Welcome to the last day of the meeting. My name is Don Dizon, and I will be the moderator for this plenary session, along with my friend and colleague, Dr. David O'Malley. We have excellent presentations today. We have some time also after the presentations for a few questions, so you may submit your questions via the Q&A feature, and we will do our best to address them at the end. Also, stay tuned. At the close of this session, we'll be announcing the social media contest winners. On to the science. To avoid delays and lengthy introductions, I'll turn the screen to Dr. Beryl Manning-Geist to present the first abstract of the session. Dr. Manning-Geist, please proceed. Thank you for that introduction. Good morning. My name is Beryl Manning-Geist. I'm a gynecologic oncology fellow at Memorial Sloan Kettering Cancer Center in New York. Well, I would like to thank the program committee for the opportunity to present today. On behalf of our research team, our abstract is entitled Comprehensive Genomic Profiling of Low-Grade Serous Cancers and Associated Clinical Outcomes. No disclosures. Serous carcinoma of the ovary accounts for up to 80% of epithelial, ovarian, tubal, and peritoneal cancers, and it's subclassified into low-grade and high-grade disease based on morphologic, immunohistochemical, and molecular features. Now, low-grade serous carcinoma represents about 5 to 10% of serous ovarian cancer, and it's characterized by low mutational burden, low frequency of TP53 mutations, and frequent alterations in the map kinase pathway, and an unclear germline association. Clinically, low-grade serous cancers has a bimodal age of onset in patients ages 20 to 30, and then about 50 to 60. It's less platinum responsive, and it can have either an insolent or aggressive behavior. Meanwhile, high-grade serous carcinoma is characterized by high levels of chromosomal instability, highly recurrent TP53 mutations, and frequent germline alterations primarily affecting BRCA1 and 2. Clinically, high-grade carcinomas present in a median age of 63, it's highly platinum responsive, and often has an aggressive disease course. Unfortunately, little is known about the molecular landscape of low-grade serous cancer due to its relative rarity. From the available data, we know that alterations in the map kinase signal transduction pathway, which is pictured here to the left, are observed in about 60% of tumors. The map kinase pathway regulates cell proliferation through a series of protein cascades that include the RAS family as well as BRAF. In low-grade serous carcinoma, alterations in this pathway, including genes like KRAS, BRAF, and NRAS, are common, and recent therapeutic efforts have really focused on this cascade. For example, a phase 3 trial investigating the inhibitor bumetanib reported a significant association between KRAS mutation and progression-free survival in patients receiving bumetanib compared to patients with KRAS wild-type receiving bumetanib. KRAS mutation was not associated with progression-free survival in patients receiving chemotherapy. Although notably, other studies have reported significantly improved overall survival in patients with KRAS or BRAF mutation compared to patients with wild-type. The varying clinical course of low-grade serous carcinoma and its challenging treatment landscape underscore the importance of identifying common genetic alterations that can be associated with clinical outcomes or potentially leveraged for targeted treatment. We sought to further characterize the mutational landscape of low-grade serous cancers, to investigate the correlation between specific mutations and clinical outcomes, and to characterize the burden of germline mutations in a cohort of low-grade serous carcinoma patients undergoing somatic mutational testing. Ovarian cancer patients diagnosed from April 2015 to February 2021 with paired tumor and normal clinical sequencing of cancer-related genes were selected. 182 cases underwent secondary central pathology review, 63 were excluded as were duplicate cases, and this yielded a final cohort of 119 patients. The leftmost image here is representative of a low-grade serous carcinoma. The tumor is comprised of small mass of monotonous tumor cells that infiltrate through the fibrotic stroma. There's occasional somatous calcifications. On the right are examples of excluded cases, and you can see a high-grade serous carcinoma up top, serum eusinous carcinoma, and then finally tumors with low cellularity precluding identification as low-grade serous cancer. To characterize molecular alterations, patients underwent massively parallel sequencing with a proprietary sequencing platform at Memorial Sloan Kettering that targets 410 to 468 cancer-related genes as shown on this slide here. Patients provided informed consent. DNA was extracted from a tumor in a blood sample as a source of normal DNA. This was subjected to sequencing, bioinformatics analysis, and then genomic alterations were ultimately reported in the electronic medical record, as well as uploaded to the cBioPortal database for data mining and interpretation. In addition, clinical outcomes data were collected. For this, demographic and clinical data were extracted by review of the electronic medical record with information related to disease progression and survival captured. Rates of somatic alterations were then determined in three different clinical comparison groups. First, patients with younger versus older age at diagnosis. Second, patients with platinum-sensitive versus platinum-resistant disease. And then finally, patients with five years or greater overall survival versus five years or less. The association of clinico-demographic features and molecular features was associated with overall survival outcomes. And then finally, germline data were collected from MSAK impact, as well as other secondary sources, and appropriate statistical tests were employed. This slide describes our baseline clinico-demographic features of the 119 patient population. Patients had a median age of diagnosis of about 49 years. And the majority of patients presented with advanced stage disease. Here, we describe treatment characteristics of this population. 90% of patients underwent a complete gross resection or had an optimal CIDR reduction. 90% of patients received postoperative chemotherapy, all of whom received a platinum-based regimen. And among patients getting chemotherapy, 73% were determined to be platinum-sensitive, as defined by recurrence greater than or equal to six months after the last dose of platinum chemotherapy. Pictured here is a heat map showing the somatic genetic alterations observed in the entire cohort. So columns from left to right are going to represent individual patients, and the colored boxes represent the presence of a mutation that's color-coded based on mutation type. And you'll note that many tumors only carried one or two mutations, and that's typical for low-grade serous carcinoma. Overall, the most common mutations were seen in KRAS in 33% of cases, NRAS in 11%, and BRAF in 11%. And these mutations were in general mutually exclusive, with only one patient having mutations in both KRAS and BRAF. Next, we turned to investigating whether certain mutations were associated with various clinico-demographic factors. Now, given the bimodal age of onset of low-grade serous cancer, as well as some prior data suggesting more clinically aggressive disease in younger patients, we looked at the distribution of various mutations between patients greater than 50 years old at time of diagnosis versus less than 50 years old. We noticed that patients who were over 50 were significantly more likely to have tumors with KRAS mutations when compared to patients less than 50. In fact, 44% of patients over 50 carried a KRAS mutation versus only 23% of patients less than 50, and the p-value here was 0.02. As low-grade serous carcinoma is known to be more platinum resistant than its high-grade counterpart, we also wanted to see if certain mutations were more likely to be observed in platinum-sensitive low-grade serous carcinoma compared to platinum-resistant disease. And in fact, 42% of platinum-sensitive low-grade serous carcinomas carried a KRAS mutation compared to only 17% of platinum-resistant. This difference was also statistically significant. And finally, we wanted to investigate if certain mutations were disproportionately observed in patients surviving over five years, who were followed for at least five years, compared to patients surviving less than five years. And again, we noticed that KRAS mutations were significantly more frequent in patients surviving over five years at 41% compared to patients surviving less than five years at 11%. We conducted univariate and multivariate analyses to compare the association of both clinico-demographic and molecular factors with overall survival, and this table represents our univariate analysis. We found that platinum sensitivity was significantly associated with overall survival. And additionally, patients who had an alteration in the mount kinase pathway had significantly prolonged overall survival compared to patients with no mount kinase pathway alteration. This is the survival curve illustrating this difference in overall survival between patients with a mount kinase alteration, pictured in red up top, versus no mount kinase pathway alteration, pictured in blue. And in fact, the hazard ratio for death was 2.3 in patients with no mount kinase alteration, indicating that alterations in this pathway are significantly associated with improved overall survival. And in fact, this was true on multivariate analysis, including both platinum sensitivity, as well as mount kinase alteration in the logistic regression model. Under this model, patients with no mount kinase alterations were 2.4 times more likely to experience death compared to patients with mount kinase alterations, with a p-value of 0.02. Lastly, our germline analysis among 79 patients with available data revealed that seven patients carried a pathogenic germline mutation. Bioallelic inactivation was evaluated by inferring loss of heterozygosity, and this was defined as the loss of the wild type allele in the tumor at the locus of a germline mutation. In the absence of loss of heterozygosity in a tumor, germline variants were also considered to be bioallelically inactivated, if a second clonal or subclonal truncating mutation was observed in the same gene in the tumor, or in the case of germline bioallelic loss. And among the seven patients with pathogenic germline mutations, only one was found to have a loss of heterozygosity, and this was likely unassociated with her low-grade serous cancer. And interestingly, no patients carried a BRCA mutation. Overall, we were able to draw several conclusions from the data presented here. First, KRAS mutations were associated with older age, platinum sensitivity, and prolonged survival. Clinically, this is of interest as it's possible that KRAS mutational status may help risk stratify patients. Secondly, we observed that alterations in the MAP kinase pathway, including KRAS, were independently associated with improved overall survival. So it's possible that MAP kinase alterations may be used to identify patients who are more likely to have improved outcomes. And finally, although more research is needed, we reported that there is no germline mutation established that's associated with low-grade serous carcinoma. Notably, the population at our institution is enriched for Ashkenazi Jewish patients, and so the lack of observed BRCA mutations was thus surprising, and likely indicates that there's a minimal role of homologous recombination deficiency in low-grade serous cancers. Thank you for your time. Fascinating work. Thank you very much, Dr. Manning-Geist, and congratulations. We will proceed with our presentation from the esteemed Dr. Robert Coleman. Dr. Coleman, please proceed. Thank you, Dan. Thank you, Dan. Let me get the slides up here. Hey, great. Welcome and good morning to everybody, and thank you all who have contributed to this fantastic meeting. I'm so excited for what's occurred and for the rest of the session. So on behalf of my co-investigators, I'd like to thank the program committee for the opportunity to present clinical and molecular characteristics of Arial 3 patients who derive exceptional benefit from ReCAPRIV maintenance treatment for high-grade ovarian cancer. These are my disclosures. So we all know that ReCAPRIV is an oral PARP inhibitor that's approved in the United States and Europe, and as a maintenance treatment for women with recurrent ovarian cancer who have responded to platinum-based therapy. The Phase 3 Arial 3 study demonstrated significant improvement in progression-free survival across all predefined subgroups. In the current study, we were interested in evaluating the characteristics that were associated with exceptional benefit from ReCAPRIV maintenance treatment. To provide context for this analysis, we defined exceptional benefit as a cohort of enrolled patients who had a documented progression-free survival of two or more years. In contrast, we defined short-term responders as those who had progressed at or before their first planned assessment imaging evaluation, which was around 12 weeks from randomization. The tissue was retrieved for genomic testing analysis and is the subject of this investigation against the defined response. Overall, approximately 21% of ReCAPRIV patients and 2% of placebo patients met the criteria for exceptional benefit. The median progression-free survival of these two cohorts was very similar as seen in this whisker plot. To better understand the magnitude of benefit of ReCAPRIV treatment in the exceptional responders, we calculated a numerical difference in months between the patient's progression-free survival and their penultimate platinum-free interval. You can see that in the graphic at the upper left. The whisker plot on the right shows this distribution and the range segregated by ReCAPRIV treatment and placebo. Interestingly, among exceptional responders, only patients allocated to ReCAPRIV treatment had a median difference above unity. In other words, they were longer than their previous interval. In this case, 86% of patients had a longer progression-free survival than their penultimate platinum-free interval. Here we provide an analysis of prognostic factors that may have been associated with exceptional benefit among ReCAPRIV treated patients. Age, performance status, number of prior chemotherapy regimens, and number of prior platinum regimens were not associated with exceptional benefit. However, as might be expected, lack of measurable disease at randomization, complete response, and long penultimate platinum-free interval were associated with exceptional benefit phenotype. So to better understand the molecular drivers of this exceptional ReCAPRIV response, we evaluated tissue for genetic and epigenetic alterations associated with PARP inhibitor response. As might be expected, the genomic landscape among exceptional responders relative to short-term responders is enriched for BRCA1 and BRCA2 mutations. However, nearly 42% of exceptional responders were wild-type for BRCA1 or BRCA2 mutation. Among BRCA wild-type tumors, alterations in RAD51C or D were only seen in the exceptional responder cohort. Genomic loss of heterozygosity serves as circumstantial evidence of noncompliant homologous recombination and potential PARP inhibitor response. Thus, BRCA wild-type tumors with low LOH would be expected to have lower potential for response to PARP inhibition. In this analysis, the short-term responders had more prevalent BRCA wild-type low LOH tumors compared to the exceptional responders. In this slide, we focus on BRCA1 methylation as assessed in archival specimens. As is seen, high archival BRCA1 methylation was similar among those patients who derived exceptional benefit and those with short-term response. Prior research has shown that although high methylation measured immediately prior to ReCAPRIV treatment is associated with response to ReCAPRIV, archival methylation is not. The loss of methylation can occur during the course of platinum treatment. In this slide, I'm summarizing all of that preceding data with the corresponding odds ratios and relative to randomized therapy arm. It was highlighted if the tumor carries a BRCA mutation and the patient was treated with ReCAPRIV, they were six times more likely to be classified as an exceptional responder than if they had received placebo. Conversely, the likelihood of being a long-term ReCAPRIV responder in a tumor lacking characteristics of HR deficiency, namely lack of BRCA mutation and low loss of heterozygosity score, was about seven-fold less likely, or about 1 over 0.14, as shown here, than being in the category of a short-term response. Now the next slide, I'm going to focus on this cohort of patients with tumors harboring BRCA mutations. The top row represents the cohort of patients treated with ReCAPRIV and the bottom panels, those that were treated with placebo. Patients with BRCA mutations appeared to derive exceptional benefit from ReCAPRIV treatment, regardless of which BRCA gene was mutated, the mutational origin, or the mutation variant type. Similar trends were observed in the placebo patients, but the low number of exceptional responders in this category really hinders any meaningful statistical analysis. Given the overall results of the ARIEL3 study, it was not surprising that the most common treatment emergent adverse events in the exceptional responders was similar to the overall population. However, there was a higher instance of grade three or higher treatment emergent adverse events, largely due to the length of time patients were on treatment. In this cohort, treatment interruption and or dose reduction were also increased, as well as any grade abdominal pain. While more than 70% of exceptional responders had at least one dose reduction, the median dose intensity on treatment was 83%. A note of concern of part maneuver therapy is the risk of MDS-AML. In this updated safety analysis, a total of 14 ReCAPRIV patients, or 3.7% of the total population, and four placebo patients, or 2.1% of the total population, developed the condition. Nine of the 14 ReCAPRIV patients were also exceptional responders. However, the relationship between the duration of exposure to PARP inhibitor and the instance of this condition is unclear. So in summary, in ARIEL3, 21% of patients in ReCAPRIV treatment arm derived exceptional benefit, or a progression-free survival of more than two years, versus only 2% in the placebo arm. Exceptional benefit in ARIEL3 was more common in, but not exclusive to, patients with favorable characteristics and known mechanisms of PARP inhibitor sensitivity, including BRCA1 and BRCA2 mutation, RAD51C and RAD51D mutations. Our results suggest that ReCAPRIV can deliver exceptional benefit to a diverse set of patients with high-grade serous ovarian cancer. On behalf of my co-investigators, I would like to express our gratitude to the patients who generously participated in ARIEL3, enabling this work, and to you for your attention. Thank you. Thank you, Dr. Coleman. That was wonderful work. I want to go ahead and stop sharing your screen. Thank you. I really want to applaud you and your efforts on this trial, though it's a pharma-sponsored trial. You've done amazing work from a translational and a molecular standpoint, so thank you for your effort and your leadership. I'd like to now introduce the next presenter, Dr. Gong-Young Ong. Dr. Ong, please go ahead and start sharing your screen. Okay. Thank you very much for this opportunity to present our research at the IGCS conference. I'm Dr. Gao Yudong from the Department of Gynecology, Peking University Cancer Hospital and Institute. Today, I will be presenting to you the efficacy and safety of knee rupture maintenance treatment in platinum-sensitive recurrent ovarian cancer after shorter or longer chemotherapy, a post hoc subgroup analysis. I have no potential conflicts of interest to disclose. This study was sponsored by Z-Lab and passionately supported by National Research Grant. Traditionally for PSROC, six cycles of platinum-containing chemotherapy are recommended. Maintenance treatment with PAP inhibitors can lengthen the PFS and CFI for PSROC patients. Knee rupture has been approved by FDA for the treatment or maintenance treatment of advanced or recurrent ovarian cancer. As a PSROC maintenance treatment, it can be initiated upon CR or PR after at least four cycles of PT chemo. The aim of this study is to evaluate the efficacy and safety of knee rupture versus placebo as maintenance treatment when administered after at most four or more than four cycles of PT chemo. This study is post hoc analysis of the published study, which is a randomized placebo-controlled double-blind phase 3 study that evaluated the efficacy and the safety of knee rupture maintenance treatment in Chinese PSROC patients. The primary endpoint is PFS by BICR. Patients with PSROC and CR or PR to most recent PT chemo were randomized two to one to receive the knee rupture or placebo. In this post hoc analysis, the knee rupture and the placebo groups are further divided into subgroups of patients with at most four or more than four cycles of most recent PT chemo. The baseline characteristics of the patients were overall balanced between the knee rupture and the placebo arms for each of the two subgroups defined by PT chemo durations. However, between the two knee rupture treated subgroups, some disparity was noted. Compared to the subgroup with more than four cycles of PT chemo, the subgroup with at most four cycles of PT chemo had a higher proportion of patients with CR to most recent PT chemo. And a lower proportion with complete platinum sensitivity. Media PFS was significantly longer with knee rupture than with placebo. Both in patients with at most four cycles of most recent PT chemo, 18.37 versus 3.88 months, HR was 0.36. And in the patients with more than four cycles of most recent PT chemo, 18.33 versus 5.49 months, HR was 0.33. Thus, knee rupture conferred PFS benefit regardless of PT chemo duration, affecting about 65% risk reduction in terms of disease progression or death. Here, the KM curves of the two knee rupture treated subgroups are overlaid side by side. Virtually, the trend of PFS probability over time was highly similar regardless of the duration of PT chemo. But do note that, as mentioned earlier, the baseline characteristics of the two knee rupture treated subgroups were not comparable in terms of best response to most recent PT chemo and platinum sensitivity. For CR patients, knee rupture conferred greatest PFS benefit when initiated after at most four cycles of PT chemo. For PR patients, knee rupture conferred greatest PFS benefit when initiated after more than four cycles of PT chemo. Although definitive association remains to be verified in the larger samples with statistical testing, these results may be of interest to physicians as potential guidance on when to initiate knee rupture maintenance treatment. This table summarizes the TEAs that occurred in at least 20% of patients in any one subgroup. The most common TEAs were hematological events. Similar percentages of patients in both knee rupture subgroups experienced hematological toxicides. For knee rupture treated patients compared to the subgroup with more than four cycles of PT chemo, the subgroup with at most four cycles of PT chemo had higher percentages of patients who experienced hematological TEAs of grade 3 or above, except for white blood cell count decrease. Despite this observation, we could not yet conclude whether four or fewer cycles of PT chemo might be associated with a higher incidence of grade 3 or above hematological TEAs. In conclusion, similar clinical benefit was observed with knee rupture maintenance treatment after four cycles of PT chemo as compared to after more than four cycles of PT chemo. The result of this study may partially provide guidance on when to initiate knee rupture maintenance treatment to achieve maximal benefit depending on whether the patients have CR or PR. The safety profiles of the two knee rupture treatment subgroups were generally similar based on the incidence of common TEAs. The efficacy and safety of knee rupture maintenance treatment after shorter PT chemo remained to be further verified, preferably in prospective studies. That's all with this. I conclude my presentation. Thank you. Thank you. Dr. Gao, thank you very much. It's a really interesting presentation, especially to go after the molecular description that Dr. Coleman just went through, now looking more at the clinical features. I cannot wait to this next presentation. Dr. Shannon Weston is a good friend of mine, probably one of the smartest, not probably, she is one of the smartest people I know and one of the best presenters. I always know how people who are so smart and can make it so I can understand it, just show you that much more. I'm really looking forward to this. Dr. Shannon Weston. Thank you so much, Dr. O'Malley. Hello, everyone. Many thanks to the program committee and these distinguished co-chairs for the opportunity to discuss these exciting abstracts. I will say as I looked across the three presentations, I was interested in the common theme of how we can use different clinical or molecular features as biomarkers in ovarian cancer. These are my disclosures. So I wanted to quickly level set as we discuss biomarkers throughout the next 10 minutes. Our goal is to use these clinical or molecular features to help us understand prognosis. And that can be exemplified as the association of platinum free interval or stage with prognosis. Or even to potentially predict response to therapy, such as again, platinum free interval, as well as BRCA mutation predicting response to PAR. And I plan to return to this figure after discussion of each abstract to help us put these data in context as presented today. So first, Dr. Manning-Geist and her work profiling low-grade serous ovarian cancer using the MSK impact test. Now this savvy audience will know that low-grade serous is a unique entity characterized by younger age of diagnosis, relative chemo resistance, and longer survival as compared to high-grade disease. And when we look at the population from Dr. Manning-Geist's work, we see they generally had favorable characteristics, including a high proportion of optimal site reduction. Good job, MSK. And high levels of platinum sensitivity. It will be interesting to see exactly how this was defined, because we know that these patients can be mostly platinum resistant. And please do notice that only a small proportion of patients receive hormonal therapy and maintenance, or as an adjuvant therapy, which may be reflective of just the timing of diagnosis of this patient population. But we should consider this in context, as we know that hormonal maintenance can confer improved overall survival in this patient population. The bottom line of her work is that we are much more likely to find a somatic mutation in the MAP kinase pathway in a low-grade serous tumor as we are to discover wild-type disease. And this includes mutations in things like KRAS, NRAS, or BRAF. Now, these findings are very consistent with prior literature on this topic, and you can see here the results of a number of pathologic studies in low-grade serous ovarian cancer. And this consistency is quite reassuring in regards to consideration of the remainder of her findings. Interestingly, when exploring the clinical features, the team found that the presence of a KRAS mutation was associated with older age, platinum sensitivity, and most importantly, overall survival. So they very appropriately took this to the next level and looked at MAP kinase pathway mutations overall, and confirmed that the survival benefit was retained when they included any mutation in the MAP kinase pathway as compared to those patients with wild-type tumors. And importantly, this remained significant on a multivariate analysis, which included platinum sensitivity. So coming back to our figure, we can see that Dr. Manning-Geist has provided support for MAP kinase alterations and their association as a prognostic biomarker. Now, she did not yet explore the potential prediction of response to therapy, but we have seen some data around this, right? This has been explored in both Dr. Monk's MILO study, which compared the MEK inhibitor Vinimetinib to physician-choice chemotherapy in low-grade ovarian cancer. Although there was no progression-free survival benefit overall in the group, they did observe an important finding in the approximately 30% of patients who exhibited KRAS mutations. In that group, there was a clear progression-free survival benefit to the use of Vinimetinib over chemotherapy. Now, we're eagerly anticipating the upcoming GOG281 publication to see if this finding is confirmed with the MEK inhibitor Trimetinib. Now, as I transition to the next two abstracts, we'll turn to PARP inhibition. Now, this group knows that the expectation for PARP inhibitors to work in patients with homologous recombination deficiency was based on the idea that inhibition of PARP leads to the accumulation of double-stranded DNA breaks. These breaks would not be able to be successfully repaired in the setting of homologous recombination deficiency, thus leading to genomic catastrophe and cell death. Now, we anticipated that any aberration in the homologous recombination pathway would yield similar results to what we observed in BRCA mutant tumors. However, you all know that has not necessarily been the case. And Dr. Coleman's study further supports the idea that not all homologous recombination gene aberrations are created equal. Now, this study was a subset analysis of ARIEL3, which you all remember was a study that took patients with platinum-sensitive ovarian cancer and randomized them between rucaparib and placebo. And it was an all-comers population, regardless of biomarkers. And they demonstrated a clear benefit in the intention to treat population. Now, for this study, the team has teased out a group of so-called exceptional responders, as defined by progression-free survival, for more than two years, and then compared them to a group with rapid progression. Their findings confirmed several clinical features we know are important, including lack of measurable disease, complete response to last platinum, and platinum-free interval greater than 12 months. Now, to set up their molecular assessment, they used existing data from an analysis of the ARIEL2 rucaparib single-agent study, and this directed their exploration of both genetic and epigenetic features in that exceptional responder group. Now, Dr. Swisher and colleagues recently published these data, which demonstrated that patients with either RAD51C or RAD51D mutation, or the presence of BRCA1 hypermethylation on a recent biopsy, had a similar outcome from rucaparib to those patients with the BRCA mutation. So, either they had those mutations, or the presence of recent BRCA hypermethylation. It looked just like they had a BRCA mutation. Now, importantly, this benefit was not found in tumors with BRCA1 hypermethylation only on archival tissue, which indicates that methylation status can evolve, and is potentially important in the prediction of benefit. So, in the current analysis of ARIEL3, it's no surprise that BRCA1 and 2 mutations were enriched in the exceptional responder group. Further, they confirmed the importance of RAD51C and RAD51D mutations in those patients that were BRCA wild type. Now, conversely, tumors that had low levels of loss of heterozygosity, indicating the presence of homologous recombination proficiency, were enriched in that rapid progression group. And intriguingly, they demonstrated again that archival BRCA1 methylation was found in equal numbers across both the exceptional responders and the rapid progressors. Again, this emphasizes this marker really seems to be needed to be obtained in real time in order to predict benefit from PARP. An additional intriguing finding from this subset analysis was that the different types of BRCA mutation appeared equally represented in the exceptional responders group. And this included both BRCA1 versus BRCA2, germline versus somatic, and type of mutation such as missense or nonsense. Now, the numbers precluded any statistical analysis, but certainly this is an interesting finding. Now, in general, we've seen similar results in subset analyses of other second line maintenance trials. Only SOLO1 demonstrated a slight difference in outcomes between patients with BRCA1 and BRCA2 mutation. Now, it's important to emphasize that both groups did benefit from alloperate maintenance, and the study was not powered to compare the outcomes between these two groups. Ultimately, with that benefit in both groups, it was unclear in this difference in the hazard ratios of 0.41 and 0.20 was really simply due to a lower number of patients with BRCA2 mutations or a potential imbalance in the prognostic features. And similar to the current study within AREAL3, low numbers truly limit any meaningful statistical analysis. So back to our figure, we find support of previously identified clinical features and prognosis, and more support for the potential of PARP inhibitors to confer a similar benefit in RAD51C or RAD51D mutant tumors as what is expected in the BRCA mutant population. Finally, we turn to the study of Yunong Gao and her colleagues, who performed a subset analysis on the NORA trial. Now, this study initially randomized patients with a platinum-sensitive recurrence to norepirib or placebo maintenance. And the authors wanted to explore in this subset analysis if the prior number of chemotherapy cycles was associated with benefit or lack of benefit from this agent. Now, certainly, clinical characteristics, including presence of BRCA mutation and response to therapy, were appropriately explored. And interestingly, they found a higher proportion of complete response in the group that had less than four cycles and higher platinum sensitivity in the group with more than four cycles. But the bottom line, there was no difference in progression-free survival benefit between the two groups based on the number of chemotherapy cycles. But because of these findings and their interesting difference in the clinical characteristics, they then explored their primary objective after selecting based on response to platinum-based therapy or separating out those responses. And they found an intriguing trend that perhaps patients with complete response benefit more from a sooner transition to norepirib, while the patients with a partial response seem to benefit from more chemotherapy prior to norepirib. Now, a word of caution on this, the numbers get awfully small in these groups as the time passes. And it's unclear if this is more a reflection of our clinical practice, where patients generally get more chemotherapy if there's still measurable disease, and maybe we feel a little bit more comfortable transitioning to maintenance earlier when patients have had a complete response. Back to our figure, it does not seem that the numb chemotherapy cycles had a diagnosis in this population, and the jury's still out. We need a little bit more data to determine if response to therapy should be considered in our decision when we transition to interoperative maintenance. I just want to congratulate all the authors on their great work. These types of studies are exactly how we're going to generate new hypotheses and clarify clinical questions. I will caution, we must be clear on the goal of our biomarker studies, and then prepare to validate these findings in a prospective manner in order to truly move the needle on this disease. I'll thank you all for your kind attention, and to the group for allowing me to work on these excellent abstracts. Dr. Weston did not disappoint. Wonderful distillation, as always, and learned so much. We're now going to have a discussion. We have about 15 minutes for questions. Go ahead, and our presenters, please join us back on camera. I see Dr. Coleman, Dr. Gao, and Dr. Manning-Geist. Wonderful. My first question, and Dr. Weston just alluded to this, to Dr. Coleman. Dr. Coleman, is it time we start talking about RAD51C and D in the same breath as BRCA1 and 2 with regards to our management? I know it's a lot smaller numbers. As a follow-up, are there other mutations that we have that type of data that we should be considering it in our management of patients with ovarian cancer, specifically the PARP? First, let me say I love your passion in the question. Yes, Dave, I think that- No brains, but plenty of passion. Lots of passion. Lots of passion. I love it. It's a very important question to address. I think that we have learned a lot more about these specific mutations. This work goes back now more than about six or seven years where we tried to isolate individual mutations and see what their impacts are on the homologous recombination machinery. I don't think we've actually completely sorted it out, but it is absolutely clear, and we've seen this not only for RCAPRIB, we've also seen this in studies that have been done with the LAPRIB and the RAPRIB for patients that have been treated with those PARP inhibitors, that the genes, the connection between loss of heterozygosity, for instance, and mutation on these specific genes that Shannon showed in her distillation are disconnected. Some of them are highly associated with them, and some of them are not. What we don't know to the degree that we can test is what interactions necessarily are important. In other words, can you have two mutations, let's say in ATM and a Fanconi gene in the same tumor that actually does independently don't lead to an HR deficient state, but the combination does? These are the focus of the strategies that are looking at different types of inhibition of those particular activators in homologous recombination deficiency. That's work still to come. I would say that when you, and I have seen this personally, when you see a patient who has actually a mutation in RAD51 CRD or a germline RAD51 CRD patient, those patients are sensitive to PARP inhibition. Yeah, and I think coming back to some of the things Dr. Weston said with regards to our LOH testing and our genomic instability, and Dr. Weston, please chime in, Dr. Kazan, please chime in. I want to think about that as what are the best testing? We need to get better at our testing. I want to go to now Dr. Manning-Geist and wonderful work that you've done here and at Memorial Sloan Kettering on low-grade that continue to be one of the leaders in the world on low-grade cancer. At which point, recommend to the group here, we have a couple hundred people on, when should we be doing testing on low-grade and what type of testing? Should we be doing germline on everybody? Should we be doing somatic and germline? Tell us what you're doing and what you would recommend after evaluating this data. Sure, thank you for the question. I think that the jury is still out on the germline testing. As I alluded to in the presentation, we were a little bit surprised to see a lack of BRCA mutations seen in the germline analysis of our patient population. Dr. Norquist has previously published on this and I think cited about a four out of 70 patient rate of BRCA1 and 2 mutation. We're going back and looking to see if there's some sort of ascertainment bias or something else that might be in fact driving our observations here. Certainly our patient population is enriched, as I mentioned, for Ashkenazi Jewish women. I don't think right now that there's enough data to validate straying from the NCCN guidelines that do still recommend doing germline testing in all women with epithelial ovarian cancer. I think we've seen certainly a push to start doing that, especially as targeted therapies emerge for these patients. In terms of somatic testing, Dr. Weston kind of mentioned how many of these studies can be hypothesis generating. I think this came up a little bit as we start to think about molecular changes in endometrial cancer too and how that might drive treatment. I think we need the data in terms, I guess, we need the data to generate the hypotheses. For some of these patients, we can start to associate map kinase pathway alterations with outcomes or things like this, but as we advance therapies, as we think about MEK inhibition and what line of therapy this should be used in, as we think about hormonal maintenance and should this be used instead of platinum-based chemotherapy for some of these women, we certainly need the data in order to answer these questions and start generating safe and good prospective trials for these women. I'd advocate for early on. I think that is absolutely what we need to continue to definitely test somatic on this. It's a predictor. Then what's the next trial after we answer the question on hormonal therapy? Is it going to replace chemo? Are we talking hormonal and MEK in these patients, especially in those that are mutated? I think, Dr. Dzong, you had a question. This is actually for the entire panel, just trying to harmonize. It's actually going by Dr. Weston, your biomarker slide from Dr. Cohn. We know that platinum sensitivity seems to be a predictor for response from PARP inhibitors, but we also know that the the lack of HRDD mutations, methylation status, as we've just shown in now two, RL2 analyses can also predict for that. What's the role of PARP inhibitors outside of high-grade ovarian cancers? Would you use it, Dr. Manning-Geist, in low-grade seroset as platinum sensitive, for example? I'm going to ask, I would like the opinion of all five of you on the screen on that one question. Again, the FDA approved for all of these is not restricted to high-grade tumors. This has been a question for significant debate in our community. I ask the question, Dr. Manning-Geist, if you want to start. I don't think the prospective evidence that we have right now really justifies use of PARP inhibition in patients outside of high-grade seros and maybe high-grade endometrial, excuse me, endometriate ovarian cancer. However, that being said, of course, you know, any therapies that we can introduce for a patient population that develops a kind of recurrent chemo resistance over what can be a long disease course is helpful. So right now I'm not necessarily convinced that PARP inhibition is justified in these platinum sensitive women. Certainly we had a higher percentage, as Dr. Weston mentioned, of platinum sensitivity than one might have predicted based on some of the prior publications. But, you know, I'm not quite sure it's ready for primetime and low-grade serous cancer, but I look forward to the thoughts of the other panelists. Any different thoughts from Dr. Manning-Geist? Well, I would just add, I don't know that we have a lot of data for it, especially in the maintenance setting based on the populations that were included in the trials. But, you know, we do have some intriguing data around combinations with PARP inhibitors in patients with low-grade serous ovarian cancer that are moving. So some further trials that are moving into the NCI platform. And so hopefully we'll get some answers of, you know, whether or not a PARP inhibitor in combination with, say, a MEK inhibitor could yield better response and progression-free survival in that disease. So I don't know about the single agent, but I am intrigued by some of the combination strategies. Yeah, I look at this as a, you know, as a modality-based treatment and the modality or a context-dependent treatment. So in other words, the context here is homologous recombination deficiency. So you asked about it, how does this apply into other tumor types? Well, one of the first things that we need to determine is whether or not HRD status, if we can determine it, you know, accurately, does that actually reflect a biological element of the tumor? So whether it's lung cancer or pancreas or, you know, bladder or clangial or ovarian or endometrial or low-grade serous, if it's, if HRD is relevant to biology, PARP is a good tool because PARP actually takes advantage of an endogenous tumor-based deficiency. It's not a direct tumor target. And I think what Shannon and Dr. Weston is alluding to is that are there situations where we can break other components of the machinery where then PARP becomes relevant? And I think that would be another opportunity, Don, as you mentioned, to kind of broaden the spectrum. But I think we've got to get away from thinking about this as just an ovarian-specific treatment and think about it as a treatment for a contextual impact or a contextual situation where a tumor is actually dependent on a homologous recombination deficiency and can be leveraged. Interesting. Dr. Gao, I think that's a great segue into your work, which is, you know, we kind of looked and say, well, if you get a CR after four or less cycles, you're going to do better. So what is our best predictor? This is not the question. I will say one of our best predictors beyond BRCA, maybe now Rad51-CRD, about PARP response is exquisite platinum sensitivity. And Dr. Coleman also showed this, right? So we all know that we, well, let me rephrase that. We know that once the patient has recovered, answering a question in the chat, once a patient has recovered from the hematologic and other toxicities of the chemotherapy, we then reintroduce, we then introduce the PARP in the maintenance strategy. But my question for you, Dr. Gao, should we in the platinum sensitive introduce PARP maintenance once a patient has obtained a CR? Let's define that as clinical and serologic CR. Is that when we should be introducing the PARP rather than going to four or six or eight cycles? I think this is a very good question. I think in the clinical work, once that started, the maintenance treatment is very important. So you know, you mean the CR, the four cycles is not enough, but in clinical work, we want to start the maintenance treatment earlier, initiate it, and use the maintenance treatment. But CR maybe is not enough to the platinum sensitive patients, but the PARP inhibitors have some treatment, treatment, treatment, treatment. So maybe, according to the SOLA2 or study 19, give us this situation, maybe the PARP inhibitors can be a long treatment for this patient. Do you agree with my opinion? Yeah, no, I think, you know, I'm literally about to see a patient who's gotten a CR and she's at, I think, cycle five. And after looking at your data, I think I'm going to talk to her about PARP and not giving that six cycle additional fatigue, hematologic toxicity. We have another minute or so. Anybody else want to add to Dr. Gao's answer? You mean the full cycle is not enough for the platinum sensitive patients? You mean, is that your means? I actually think it means, Dr. Gao, what if they have a complete response after just two cycles? Yeah. Can you just start it after two cycles of chemo? Or do we think that there's actually a threshold by which there's a minimum amount of platinum people need to use before you start the PARP? I think it's an intriguing question. I just want to, at the MD Anderson in the breast group, they did a study of a PARP inhibitor as neoadjuvant treatment in breast cancer, no chemo, just talisoperin in breast cancer. And they saw a really high pathologic CR rate with talisoperin alone, as long as someone had a BRCA mutation. We're actually doing that study at Brown. I was going to say, I can see. It's great. I stopped the chemo. The chemo is too high into the patients. So we want to start the betterness treatment as the early, so we do according the study, the previous clinical studies. So we less the chemo cycle, less and less. We want to start more maintenance treatments. I think outside of molecular testing, for me, it's a much easier decision if I know that BRCA. But it's that patient who doesn't have a molecular marker and or unknown as the clinical marker of platinum sensitivity. Well, we're at the bottom of the hour. Dr. Desan, please take us away. I want to just thank everybody for the wonderful discussions that we just had. And thanks to the presenters for the outstanding studies. So before we close the session, we're going to bring up some slides, because I have the honor of announcing the winners for the IGCS social media contest. So IGCS has been promoting these contests for the last few weeks, and the winners will receive their choice of a complimentary registration for IGCS 2022 in New York, New York City, or one year of free IGCS membership, which comes with a subscription to the International Journal of Gynecologic Cancer. For the photo contest, each day, two photos were selected that best portrayed how attendees were experiencing the meeting. And it was fun to see how all of you were sharing your experience, albeit in a virtual environment from either your home or your office. So next slide. We can move to the next slide. Perfect. So the winners were Emma Allenson from Australia, and Jay Girmar from the Philippines. And their pictures are here. Next slide. This is the day one winners. And here are the day two winners. It was apparently Take Your Child to IGCS Day. The winners are Juliano Rodriguez from Colombia, and Dr. Ram Imperial-Anglao from the Philippines. Next slide. Here are day three's winners. Directors Reikhan Bolatbekova from Kazakhstan, and David Aktala from Lebanon. So nice to see people coming together to watch the sessions. And I just want to point out, look how safe they're being with their masks. Next slide. Correct. Nice. Love it. Just FYI, the winners for today will be announced on social media later on today after the live sessions are done. And with that, just remember, and Dave O'Malley, this might be for us, there's still time to tweet your photos. Next slide. Thank you. That is great. The top influencers are the delegates who tweeted our hashtag IGCS 2021 the most often for the past few weeks. Here are our winners, Dr. Fernando Hidalgo from Venezuela, Dr. Thales Paolo-Batista from Brazil, and Dr. Christina Ewens from the UK. Thank you for the great dialogue you brought to Twitter. And for those of you who won, the IGCS team will be in touch if they haven't already. So congratulations. Next slide. Thank you. Let me just plug the IGCS's social media accounts. Make sure to like, subscribe, and follow for the latest updates from our society. We are ready to wrap up here. And IGCS has a couple more hours of context for you today. So please stick around. Coming up next in this hall will be a debate on the controversies regarding sentinel lymph nodes in endometrial cancer. Hall two will feature a session on gender and cancer care. And hall three will include a session on pre-invasive disease of the lower genital tract. Immediately following those sessions will be our two final industry-supported symposia. You really will not want to miss them. For Dr. O'Malley and this esteemed group of presenters, thank you once more for joining, and please take care. Thanks, John. Thanks, guys. Great job. Okay. Take care, guys.

ovarian cancer

genomic profiling

low-grade serous cancers

MAP kinase pathway

platinum sensitivity

Rucaparib maintenance treatment

BRCA mutations

Niraparib maintenance treatment

chemotherapy cycles