Good evening, everyone. So this is the last Advances and Update webinar of 2022 and the Advances and Update workgroup of the Educational Committee has had a successful first year of year-long education and are excited to continue offering excellent education in 2023 and beyond. IGCS is committed to providing meaningful opportunities to our industry colleagues to gain exposure to our gynecologic oncology community through a unique year-long educational engagement program. This platform provides the level of strategic engagement and exposure needed to educate and inform gynecologic oncology professionals on current and future to optimize patient care locally and globally. Before I get started with my presentation, I want to mention a few housekeeping items. Please know that the recording of this webinar will be available on IGCS Education 360 Learning Portal by the end of the week and we encourage you to submit questions via the Q&A feature at the bottom of your screen and we will do our best to address as many questions as possible. Now I will try to share my slides and my screen. Just give me a moment. Okay, so the topic of today is very hot. As you know what is happening within the regulatory agencies, looking at the data on overall survival in the relapse setting in the patients who are receiving maintenance therapy in platinum sensitive relapse. So I've called my talk overall survival data with PARP inhibitors myth versus reality. My name is Mansoora Samirza, I'm Chief Oncologist at Department of Oncology at Rijkshospitalet in Copenhagen, Denmark. I'm also medical director of Nordic Society of Gynecologic Oncology. And it's a pleasure that I can share with you my thoughts about this very important topic and I thank our society IGCS to giving the possibility that we can discuss this topic. And we have gone through the practicalities. These are my declarations of interest. So this is my first slide which shows what we have done with maintenance therapy by getting the maintenance therapy, by getting introduced maintenance therapy a decade ago, first with Bevacizumab and then with PARP inhibitors, we have completely changed the management of our patients. When first PARP inhibitors were introduced, they were introduced in the platinum sensitive relapse setting as a maintenance therapy in the patients who were responding to chemotherapy. And the first study was performed by Jonathan Lederman and then we saw multiple studies coming in. And in 2018, we saw the first study in the first line. So the impact of PARP inhibitors you will see first was because of platinum sensitive relapse, using platinum sensitive relapse setting. And lately we have introduced PARP inhibitors in first line. I just want to make some statements before I show any of the data. And these are some considerations I would like you to have when looking at the data. All these studies, whichever PARP study you take, all these studies are powered for progression free survival. None of these studies are powered for overall survival. And we know that in ovarian cancer, survival past progression is very long. And post-progression therapies are not controlled in some studies, not properly registered. We do not have power to answer overall survival as OS was a non-analytical endpoint in these studies. So we can only discuss when it comes to the statistics about the trends due to the non-analytical data, what we would have. These are the studies which were presented since 2012 until today in the platinum sensitive relapse setting as a maintenance therapy. The first study was by Jonathan in study 19. And then the first phase three trial was NOVA trial with Niraparib. And then we saw the confirmatory trials and aerial three trial coming in with Rukaparib. And we also saw one very important trial, the NORA trial with Niraparib in Chinese population. And actually today at the ESMO virtual plenary, I presented the overall survival data of a NORA study. And I will share that with you as well, as it is just hot from the press, we finished that ESMO plenary an hour ago. So this is the first trial we saw in 2012, study 19, which was done in all patients with high-grade serious ovarian cancer. These patients received four to six cycles of chemotherapy and upon response, they were randomized to receive either Olaparib or placebo until progression of disease. I said all patients were recruited and entered in this trial and it showed a very significant benefit in whole population with a hazard ratio of 0.35. Jonathan went back and completed the analysis of BRCA status. And it seems that the BRCA mute population had a hazard ratio of 0.18 and not even the BRCA wild type had hazard ratio of 0.54. So this trial has established the role of, although it was a phase two study, role of PARP inhibitors in ovarian cancer. And actually we did not see the approval in FDA coming in, but there was a huge off-label use and you will see the outcome of that off-label use in US population in a moment. So Jonathan Letterman presented the data or it was Friedlander on the long-term benefit on overall survival of study 19. And there was a trend, as I said, the study is not powered to show overall survival. There was a trend towards benefit of giving Olaparib to these BRCA mute, but this whole population overall survival. The subsequent study was performed only in BRCA mute population with Olaparib, solo two, which showed again, very strong benefit in progression-free survival, which was primary end point. And later the overall survival data was presented by Andres Boveda showing that there was again a trend towards benefit of giving Olaparib to these patients. So I say trend, why? Because these, first of all, alpha was not allotted to these secondary end points. And that's where these are non-analytical end points. And then the first phase three randomized trial in this population, NOVA trial, which was presented in 2016, had three primary end points. One was in G-BRCA cohort, which showed a clear benefit. All primary end points were median PFS. And then we saw in the non-G-BRCA cohort, again, a hazard ratio of 0.45. And the last, but not the least, within the non-G-BRCA cohort, HIV positive population had a hazard ratio of 0.38. So that was positive in all population, regardless of BRCA, regardless of HIV status. And we saw approval of Neuroparib in whole population to receive treatment as maintenance therapy in platinum sensitive relapse setting. The subsequent trial, which was presented, was with Rucaparib Arial 3, which showed similar results as in NOVA study. In whole population, highest benefit in the BRCA-mute population, while quite a significant benefit also in the LOH-negative disease, so the whole population is benefiting from the treatment. But when we saw the results of these two studies for overall survival, and we look at the non-G-BRCA population of NOVA study, we see the non-G-BRCA has a ratio of 1.1. It has been updated to 1.06, and non-G-BRCA HIV positive has a ratio of 0.32, 1.32, which actually says that it's a detrimental effect. And in Arial 3, we saw the similar results with 1.31. So why these results are switching over, when we have seen that the primary endpoint was positive, the time to progression on the subsequent therapy, so-called PFS2, was very positive in all these trials, and why we see this. And there are several reasons, and we can discuss that. I think one of the major reasons, I will take it to the NOVA study, one of the major reasons is that we did not register for quite a substantial number of patients what these patients received, how many patients did receive the placebo, the patients who were receiving placebo, how many of them did receive a crossover, a PARP inhibitor, what other treatments were given. So it is impossible to trace anything in this population, and that makes it very difficult to trust on the results of this overall survival data which is presented, which we have today, because it's quite incomplete. However, the primary endpoint was progression-free survival, and I think this slide tells the whole story. This is the slide from CIR, from National Cancer Institute, the surveillance epidemiology and end results data. Here you can see in the yellow line that the incidence of ovarian cancer in the last 20 years has been gradually decreasing, and the prevalence in green line shows a gradual increase, probably due to better surgery, centralization, and so on. And after introduction of PARP inhibitors in 2012, you see a steep increase in the prevalence of ovarian cancer. What does that mean? That means that more and more patients are living with the disease and not dying of the disease. And what we have done is we have prolonged their time to subsequent progression and subsequent therapy, and that means that all the symptoms they may have, we have prolonged that intensively. So this is a huge achievement, and this is not being shown in overall survival, probably because the data collection, the cause of past progression, long progression-free survival, long past progression survival, and that we have small sample size for ovarian cancer. We don't have a luxury like in breast cancer to do trials in 10,000 patients. So it is impossible for us to come up to a conclusion on overall survival. So I think the serograde of PFS2 is telling us that it's working, and you increase the PFS2 as well. On top of that, today I presented the data on overall survival of the Chinese study, the NOVA trial. So NOVA trial was much similar to NOVA trial. These are the patients who had platinum-sensitive relapse. They were either BRCA-mute or BRCA-wild type. And these patients, upon response, received either norepinephrine or placebo. There are some differences from NOVA trial. One of the differences is that individualized dosing was given to all patients, while in NOVA trial we learned what dosages should be given. And the second difference is that in NOVA trial, most, if not all, patients have received treatment at the first relapse. So in NOVA trial, there are quite a mix of patients with two relapses, three, four relapses, and so on. So these are the differences between the two. But you can see that hazard ratio is very positive in whole population with 0.32. And when you look at the subgroups, according to the BRCA status in the G-BRCA, you see a hazard ratio of 0.22. And in non-G-BRCA has a ratio of 0.40. These results were already presented by Dr. Wu and are published in Annals of Oncology in 2021. And today, I presented the data on overall survival. So the overall survival data should have been analyzed with 50% maturity. However, because of all the issues with right now, all the, I want to say, unrest in the community in the US and in Europe, we decided to do an ad hoc analysis at 44% maturity to get some sort of information which will help us taking decisions. As we know that in NORA trial, a very well registration of past progression therapy is very complete. And the maturity is 44%. And we have OS data. And we know that 54% of the patients in the BRCA-mute population in the placebo arm were crossed over to another PARP inhibitor. And even in the non-G-BRCA in the placebo group, 36% of the patients crossed over to a PARP inhibitor. And there were multiple other chemotherapies were given to these patients. So when we look at the ITT population, overall survival, the hazard ratio is 0.82. That means that there is a trend towards efficacy of norepirib. When we adjust this and remove the patients who had received subsequent PARP inhibitor, so this is the adjusted analysis, you see the hazard ratio of 0.69, which is quite comforting telling us that there is a strong trend towards efficacy of norepirib on overall survival. When we look at the subgroup analysis of overall survival in the G-BRCA, on the left, you see the unadjusted overall survival. On the right, you see the adjusted overall survival, which is adjusted after censoring the patients who were crossed over. And you see that hazard ratios are 0.76 and 0.88. So there is trend towards positivity. When we look at the overall survival subgroup analysis in the non-G-BRCA population, again, in an adjusted group, you see the hazard ratio of 0.85. And in adjusted, it is 0.62. So I think all these results tell us that there is a trend in overall survival towards the benefit of Neuroperib, and knowing that NOVA trial registration of past progression therapies is so incomplete, we have to, I think this trial is helping a lot because of the robustness of the data and telling us that Neuroperib given in the patients who have relapsed as maintenance therapy is helpful. So I will take you directly to my conclusion slides to discuss further. So I think key takeaways from this very short presentation is that three factors make it impossible to interpret the results. None of the, now without NOVA trial, the other, none of these trials control for choice, for timing, for sequence of subsequent therapies in the post progression period, which may have confounded OS interpretation. Moreover, considerable number of patients in some studies had missing information on type and timing of subsequent therapy. Typically NOVA trial, 25% of the patients, we don't know what they received later if they received PARP, especially in the, also in the placebo situation. Substantial post progression crossover to a PARP inhibitor therapy has occurred as you saw in all trials and OS was a non-analytical endpoint in these studies. So in these studies, the OS analysis is underpowered and there are issues with crossover to PARP inhibitors in the control arm as a consequence with the current data, these studies are just not able to demonstrate a difference between the control arm and the experimental arm. Hence the data from NOVA and Arial 3 simply does not, simply do not support a demonstration of lack of efficacy in terms of overall survival. And there comes the NORA data, the robustness of NORA data study makes it possible to see the favorable trend. I think it is important to understand what we can see after seeing the data from the first line that we see now overall survival benefit, NORA study had mostly, if not all, the patients with secondary labs and you see a positive outcome also in the overall survival. What it tells us probably is that we have to push a use of PARP inhibitors up front. And but, but there we should also remember if a patient has not received PARP inhibitor up front and has platinum sensitive relapse and has responded to therapy, the platinum therapy, NORA trials gives us a very strong evidence that we shall treat these patients with PARP inhibitor upon relapse in the maintenance setting. So I think it just came right in time. So the other takeaways is that although the incidence of ovarian cancer has decreased, the prevalence has increased unprecedentedly in the recent years, probably due to the introduction of PARP inhibitor maintenance therapy in the platinum sensitive relapse setting. We are seeing unprecedented improvement in the outcome of our patients. And also after introducing PARP inhibitors in first line, we probably are curing some of our patients. So the use of PARP inhibitors as maintenance in therapy in platinum sensitive relapse leads to a significant benefit in progression-free survival. All PARP naive patients responding to subsequent platinum based therapy should be considered for maintenance therapy with a PARP inhibitor. That would be my major conclusion here. I think that this is important to understand because of a lot of discussions and uncertainty, it is important to differentiate between what is the incomplete data information which we cannot rely upon and which is the information we can rely upon. So we cannot rely on the myths, on the information which is not helping us against the reality that the data, the real data, which is on PFS and the robust data of NeuroTrial and other studies. So I will stop here and I would like to thank you for going to a question and answers session. Let me see if I can stop sharing my slides, yes. Okay, please go to chat and ask the questions and I'll open the chat now and see what we have. No, actually there are right now no questions, so you are so welcome to ask any questions if you have. I don't know if you had time to attend the session earlier today, the ESMO virtual plenary. We also had a very nice discussion there with Isabel Ricoquart and Antonio Gonzalez. I think this is a very, very positive thing that we can already now share by the help of IGCS, the data with all of you. So, any questions? And so, thank you very much for that. I was wondering, you know, the FDA has taken an approach that is probably somewhat different from the EMA and would love to hear your comments on that in terms of how this is being viewed in Europe as opposed to the US. That's a great question and that is the reason why I pushed, I was very much involved in where I was very much involved in NeuroTrial, I pushed that we have to look at the data already now on OS while it was 44% maturity and that helps us a lot. So, when I, please forgive me if this is a rude way to say it, but when I look at the way European Medicine Agency evaluate ODAC, evaluate the EMA ODAC, which is called SAG, Scientific Advisory Group, evaluate the efficacy of a drug, they just don't stick to some specific hazard ratio. 1.01 or 0.99 are the same. But for us, it's for clinicians are the same. But for some regulators, they feel, oh, if it is 1.01, it's a detrimental effect. If it is 0.99, that's good enough. So, this is wrong way to put it and I feel that the European Agency is very pragmatic. They look at the holistic value of the drug with what benefit patients are receiving and where there's very important data taken into account, not only overall survival, but all the primary endpoint progression, free survival, PFS2, the second progression, and the patient reported outcomes. So, I strongly believe that they will come to a positive conclusion to keep the label as it is. So, our patients who are PARP naive can continue to benefit from PARP at the time of relapse. However, FDA has taken a very different approach. They looked only at the hazard ratio of OS without looking at the holistic value of the PARP inhibitors in this population. And this is really sad. And I hope if EMA will come, European Medicines Agency will come with a different conclusion, that will help probably the patients in US as well, because I'm sure that your societies, SGO, GOG, and Patient Advocacy Group will go back to FDA and discuss that why the other major agency has taken a different decision than if they can reconsider. So, this is my dream. I hope that we can still give our patients this very important therapy. I hope I answered your question. Absolutely. I think that's an important point. You know, the SGO went to the FDA a number of years ago to educate on how important it was to use PFS as an endpoint, because OS is just unobtainable in most cases in the upfront setting for ovarian cancer, and even in recurrent ovarian cancer, particularly for platinum sensitive, because of the long post-treatment survival times that people have, and that these trials cannot be powered to do that. Deb Armstrong asked a question about if you think that there is any problem with secondary hematologic malignitudes of myelodysplasia that might contribute to the OS data in the maintenance PARP inhibitor. Well, that's a great question. That's a great question. Let's start from the trials in the platinum sensitive relapse. There, if you look at the BRCA mute population, so what has happened? These patients have received multiple lines of platinum therapy, which also increased the MDS AML risk, and they have received PARP until progression of disease, which increases. And we see that the baseline in placebo patients are having a risk of about 4% in long term, and that has increased to, we saw in Solo2, 8%. So it has doubled. But when it comes to the non-GBRCA cohort, we don't see that serious increase. There's a very, very little increase. We saw in NOVA trial only two patients who have been reported to have one MDS and one AML, and very few patients in the NOVA trial in the non-GBRCA group. So I think that is quite comforting still that this is not probably adding to the survival detrimental effect. The difference is about 1.5% between the two groups. And when we go to upfront, you don't see this. We have now long term data of both Solo1 and Paola1 and Prima trial. It seems very comfortable that we don't see that increase. It stays at about 1% all the time. So I don't believe that this is the reason why we don't see benefit in overall survival. In NOVA trial, it's clear that the amendment was made that patients who want to get unblinded, they were excluded from the study. And then that means that we don't have any data on what they received past progression. So it's difficult to make any decisions on subsequent efficacy endpoints. Yeah, so that actually leads into the next question of, I think there's been some discussion about the issue in the upfront setting of stopping the PARP inhibitor, whether it's two years or three years, depending on the study. And you think that there would be benefit to continuing it or detriment to continuing it? Is that what we should be doing? Obviously, we stopped it in two years in Solo1 and it turned out very well. But who knows? It was somewhat of an arbitrary decision. But could it put pressure on the tumor to become platinum resistant is the question. Yeah, I think this is a great question because we may be causing platinum resistance in some and we have seen some data, but that's difficult to understand yet because that's a very highly selected population, patients who responded who had residual disease, but regarding the resistance issue. But I think we need studies before we decide to change our practice. These are two different populations. Upfront, we have population which can be cured and we are seeing that's why we did not want to continue until progression of disease, which is great. But when you have relapsed and the statistics shows that these patients are prone to die. So there it was difficult to stop treatment before progression of disease. But now I think we are mature enough to do such trials and look at it. If this is the case, at some point we have to stop the therapy or do the break or whatever. But these trials have to be done. The initial trials which were performed, Study 19, NOVA, Arial 3 could not answer that question because all of these trials have given treatment until progression of disease. We really need your help from SGO, from GOG, from patient advocacy groups. Everybody should work to make them understand why it is difficult to use overall survival in ovarian cancer because of the long past progression. I think one more thing what we need to do next trials. Now we are talking about it. We have to control subsequent therapy, at least this PFS2, until PFS2. We have to design trials where we try to design what is patient going to receive once they progress, at least until PFS2. That will give us a lot of knowledge. At least track it because these patients fall out of the trial. So we don't always know. Absolutely. So I think it's so important to understand what treatment they are receiving, when they are progressing and all this, we have to get it very nicely registered in future. That we have learned the hard way and we have to work on that in our future trials. So I keep my fingers crossed. I think we would know the outcome from European Medicines Agency in a day or in a week. And then let's see how FDA is going to react on that. Hopefully, they will go back to their. Hopefully, we'll see. But thank you for that excellent presentation. And we really appreciate your time and expertise. Thank you. And again, thanks to IGCS that we can discuss this very important topic today. And I really hope that we can be able to give this very important treatment to our patients. The patients who are still PARP naive, they must receive PARP inhibitor at the time of relapse.

PARP inhibitors

gynecologic oncology

overall survival

platinum-sensitive relapse

progression-free survival

maintenance therapy

NORA trial