, thank you for participating. This concludes our symposium. Thank you to our presenters, audience for joining us this afternoon. This session will be available as part of the IGCS on-demand program following the meeting. Have a great afternoon. Thank you.

symposium

non-eligibility

platinum-based therapy

ovarian cancer

Novacure

Ju-Ju Foundation

panel of speakers

PARP resistance

combination therapies

replication fork

research

biomarker-driven studies