But what we're going to do is we're going to try to go fast through the things we can go fast through so we don't take away from the conversation. Dr. Letterman will join me after the presentations. And what I will do is when I give the presentation, when I introduce the speaker, I'll actually read the title on their way up. So if the speakers could do me a favor and not repeat their title, we'll save a couple seconds anywhere we can. Because I know what's between us and drinks on the roof are these two sessions. So we're really excited for a robust panel. And we've got to figure out what we're going to do with the parts. Our first speaker, the five sessions are seminal sessions. They were presented at other meetings, but they are tremendously important. So we need to represent them here. Our first speaker is Dr. Bradley Monk. He'll be presenting Athena Mono, a randomized double blind phase three trial evaluating recapitative monotherapy versus placebo as maintenance treatment following response to first line platinum-based chemotherapy in ovarian cancer. Brad? Thank you, Brian. I hope you're all enjoying New York. I've been having a great time. A little tired, I think, because I've been having too much fun, if you know what I mean. But I'm hanging in there. These are my disclosures. They have not changed since yesterday. So I think all of you are aware of Athena. Athena was an international randomized phase three trial of PARP recaprib versus placebo in patients with newly diagnosed advanced stage three or four high-grade ovarian cancer who responded to platinum-based chemotherapy. Now, this is part of a bigger trial, where in Athena Mono, recaprib was the experimental arm, and Athena Combo, which will be reported at another date, recaprib is the control arm. So this is now Athena Mono, 100 or so patients, and I'll show you in the placebo arm, and 400 patients in recaprib, which will be compared to about 400 in the nivolumab recaprib arm. So I'm here to talk about the first and second step down. The first step down is HRD. We'll talk about that, and then ultimately all comers. And I also show some hypothesis-generating subsets. Ultimately, we will get to overall survival. Studies well-balanced. I point out to you that there were fewer, I don't know if I have a pointer here, fewer BRCA patients than most of these other studies. Many of our other studies have a 30% BRCA rate, because solo one was available. There were patients that were getting solo one in the community, so it was only about 20%. I also point out to you that you say that HRD positivity is about 50%. It's not. It's about 43%. It's true. It's equal to the negative rate, 43%. But there are unknowns here, about 14%, 10% to 15%. And those unknowns act more like HRD, because the reason they're unknown is because we send necrotic tumor where platinum is working, and that's a surrogate for homologous recombination repair deficiency. So again, well-balanced, 20% BRCA here, and about 43% HRD. So the primary endpoint was published in the Journal of Clinical Oncology the same day it was presented on June 6th. Really, the largest number numerically that we've seen, not that we do cross-trial comparisons, but a 28.7 versus 11.3 months with a hazard ratio of 0.47. And when you step it down, you get a 0.52 hazard ratio with 20.2 versus 9.2, still more than double. Some of the other studies in the frontline space have a Bicker endpoint. Primary endpoint of Athena was Investigator PFS. So in the publication which you can refer to are the Bicker, if you sort of want to inferentially get a sense of how they sort of stand up but not compare to similar studies. Subgroup analysis, I point out to you the HRD test negative where the hazard ratio is 0.65. In the Blind and Independent Central Review, if you want to do sort of some inferential, it was 0.60 with a 5.6-month improvement in progression-free survival. So in these exploratory subgroups, you can see that all relevant prognostic factors trended to favor ReCAPRIT. And in the highest risk groups, these stage fours, the interval debulking, the persistent disease or those with an elevated C125, the hazard ratios were even more favorable. The discontinuation rate due to treatment of emergent adverse events was 12%. And so this study showed now that progression-free survival is improved like other PARP inhibitors in this setting except this now is the second PARP inhibitor that shows a treatment benefit in the non-HRD subset. We're gonna talk about overall survival, how that's important. A quarter of the patients unfortunately have passed and there is no decrement, if we can say that, in the survival status. So I wanna acknowledge all of you, many of you participated. And this study is ongoing, right? Because Athena Combo is coming and hopefully with the synergy between checkpoint inhibitor nivolumab and ReCAPRIB, there will be an additional treatment benefit. So this study was filed both in the EMA and in the FDA environment two and a half weeks ago on September 13th. So hopefully this will be coming to the clinic soon. Thank you for having me. Great, thank you. Thank you very much, Brad. And I failed to mention, unlike the other sessions, I'm actually gonna keep everyone on time. So Brad, you got 15 seconds, you saved us. So thank you for that. Our next abstract is gonna be presented by Dr. Isabel Ray Cucar, a dear friend. She's gonna present the final overall survival results from the phase three PIOLA study evaluated trial, evaluating maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced ovarian cancer. Isabel. Okay, thank you very much. On behalf of my colleague, this is my disclosure. I just would like to remember you the PIOLA-1 trial. The patient who are included in this trial are patient with an high-grade ovarian cancer with platinum-based chemotherapy, adding bevacizumab as a standard of care. They were in response to the first-line treatment before to be randomized to receive olaparib or placebo for up to two years, and bevacizumab was administered for 15 months. The primary endpoint were the PFS, according to investigator, and PFS-2 and overall survival were key secondary endpoint. In the primary analysis of the PIOLA-1 trial, olaparib plus bevacizumab demonstrate a significant PFS benefit over placebo plus bev, mainly in the HRD-positive population. The overall survival analysis was anticipated to be delivered three years after the primary PFS analysis, or with 60% of data maturity. We today present the final overall survival analysis in the ITT population, whereas in the pre-specified molecular subgroup, three years after the PFS analysis, with 55% of data maturity. In the ITT population, the olaparib plus bevacizumab maintenance report a median overall survival of 56 months compared to 51 months with a placebo plus bevacizumab. A statistically significant benefit was not observed in the ITT population. Also, we have to note that close to 50% of the patient in the control arm receive a PARP inhibitor as a subsequent therapy. If we move in the HRD-positive population, our current label, the olaparib plus bevacizumab maintenance report a median overall survival of 75 months compared to 53 in the placebo arm. If we look at the five years overall survival rate, 65% of the patient with the combination are still alive at five years compared to 48%. Also, we have 50% of the patient who cross over to a PARP inhibitor in the placebo arm. This means that this combination prolongs the overall survival and provide a 38% of risk of reduction of death using the combination compared to the monotherapy. The US benefit observed in the HRD-positive population was observed regardless of the BRCA mutation status. In the BRCA-mutated population, at five years, 73% of the patient were still alive with the combination compared to 53 with the monotherapy, translating in a 40% reduction of the risk of death with the combination. In the HRD-positive population, excluding the BRCA-mutated population, 55% of the patient were still alive at five years compared to 44 with the monotherapy, translating in a 29% reduction of the risk of death with this combination. In the HRD-negative population, we did not observe a benefit adding Olaparib to Bevacizumab. Also, we have to note the worst prognostic of this population compared to the other group. All the patients stopped the treatment at the time of the PFS2 analysis, but we continue to monitor the adverse event of specific interest, and with a longer median follow-up, the rate of myelodysplasia, leukemia, and the incidence of new primary malignancy remain low, and there is no difference between both arm of treatment. To conclude, in the PARLA-1 trial, also 50% of the patient in the control arm receive a PARP inhibitor post-progression. The addition of Mantenol-Solaparib to Bevacizumab provide a clinically meaningful benefit in the population of patient with an HRD-test positive. This clinically meaningful benefit was observed in the HRD-positive patient, regardless of the BRCA mutated state. There is no overall survival difference observed in the HRD-negative subgroup. No new safety signal was observed with a long-term follow-up, and the incidence of myelodysplasia, leukemia, and new primary malignancy remain low and well-balanced between both arm. Finally, this data confirmed the addition of Solaparib to Bevacizumab as a standard of care in the HRD-positive patient in this setting, and the importance of precision medicine and biomarker testing to give treatment decision in newly advanced ovarian cancer. We would like to thank all the patient family and investigator who participate to PARLA-1 trial. Thank you very much. Thank you, Isabel, and Brad, I know you're very competitive. She actually saved us 25 seconds, while you only saved us 15, so you lost on that one, sir. Next, it gives me great pleasure to introduce Paul DeSilvestro. He'll be presenting the seminal abstract, overall survival at seven-year follow-up in patients with newly diagnosed advanced ovarian cancer and a BRCA mutation who received maintenance Olaparib in Solo-1. Paul? Thank you, I'm going to bring it home a minute early. All right, these are my disclosures. As you know, women with advanced ovarian cancer at higher risk of relapse with only about 17% alive after 10 years, relapse is commonly fatal, so it highlights the need for having effective frontline therapies that reduce relapse, increase survival, and enhance potentially that of cure. The Solo-1 trial enrolled 391 women with high-grade serous or endometrioid advanced ovarian cancer and a BRCA mutation. Patients were in clinical response after undergoing upfront platinum-based chemotherapy and surgery. Their arms were well-balanced. Patients were randomized in a two-to-one ratio to maintenance Olaparib versus placebo and treated for two years or until progression, whichever came first. Overall survival was a pre-specified secondary endpoint. In the initial analysis in 2018, maintenance Olaparib produced a 70% reduction in the risk of progression or death as compared to placebo, and in a 2020 updated analysis at five years after last patient randomized, the median progression-free survival was identified as 56 months versus 13 in the placebo arm or hazard ratio of 0.33. This descriptive overall survival analysis was performed seven years after the last patient was randomized and unadjusted for subsequent PARP inhibitor therapy. Given the descriptive nature of this, the alpha spend was very restrictive with a p-value of less than 0.0001 required for statistical significance. I will note that the pre-specified overall survival analysis and protocol is set to occur at 60% data maturity. Results show that the median overall survival in the Olaparib arm has not yet been reached versus 75 months in the placebo arm or a 45% reduction in the risk of death with 67% of women in the Olaparib arm alive versus 46% in the placebo arm seven years after the last patient was randomized. This is, it's also interesting to note that 44% of patients in the placebo group received subsequent PARP versus 14% in the Olaparib group. Time to first subsequent therapy, which is really another indicator of progression-free survival, favored maintenance Olaparib with a highly significant hazard ratio. This is interesting in noting that with 45% of women in the Olaparib arm yet to have received a subsequent therapy, this represents the majority of women actually still alive in that arm of the trial. Time to second subsequent therapy also favored maintenance Olaparib and indicates a prolonged benefit even beyond the first subsequent therapy. There were no new safety signals identified. So along with survival data, data regarding safety events such as MDS and AML and second, excuse me, a new primary malignancies have been followed. There was one case each of MDS or AML in each of the arms of the trial since the 2018 analysis. In terms of new primary malignancies, they're well-balanced, breast cancer being the most common in this at-risk population. So in conclusion, SOLA-1 is the first study to demonstrate a clinically meaningful, albeit not statistically significant due to alpha assignment improvement in overall survival with PARP inhibitor maintenance monotherapy in the first-line setting. The hazard ratio was 0.55. 67% of Olaparib patients are still alive versus 46% in the placebo arm. This was seen despite over 40% of patients in the placebo arm receiving a subsequent PARP inhibitor treatment. It is also noteworthy that with a 60% data maturity required for the overall survival analysis, it's going to be many years. This overall survival data maturity was 38% and events are infrequent. Time to first and second subsequent therapy favored maintenance Olaparib over a placebo. These seven-year results further provide confirmation that the benefit extends obviously well beyond the two-year treatment cap. Is this on? Can you hear me? All right, anyway, so there are no new safety signals identified. We lost the mic guys in the back. And the results obviously support the use of maintenance Olaparib in this setting to achieve long-term remission and enhance the potential for cure. Thank you. We keep getting better, that was 35 seconds, thanks Paul. Next up, Brad, third out of three isn't that bad. Next up, can you hear me? Next up, we have Dr. Amit Oza presenting overall survival results from the Phase 3 Arial 4 versus chemotherapy in patients with advanced relapsed ovarian cancer and a deleterious BRCA1 or 2 mutation. Amit? Thank you so much. These are my disclosures. So I'm going to present the data related to Arial 4 study. Just to remind you, this was a study in patients with high-grade serious epithelial ovarian cancer, patients who had had more than two prior lines of chemotherapy and at least one prior line of platinum-based therapy. All patients had to have a deleterious BRCA1 mutation to participate and had no prior part inhibitor therapy. The randomization was 2 to 1 between Rucabarib versus standard of care chemotherapy, which was defined as weakly paclitaxel for patients who had platinum-resistant disease or partially platinum-sensitive disease or platinum-based chemotherapy in patients who were fully sensitive. The primary endpoint of the study was radiologically confirmed progression or unacceptable toxicity or death. There was a crossover that was actually built into the study and patients who were receiving chemotherapy could cross over to Rucabarib and 80 out of the 116 patients, 69% of patients crossed over to Rucabarib following completion of chemotherapy or progression from it. The pre-specified endpoints were progression-free survival and overall survival was specified in the intent-to-treat population. The overall data maturity is 70% at this time. Just to remind you that the primary endpoint, which was presented last year, was progression-free survival and the study met the progression-free survival endpoint in the efficacy population, which was defined as the patients excluding patients who had BRCA reversion mutations. It's interesting to note that then the patients who had BRCA reversion mutations identified the outcome in terms of PFS seemed to be better in terms of patients who received chemotherapy compared to Rucabarib, although you can see that all patients who had BRCA reversion mutations did fairly poorly. It's important to note a couple of things in terms of analyzing the results. First of all, there was a crossover that was built in and the proportion of patients who crossed over to subsequent therapy is highlighted here in the first bar. In terms of patients who received Rucabarib, about 40% of patients who did not receive subsequent therapy following progression. In terms of patients who received chemotherapy, the majority of those patients crossed over to PARP inhibitor therapy, either Rucabarib or other PARP inhibitor therapy. Of the patients who were treated with initial therapy, the majority of patients, when they crossed over to chemotherapy following Rucabarib, received platinum-based chemotherapy. This was evident also in 40% of the patients who received initial therapy for platinum-resistant disease. The median duration of patients staying on Rucabarib following crossover after chemotherapy was more than six months in a lot of the patients. In terms of the overall results, these are the results of the intent-to-treat population, and as you can see, that in the intent-to-treat population, patients who received chemotherapy did somewhat better than patients who had Rucabarib. The hazard ratio was 1.313. If we actually drill down at the results for the adverse overall survival, you can see that this is driven mainly by patients who are in the platinum-resistant subgroup, where the hazard ratio for patients who received Rucabarib compared to chemotherapy was 1.51. There was no significant difference in terms of overall survival in patients who were either fully platinum-sensitive or partially platinum-sensitive. PFS-2 was also analyzed, and as you can see, there was no difference in PFS-2 in patients who were platinum-resistant or fully platinum-sensitive. There was an advantage in terms of Rucabarib for patients who were partially platinum-sensitive. So in conclusion, Rucabarib significantly improved progression-free survival compared to chemotherapy in the intent-to-treat population. The overall survival favored those randomized to chemotherapy versus Rucabarib in the intent-to-treat population. The overall survival was similar in the patients who were platinum-sensitive or partially platinum-sensitive, but there was a significant advantage towards chemotherapy in patients who were in the platinum-resistant subgroup. This was confounded by a high rate of crossover. This was part of the design, and 90% of the patients received Rucabarib after randomization or crossover. It's also important to note that about 40% of patients who were treated in the Rucabarib arm did not have any subsequent post-progression therapy, and I think it's important to try and identify why. PFS-2 was similar between treatment groups in the platinum-resistant group and favored Rucabarib in the platinum-sensitive group. The safety data are consistent with previous reports, and further work is ongoing to understand the biologic basis of resistance as well as optimal sequence of therapy. I'd like to acknowledge all of the patients who participated in the trial as well as all of the investigators who carefully paid attention to accruing these patients. Thank you so much. All right. Thank you. Thank you so much, Amit. Last, but certainly not least, is our dear friend, Antonio Gonzalez-Martin, who will be presenting PRIMA, the updated long-term PFS and safety data. Antonio? Thank you very much, dear chair, for your kind introduction, dear colleagues. On behalf of my co-authors, it's my privilege to present the updated long-term progression-free survival and safety data of the PRIMA-ENGO-TOBY-26 GOG 3012 study. These are my disclosures. PRIMA study evaluated neuropathic first-line maintenance treatment in patients with newly diagnosed advanced ovarian cancer after a response to first-line platinum-based chemotherapy. In the primary analysis published in 2019, neuropathic maintenance treatment significantly extended the blinded independent central review assessed progression-free survival of the patients treated with neuropathy compared with placebo, with a hazard ratio of 0.43 for the population with homologous recombination-deficient tumors and 0.62 for the overall population. For the first primary analysis, the clinical data cut-off was done on the 17th of May 2019, with only 1.2 years of follow-up. For this updated analysis, the clinical cut-off date was on 17th November 2021, with a median follow-up of 3.5 years. As you can see in this graph, neuropathic treatment significantly extended the progression-free survival assessed by the investigator compared with the placebo in both the HRD and the overall population. The hazard ratio for the HRD population was 0.52, with an increment in the median PFS from 11.2 to 25.4 months. In the overall population, the hazard ratio is 0.66, and the increment in the median PFS is from 8.2 months to 13.8 months. The overall survival remains in measure, with 41% of events at the time of the data cut-off. In this slide, you can see that neuropathic treatment increased progression-free survival duration compared with placebo treatment across all the biomarker subgroups, with the highest treatment effect seen in patients with HRD tumors and BRCA mutated. Importantly, the long-term neuropathic monotherapy was associated with a low rate of discontinuation. Only 11 new patients have discontinued neuropathic due to treatment-emerging adverse events. There were no new safety signals. The most common grade 3 or higher treatment-emerging adverse events were hematological, thrombocytopenia, anemia, and neutropenia. And consistent with the primary analysis, the individualized starting dose implementation generally improved the safety. Importantly, MDS and AML events reported were the same in the population treated with neuropathic and placebo. It was 1.2% and it was low. In conclusion, after a median follow-up of 3.5 years, a sustained and durable progression-free survival benefit was observed in the overall population and across all the biomarker subgroups as determined by the investigator assessment. In the HRD and HRP population, respectively, we saw a clinically meaningful reduction of the risk of progression or death of 48% and 35%. Neuropathic treated patients were notably more likely to be free of progression of death at 4 years. In the HRD, from 17% to 38%, and in the overall population from 14% to 24%. Importantly, no new safety findings in terms of adverse events have been described. So I would like to summarize saying that these data demonstrate that neuropathic as first-line maintenance treatment provides durable and long-term remission in women with newly diagnosed advanced ovarian cancer who were at high risk for relapse or progression or death after the platinum-based therapy. I would like to finally sincerely thank the patients, their families, for their participation in the trial, as well as the investigators and the cooperative groups for the commitment with the trial and with the patients. Thank you very much for your attention. Thank you very much. I failed to mention, of those five trials, four were NGUT trials, three of them were GOG trials, so we're really proud of our friendship that we have with our colleagues in the GOG and NGUT, and everyone else, so thank you for outgrowing. Next, now this is the fun part. First, I'd like to introduce Dr. Jonathan Letterman from the University College London Cancer Institute. He is going to serve as my co-moderator. In fairness, he did most of the work with the questions. My job was to hold up the clock. And now I'd like to invite our distinguished panel. In addition to the five speakers, I would like to invite Dr. Robert Coleman, Dr. Thomas Herzog, Kathleen Moore, and Mansoor Meezer to the stage for our large panel to really address this issue and hopefully come up with some answers. Okay, thank you. Well, good afternoon, everybody. That was really a tour de force, and I'd really like to thank all the speakers again for excellent presentations and keeping to time. So we've got a lot of people and a lot of questions, and it's my job with my co-chair to keep order. Fortunately, they're all my friends, so if I tell them to stop talking, hopefully I'll still be their friends. But I'm going to, when they've found their places, we're going to start the questions. We've got about 40 minutes because we are over time, but we still have, we're going to borrow some time. I'm going to start with Isabel Rekokar. Isabel, I just want to ask you about the importance of bevacizumab. Is it still important that we have bevacizumab when we use PARP inhibitors in that BRCA wild type HRD population? This is an interesting question. Thank you so much. Just to remember that in this group of patients with an HRD positive test, the combination report risk of reduction of the death of 40%. So that means that if we don't have a control arm with olaparibulone, I can't be able to answer directly to this question. If we move to indirect comparison with BRCA population, for example, where we have SOLU1, we have seen that the population of PARLA1 is not exactly the same. We have much more stage 4, more patients with partial response, more patients with residual disease, more patients with interval debulking surgery or no surgery. So it's very complex to answer to this question. We see some advantage when we have done the population adjusted comparison in this group of patients, but we did not do it in the HRD positive BRCA wild type. So to conclude, we need to develop a randomized phase 3 trial on this question, and it is ongoing in the stage 3 with no residual disease upfront surgery with the GYNECO group and also the trial with the AGO group ongoing, exploring the addition of BEV to niraparib in this population. Thank you. Thank you. My next question is to Rob Coleman. Having seen the updated data from Prima and the data from Athena, is that sufficient to recommend PARP inhibitors in the HRD negative or sometimes called HRP population? God, you would give me that question. Is it enough? You know, ultimately, that decision will be taken out of our hands, I think. I'm going to cop out on for the regulatory environment because that's really going to be a regulatory thing. You know, I think that none of the trials actually formally assess that patient population, so we don't really have an analytical vision of that patient population, which makes it really difficult to make recommendations. My personal bias is that PARP inhibitors probably have limited activity in truly well-characterized HRD or HR compliant tumors, and in that population, typically, we'll use BEV. I think our testing is imperfect, so right now, we see results across the trials in the HRD test negative cohorts, probably most notable in Athena, where we have poor annotation of, I think we have poor representation of what's actually going on in that HRD unknown cohort. But, you know, ultimately, a lot of us feel that platinum sensitivity is a biomarker for PARP sensitivity and for patients who have visible tumor that went away on chemotherapy with platinum and has an HRD test negative signature. That may be somebody I would consider it in. Okay, thank you. Turning now to Antonio, I'd like to ask you about the overall survival in Prima because this was a group of patients who were selected really as being poor prognostic group, having neoadjuvant chemotherapy, residual disease after surgery, yet we've not reached the point where we can see an OS analysis. How is that the case, and when do you think it's going to happen? Thank you, Jonathan. I don't have the crystal ball, but I can say that when the cutoff data was one year ago, November last year, and at that time, the maturity was 41% of events. So, hopefully, in one year and something, we will have 60% of event needed for the final overall survival analysis. I guess that we will see the same results that we have seen in the HRD positive population. There is no single reason to think that Neuroparif is not going to work as Olaparif in the BRCA population or Olaparif plus Bev in the HRD positive BRCA wild type, and the uncertainty will be put in the HRP population. We don't know what will happen. The only difference between Prima and the trials in the relapse is that the patients have received only one line of platinum, and they had an excellent response, and that's different to the trials in the platinum sensitive. Thanks. My next question is for you, Brad. I mean, given that we've seen positive results from progression-free survival in both Prima and Athena in the HRD negative or HRP population, do we need to bother to test for HRD, or should we just be giving PARP inhibitors to everybody? Yeah, thank you for that. Finally, I got an easy question. I think, yes, we need to test. I just want to comment, though, about this Bevacizumab issue. The beauty of Bevacizumab, if they're HRD test negative, you continue the Bevacizumab. So, I agree with the Bevacizumab. Now, whether you stop it if they get a BRCA, I'm not sure, but Bevacizumab makes a lot of sense, particularly with the high incidence of neoadjuvant, and to your point, Antonio, what happens, we're following Prima during COVID, and there's dropout. So, let's just say there's 20, and we saw what Mansour, how difficult it was to follow patients in NOVA. So, let's say that 20 are lost to follow-up in Prima. Then, we should say then the event rate should be 80 percent of 60 percent, which is 48, which is where we are today. So, I think there's some controversy in all these points, and thank you for asking me a good question, an easy question. The answer is, yes, test for HRD, of course. Okay. So, Dr. Slomovitz is telling me that we have a little bit of time to do a little back and forth, so now we get a chance to spice it up a little bit. So, Isabel, I want to go back to your comment. So, again, getting back to Bev, in some of those subgroup analyses, which, you know, of course, we all look to, love to see, and then if it aligns with our personal bias, then we believe in them, and if they don't, we don't believe in them. You know, we looked at the high-risk, low-risk cohorts in PALA-1, right, and we showed that in the patients who had low-risk disease, we had this phenomenal hazard ratio of less than 0.2. So, should we be using that criteria of, quote, high-risk to put our patients on Bev so that they have the option of getting, I mean, of low-risk, so that we can give them the combination in the maintenance? This is an excellent question. As you mentioned first, the low-risk versus higher-risk was a post-hoc analysis. Of course. And we know what is the reality of the post-hoc analysis. When we've done, again, the same analysis in different populations, we don't see exactly the same, and what we have seen in PALA-1 is that in the lower-risk group is the population where we see the best result of the combination. That means we don't have to move into subgroup analysis. Go ahead. Rob, I want to pick you on the answer you made. You mean pick on me. Pick on me. Yeah, thanks. That was in Danish. So, you said that we have now three trials showing positive results in the HR-proficient or HRD-negative disease. We have Prima, Antonio sitting here. We have Brad very nicely presented that, Tina. And we have the Chinese prime trial. All three has shown clear benefit on that, and the hazard ratios are at least 0.65. And if you look at prime trial, it's much, much stronger. And then you say that you would still use Bevacizumab. Why are you married to Bevacizumab? Because, I mean, that was a very slim difference you had, and those were the real banana curves. And you see some of these long-term efficacy in the PARP trials, and you have three randomized trials. I know that you cannot say that it's because it's not analytical. You don't want to do that. It was analytical in the prime trial, at least, HRD-negative. But was it analytical in GOG218 or ICANN7? It was not. So, why would you prefer Bevacizumab over PARP inhibitor? Is John Chan here? John Chan came up to me today and says, Monk, congratulations on the survival advantage of 218. He says the non-analytic endpoint is less than 1.0, and that's a survival advantage according to the FDA. Non-analytic, right? And I'm like, John, really? And the hazard ratio is 0.62. This is where it gets messy, right? So, we're talking about a study done from 2007 to 2009, and then published in 2011, well before we had any HRD signature annotation. But it was an analytical endpoint for an unknown biomarker population in 218 and in ICANN7, both of which showed PFS advantage that was statistically significant. None of the trials we've been talking about have a curve that doesn't come together, the banana curve, as we say. In the PARP trials, where they're using the non-analytical HRD test negative cohort. So, I just go with what the science is. The other thing is, I want to know why, you tell me why, why these homologous recombination proficient tumors are going to respond to a PARP inhibitor. Because our test is wrong. And because our test is wrong, so why would you like to say to a woman who has HRD of 38, that you are not going to, or 40, you are not going to receive PARP inhibitor, but the one who is in 42, you will give PARP inhibitor. That makes no sense. Agreed. Agreed. I totally agree with you. So, that comes back to my point to Brad, why bother to do the HRD test, why not give it to everybody? Exactly, we don't believe it. Yeah, because we don't like it, right? Just one point. We are in the first line sitting. It is the only opportunity to cure the patient. Why we have to choose? We have report positive effect in the overall survival with the combination of Olaparib plus Bev. I'm with you. And that's an analytical endpoint. Your ITT population was an analytical endpoint. So, Katie, moving on, looking to you as, looking into the crystal ball, you're a person who can do that. What do you think is going to happen with longer follow-up in the HRD positive BRCA wild-type group in Paola? Are we going to see the sort of survival improvement that Isabel showed continue, or what's going to happen? Yeah, that's a great question. I think, I wish we could show the curves again. It went up pretty quickly. I think there, you know, it's not going to look as horizontal, of course, as we see in the PARP inhibitor cohorts, especially as pronounced as we saw in SOLA1, where really the slope hasn't changed in five years. Like, it's just been this sort of really gradual coast down. I think that's going to coast right on out to natural history of just death amongst a population. I think we have a high percentage of women in that group who are cured. It's probably a little bit different in the BRCA BRCA wild-type HRD positive. I think they are a higher risk. I think we would all agree on that. But that slope is pretty horizontal. So, I do think we're going to continue to see it ride for a period of time. You know, instead of, you know, we're at five years. So, by seven years, you know, instead of being at 47 percent progression-free, we may still be at 35. That's a crystal ball prediction. But that's a heck of a lot better than 15, which is where we were before. So, I do think that Dr. Ray Cucard's work and her colleagues have likely cured more women than otherwise would have been cured with Bevacizumab alone. Did they cure more women than with PARP alone? That's what we were just arguing about. So, how many more remains to be seen. But we can probably call it around, in that population, we can probably call it around seven years. In BRCA, it's probably about nine years. So, we're a couple more years out. But I bet it's going to be, I bet we're going to be 35, 37 percent at seven. Is there a plan, Isabel, to publish? I know this was the final OS, but are you planning, you know, long-term follow-up publication? Will you be following these patients for longer? It's a great question. We also have to look at the safety profile with a more long-term. It's something that we have to discuss. Currently, it's not anticipated, but I will try to push in this direction because I think it's important. The median overall survival in this population is really unstable, and we need to continue to follow the patient. Real quickly, I want to encourage in the audience, they're killing each other up here. Feel free to come to the microphone and join the battle. May I ask, continue on that in the solo one. So, beautiful results, and we saw that from five years to seven years, there is only four percent drop in overall survival. Do you have disease-specific survival curves? I believe they will be flat. Yeah, no, I agree with you. I think we have cured them. Yes, I believe we have, and I think that's what Katie was saying. I think you have to look at a couple of elements. One is, you know, what's the modeling behind this idea of when can you call it, right? So, can you call it at seven years, nine years? And there's some nice statistical modeling that we referenced here that looks at, well, what's the rate of you dying from your advanced ovarian cancer versus what's your rate of you dying from everything else in the world that causes death? And those lines merge somewhere in that seven, probably in slightly beyond age group. You know, the overall survival from solo one, to say that it's cured, I don't know. I'm probably going to be retired, I hope, when that 60 percent maturity comes around, but you're absolutely right. Things happen to people, and they may not be disease-specific. I think, Rob, you brought that up as a question at ESMO when we were there, asking, like, can we separate that out? And that hasn't been part of the analysis yet, but certainly could be looked at. Yeah, I mean, Paul, you made a point today, which maybe you made at ESMO, and I missed it, but saying that, you know, 45 percent of the patients were free of having a second round of treatment, and they contributed to the majority of the patients who were alive at seven years. And that's, I think, a very powerful point to make, that the majority of those patients who are alive, because when we see overall survival curves, we don't know whether you're alive with disease or what, but 45 percent of those patients were alive without having had a first recurrence. Right, and I think we see a lot of these secondary analyses where maybe we don't weigh in on them as much, but in this particular trial, that time to first subsequent therapy is really powerful in looking at that idea of, who have we cured? You know, there's 18 percent of women in that arm of the trial that aren't, that have had a subsequent therapy, and unfortunately, likely, that's going to lead ultimately to their demise, but 45 percent, that's a heck of a number. Yeah. So, Tom, I haven't heard anything from you yet. Maybe it's time for you to have a question. The HRD test, I mean, we've been talking about the Myriad test, which has been used in the trials presented here. There are others available. Does it matter what test we use, and can we interchange the tests that we use for HRD? Yeah, it's a great question. So, the official answer from the FDA would be no. You should use an FDA approved test, which would be the Myriad, MyChoice, or the Foundation One Companion Diagnostic. They're both slightly different in terms of the elements that go into that. You have LOH in both of them, but they're measured differently in each of them, and then you have the large-scale state transitions and the telomeric allelic imbalance that goes with the Myriad test. I think the important thing is to recognize that up to 50% of our patients will have an HRD-positive test. And as you heard from the group today, that doesn't mean that they necessarily have HRD at that time. Either it's a false positive, or remember, this is a static test. And so genomic scarring that occurred earlier could be reversed. And you see reversion mutations and so forth. So there's a number of ways you can get there. So other companies, to your point, Jonathan, are looking at this. Keras, for example, has a 250,000 SNPs at one megabase resolution. Tempest has a test, and a number of other companies are developing tests. The question that I think needs to be faced for them is you need to validate them. So we need to see some validation that they agree. Ideally, prospectively, but at least retrospectively. And that's not easy to do. So I think there's some challenges out there. One of the other things I will say is there's a lot of appetite, if you will, for developing in-house tests. And we've seen that mostly in Europe, and specifically Germany, where we've seen reports the last couple of Congresses where they've reported what looks to be fairly favorable data, but again, small results and not prospectively validated. Real quick, we have a question from the audience. I want to make sure we bring them in. Thank you very much for this great talk. And my question is if anyone in the panel would consider a PARP inhibitor maintenance for early stage BRCA mutated patients, stage one or two. Thanks. Excellent question. I'll take it. So it's interesting. I've had several patients approach me about that very same question, as well as some friends who've unfortunately been afflicted by ovarian cancer. And it's really a question of, what are you willing to risk for what particular gain? And so what's your real risk in the long run? My real risk is toxicity in this setting. And when we talk about a 1% to 2% risk of MDS AML development versus the chance for cure, well, I'll tell you, if somebody approached me with a stage two fallopian tube cancer or ovarian cancer, which we know really may not be stage two, I'd consider strongly offering them the drug. Yeah, I think I would just say, and I don't want to ever be quoted from the podium as advocating for this, because there's no data. And there never will be data. And so we just have to say that. But there is retrospective data from some centers, specifically at the University of Washington, where they've led a large risk clinic that would suggest stage one BRCA-associated cancers have a much higher risk of recurrence than stage one otherwise, which is about 10%, maybe a little less. They track at about 30% to 40%. In retrospective analysis, single institution. So we have to take that with the level of evidence that it has. But that's probably the best data we have. And so 30% versus a 2% risk of AML MDS, I mean, I certainly discuss it with my patients. And it's a shared decision making. And have I done it? Yep, I have. But I can't tell you it's right. And I would never tell you it's right. But I don't think that you can deny it to patients who are fully informed. I completely agree with what you said. I have patients which so-called 2C and well, she's BRCA mutant. I could not give her more benefit, although there is no data. I don't think there's anyone on the panel that wouldn't offer it, right? Is there anyone that wouldn't offer it? Yeah. I would certainly offer it. But I wanted to, because this is a great audience to speak to. If you guys have databases of patients with early stage BRCA mutated tumor that's annotated, and you can publish that data, please do. I have been hunting down for that data that you mentioned. I've heard Liz say the same thing, Liz Swisher, from Washington, that there is a high risk of over as much as 30%. That's a high enough risk that we could probably see a difference with a treatment. I think the issues that come up, again, long-term risk for a second malignancy, because they're already at risk for that. There's the complications of the PARP inhibitor therapy. And we're also not really settled yet, and we haven't talked about this yet, is what's the duration of treatment? Because I think that's another key issue that we've not really settled. But I encourage you, if you guys have data sets like this, get it in the public domain, because it's something that we really need to know about. Yeah, I just want to chip in, although I'm not on the panel. Many of those patients, or some of those patients with a BRCA mutation, may have had the diagnosis made at prophylactic salpingoforectomy, therefore may be not properly staged and may indeed not be stage one. And the second is that some of those patients we know with a BRCA mutation could go on to develop primary peritoneal carcinoma some years after they've had a prophylactic BSO without disease. So I think that may partly explain the relatively high risk of recurrence of those BRCA mutated patients, and perhaps also, therefore, the need for PARP inhibitors. So Rob, how long do you keep them on PARPs? You raised the question, what do you think, how long? Yeah, so, yeah, I think in, again, this is, again, modeling from the survival curves, the PFS curves, because, you know, we looked at this and we talked about this a long time ago when we first saw the SOLA-1 data, that about somewhere between 12 and 15 months, the event rate in the placebo arm and the event rate in the treatment arm are about the same. So for that last, you know, nine months on treatment, the same number of patients per fraction essentially are recurring or progressing in each arm of the curve. So that's what they split and then they have that tail. And then when you saw the updated data out even farther, and it's actually also true for PRIMA, there is a point where you wonder if there's a lot of diminishing returns. In the recurrence setting, I think it's gonna be much even more telling because of what we think, you know, potentially maybe you heard on the initial day of the meeting here, you know, whether or not we've actually been treating patients too long as we treat them to progression. So I don't know about in the recurrence setting, to be honest with you, Brian, but I think in the frontline scenario, I do think that it's a topic that we need to visit. Antonio. Talking about the recurrence setting, I have a question for Amit. It's very surprising that the patients treated with Rucaparib has lower treatment, subsequent treatment that the patients treated with chemotherapy, but it was the same for REO3. 40%. And I'm trying to figure out what are the reasons why 40% of patients do not receive subsequent therapy after Rucaparib. So that's exactly the question that we have as well. 40% of patients not receiving treatment following recurrence is a huge number. Now, there can be multiple reasons for that. And I think that that's one of the things that we really need to dig into. Obviously, if this was electively not given to patients or the patients could not access treatment, that's one thing. But we also need to sort of make sure that it isn't because patients could not receive treatment. And I think that that's such a big number across the board that we really need to sort of drill down into it. I think the other surprising thing in AREO4 is that when patients did crossover, particularly when they were on the chemotherapy arm initially and then went on to PARP inhibitor, they actually did quite well. So the number of patients actually that received Rucaparib following crossover stayed on it for a pretty long time. And many of them, the majority of them, stayed on for more than six months. So it actually shows that the patients who had crossover from chemotherapy went on to continue to derive benefit. And what's surprising is that that also applied to patients who were in the platinum-resistant group. So it's actually really intriguing data that we need to dig into further. So you had a few patients from Eastern European countries, that is Russia and Ukraine and others. And we have a very old trial, about 10 years ago, there was a trial in tyrosine kinase inhibitor with a company from Boston. They did the same blunder, they had one-sided crossover. And what happened there was that patients there could not afford to pay themselves the chemotherapy. So when it was one-sided crossover, they could receive a PARP inhibitor, but when they progressed on, they received the tyrosine kinase inhibitor because that was given for free. But patients did not receive any chemotherapy after they progressed on active treatment. And there you saw also the hazard ratio of OS flip over. So that's exactly right, Mansoor. And we need to sort of dig into these results to find out exactly the reason. If access to treatment was related to participating on a clinical trial, and that applied at the crossover time as well, that could potentially explain some of the results. But we need to sort of dig down into those to make sure that if that's the reason, then we actually put that as one of the explanations. Dr. Skanda-Ramiz. Thanks, Brian. With all the brainpower on the stage, I feel compelled to ask this question, which is, now that there's been a precedent set to use non-analytical data to promote voluntary withdrawals of indications, in the context of what you guys are just mentioning, how do you envision this is gonna impact earlier lines of use of PARP therapy, both in the States and internationally? And I'd love to get the perspective of several of you on the stage, because I think it's an incredibly important issue that we're gonna face. Shall I? Oh, great. That's a good question. You know, I'm very concerned with what's going on, and I'm hoping that there's still time for education with the regulatory agencies, including the EMA, but I, you know, because both of them are looking at this from a similar perspective. My concern is that this could be label-restrictive, even in frontline, perhaps, and, you know, that would be a shame. So we'll see what happens, but I have that fear that the HRD test negative population could lose its label, I don't know. On that note, I mean, maybe I could ask you, Mansoor, having read the current publication of the ASCO updated guidelines, what your thoughts are on that? The polite diplomatic answer, or the? Whichever way you want. Be yourself. No, this is, I was shocked. I mean, you talk about agencies. I'm talking about my colleagues. I think we have to teach them how to read the results of clinical trials. Do they understand the statistics? Do they understand what is the primary endpoint, and where is, you have the analytical endpoint, and where you have the non-analytical endpoint, and how can you interpret that? When you read that, that came this week in JCO, so you can download the guidelines from JCO. If you read that, it's shocking. I mean, they are mixing the non-analytical endpoints to tell us something which, well, I believe what they're saying, okay, this is not our business, do it yourself, or something like that. Look, you have not seen such great effect in ovarian cancer of any other drug as we saw in PARP inhibitors since you, Jonathan, presented the study 19, and since then, we moved it to first line. All the way. We did not have the overall survival as analytical endpoint in NOVA. We did not have it in Arial-3, and we don't have that data in SOLO2 because that's only in brachymute, so how can you then conclude what they write in the JCO? I am strongly against, and I would be happy if I get support from my colleagues. I was an author on that, so I'm gonna speak up about that. So number one, the headline that came out was entirely wrong, and so it came out saying that we had spoken against maintenance in the recurrent setting, which was nowhere in the guidelines whatsoever. In fact, the guidelines still fully list all the indications for frontline and for platinum-sensitive recurrence, and it was completely misinterpreted by the press and then picked up by ASCO and SGO and all of our societies that don't know how to read, so it was very disappointing that that headline went out because it caused a lot of consternation that it's not what we said at all. One. Two, there was a tremendous amount of passionate discussion by people that you know that I won't call out, but they were very well-spoken, and you would be proud of them, to soften the language that went into that document, but we had to acknowledge the voluntary withdrawals. It's an ASCO position statement. The indications have been voluntarily withdrawn, and so the fact that we didn't come out and say don't use it, but said this is sort of what is in play is sort of as soft as we could get without saying do something off-label, which ASCO can't come out in support of. So it was very evidence-based. It was as nuanced as we could get, and I appreciate your passion about it because there was a lot of angst that went into that document. That's all I can say, and you can be mad about it and write an editorial about it. That's fine. But if you ask a community oncologist to read that article, what will be the conclusion? They can use that PARP inhibitor should be used in the front line, and in PARP naive, you can use it in the second line, and that Oreo is hard to interpret. That's not how you read it. It is read like that. Second line. Second line maintenance is there. Yes, but it's not clear. No, the treatment. The treatment was withdrawn. The language is not clear. So, yeah, I mean, you know how passionate I am about this. I really, and I wanted Tom to maybe comment on our discussion with the FDA regarding endpoints. I mean, we made a very strong statement at the FDA to advocate for PFS as a primary endpoint for these trials. Post-progression in a long, and an opportunity for many confounding factors makes OS very difficult to interpret. So I think we are very upset about the word detriment to be allocated to a hazard ratio that crosses 1-0. So either 95% confidence interval. Tom, tell us about that discussion. Sorry, I just didn't read your sign language at all. You just kept going, and Brad and I were down here going, what's he want? I think he's hungry. So, yeah, I mean, I think the biggest concern here is if you think about drug development in gynecologic malignancies, and especially ovarian cancer as an example. If you look at the timeline, and many of us have shown that timeline where there was a dearth of drug development with only two approvals in almost a 12-year period, and that occurred with JEM and then converting Doxil from a provisional to a full approval, and that's all we had. And the word on the street was, well, you need OS, and frontline trials, it would take 10 years from the time of conception to read out. So it's just not a really good place to go, and we're not developing new drugs for our patients with ovarian cancer, including the PARPS almost went away, and that's a whole nother story. But they almost didn't make it. And so we really need to, and that was part of the dialogue with the FDA, is how do we encourage drug development in our space, because that's the only way we're going to make progress in terms of improving survivals and outcomes. And it was a rich dialogue, and it culminated in a workshop and a white paper, and they agreed that PFS would be a reasonable surrogate endpoint. We established rules around that in terms of magnitude of effect and other things that needed to happen, and studies needed to be properly powered to show no detriment in overall survival. Now they're coming back with subset analysis with huge crossover, which is a big problem, and the continued problem with long post-progression survival. And when you put all that together, it makes OS an extremely challenging endpoint in overall, in ovarian cancer specifically. And that's the point that we need to discuss. And if there is a detriment, and we need to look at this data closely, we need to look at the PARP data as best as we can and rule out that there is some type of problem with later exposure to DNA-damaging drugs in terms of desensitizing to efficacy. And I totally applaud any, you know, the more data, the better, and it needs to be looked at. On the other hand, the curves to Mansur's point of what we've been seeing, these curves and these hazard ratios are so spectacular that I'd hate to see this done without very careful consideration. Listen, we have one more minute, and then Jonathan will wrap it up. So Brad, I know you've been wanting to talk. One minute. So I'm really a cautious person outside of the casino. And so I agree with the abundance of caution, but the abundance of caution is to allow women the right to choose. Mm-hmm. And the right to choose is to educate with all the data that we have. And if you think it's good for your patient, that's fine. But it has to be contemporary data at a population where you practice, for me, in the U.S. I don't have contemporary U.S.-like data to know what happens other than a very dramatic and significant improvement in progression-free survival. And that's all I have, and so we need to continue to work. But to say that there's a detriment, it is the opposite of abundance of caution, because I'm afraid we're gonna hurt women. That's cool. We could be here all afternoon, I'm sure. For the AV team, can you put up Dr. Letterman's slides? And we're gonna wrap up with a brief slideshow by Dr. Letterman to sort of let everyone on stage get their blood pressure down, and to wrap up the session. Thank you. Could I have the, how do I get the next slide up? There we go. Are you gonna put the slide up, or do I do it? It's on my monitor. It's there. Okay, so. This one, okay. So, excuse me. Good. Well, so firstly, I'd like to thank all the speakers for fantastic presentations at a time, and also all the panelists. I think we could go on for another half hour at least with questions, and I haven't got the end of my list, which just shows how contentious all this is, but you've dealt with it very well. But what I thought I would do, these are my disclosures, I would just sort of make five point, five messages from five parts. Firstly, with BRCA-mutated ovarian cancer from the SOLO-1 trial, we've seen this unprecedented benefit in seven-year survival, and that plateau in the time to the first subsequent treatment really does suggest that cure has occurred in many of these patients, and that really testing for BRCA mutations now has to be a standard investigation for all newly diagnosed ovarian cancer. And SOLO-1 confirms that elaporate maintenance is really a standard of care for BRCA-mutated ovarian cancer. Point two, in the BRCA wild-type HRD-positive patients from the PAOLA-1, we see this overall survival benefit with combining elaporate with bevacizumab in that subgroup with a five-year survival of 65.5%. There's still some uncertainty about the contribution of bevacizumab, and as Isabel mentioned, there are now ongoing trials that will dissect out the independent value of both of these drugs. We see no benefit in this trial in the HRD-negative group. But HRD testing, by whichever method we come down on, does define subgroups of patients who benefit from biomarker-driven therapy. Point three, in the HRD-negative group in PRIMA and athenamono, we see a PFS benefit in those HRD-negative or LOH-low patients with niraparib or rucaparib. PRIMA did select patients who are platinum-sensitive, which we know is a surrogate for HR deficiency, but athena did not. And one of the questions that was raised is whether or not the benefit actually represents an inadequacy of the tests that we have and whether we should, in fact, be giving PARP inhibitors to all patients. Point four is the PARP monotherapy. That's not maintenance. That's monotherapy in brachymutated ovarian cancer. That was the ARIL-4 trial. There was this important PFS benefit of rucaparib, but it did not translate into an overall survival benefit, and we began to discuss some of the reasons for this and whether this is related to, if you like, a statistical anomaly, small numbers of patients, lots of crossover, long post-progression survival, and whether the results that we saw in ARIL-4 are largely driven by that platinum-resistant subpopulation. But there is also the question as to whether or not there is an induction of resistance to subsequent therapy by the PARP inhibitor. But I think what we can conclude is from all these maintenance studies in front line that there's been consistency in the results, consistency with Paolo1, Sola1, and Athena with a potential of cure for a proportion of these patients. We've seen the consistency in Paolo1 and Prima and Athena in the BRCA while type HRD-positive, again, reinforcing the importance of biomarker-driven therapy for these patients. And this PFS benefit in the HRD-negative LOH tumors, it's difficult to know where PARP inhibitors sit there or whether bevacizumab will produce a similar benefit or whether we should give PARP inhibitors to all. So on behalf of my co-chair, Brian Plomovitz, I would like to thank all the panel presenters and audience for participation. Thank you.

PARP inhibitors

ovarian cancer treatment

panel discussion

clinical trials

bevacizumab

HRD-negative population

early-stage BRCA mutated patients

duration of treatment

overall survival data

research

patient populations