Since. Via, the Q. A. Feature at the bottom of your screen, and we will to our best to address as many questions as possible. No 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 the Relapse Setting in the patients who are receiving maintenance therapy and Platinum Sensitive Relapse so I've called my talk overall Survival data with perpendicular myth versus reality. My name is Mansura, Amersa, I'm chief on colleges. That Department of Oncology at Rick's Hospital in Copenhagen, Denmark I'm also director of Medical Director of Nordic Society, of Kann Logic 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 this topic, and then 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 with the with by by getting the Maintenance Therapy. By getting Introduced Maintenance therapy a decade ago, first with Bever system, up and then with perpendicular. We have completely changed the management of our patients in in when first, part inhibitors were introduced, they were introducing the Platinum, Sensitive, relapse, Setting as a maintenance therapy in the patients who were Responding to to to to to Chemo to Chemotherapy and their first study was performed by Jonathan Letterman, and then we saw multiple studies coming in and and in 2,018, we Saw the first study in the first Line so the Impact of Powerpoint, because you Will See, first was in because of Platinum, Sensitive Relapse Using platinum Sensitive Relapse setting, and lately the we have introduced perpendicular in first line and and if we if we I I I just want to make some statements before I show any of the data and these are some considerations, you I would like you To have when looking at the all these studies, whichever pop study you take all these studies are powered for Progression-free, survival. None of these studies are powered for overall, survival. Then 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 the the non analytical data. What we will have. These are the studies which were presented since 2,012 today, until today, in the platinum Sensitive Relapse set as a maintenance, therapy, the first Study, was by Jonathan, in 2,019 and then the may first first line first phase 3 Trial, was Noba trial no, with their operators, and then we saw the confirmatory trials and aerial 3 trial coming in Withrocarri, and we also saw one very important trial the Noah, trial with the Rapper Abbey Chinese, population, and actually today, at the Asthma 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. If finished that I Smoke Leonardy an hour ago So this is the first trial we saw in 2,012. Study 19 which was done in all patients with hybrid series of iron cancer these patients received 4 to 6, Cycles of Chemotherapy and upon Response they were Randomized to receive either a Laptop or Placebo until Progression, of Disease I said, all patients, were Recruited and entered in this Trial, and and and it showed a very significant benefit in whole population, with the hazard Ratio of point 3 5 Jonathan went Back and did then completed the Analysis of Bracca Status and It seems that the Pra Commute Population had a Hazard, Ratio of Point 1 8, and not even the brack of wild tipad, has a ratio of point 5 4. So this trial has established the role of although it was a phase 2 study role of of Perpendicular in a variant cancer and and and and actually we did not See, the the Approval in FDA Coming in but there, was a huge off Label Use and you will See. That if the the outcome of that off-level use in us, population in a moment to 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 As I said the Study, is not Powered to show overall survival. There was a trend towards benefit of giving a lap to these bracker Mute, but this whole population overall survival the the subsequent Study was Performed only in Bracca Mute Population with the Elaborate Solo too which showed again, very Strong benefit in progression, free survival, which was primary, endpoint, and later, the Overall survival data was presented by Andres Pervada showing that there was again, a Trend, towards benefit of of giving Elaborate to these Patients. So I say, trend, why because these first of all Alpha was not allotted to these secondary endpoints, and these are that that's, what these are non and analytical endpoints and then the the first phase, 3 randomized tree, in this Population nova trial, which which was Presented in 2,000, And 16 had 3 primary endpoints, one was in G. Praker cohoot, which showed a clear benefit. All primary Endpoints were Median, Pfs, and then we saw in the Known G Praker, Cohort again, I has a Ratio, of Point, 4 5 and the last but not the Least within the Known G Praker Cohort HD Positive Population had a hashtag of Point 3 8. So so that was positive in all population, Regardless of broccoli, Regardless of which at T. Status, and and we saw, approval of narrative in the whole population to receive treatment, as maintenance, therapy in Platinum Sensitive Relapse Setting, and that subsequent Trial, which was Presented was with Recovery Aerial 3 which Helps similar Results as in Nova study in whole population, highest, benefit in the Bra commute Population while quite a significant benefit also in the negative disease, so the whole population is benefiting from the Treatment, but when we saw the the results of the of the of these 2 studies for overall Survival and we look At the Known G. Praker, Population of Noaa, Study, and we see the non G. Praker, our has a rich of 1 point, one. It has been updated to 1.6, and and and and non G. Brack actually positive. Has a ratio of point 3, 2, 1.3, 2. Which actually says that it's a detrimental effect and then a real strong. We saw that similar results with 1, point 3, one, so why why these results are switching over that we have seen that the primary Endpoint was positive, this the time to progression on the subsequent therapy subsequent therapy so called pfs, 2. 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 reason. I will take it to the Nova study one of the Major. Reason is that we did not register on for quite a substantial number of patients what these patients received how many patients did receive at the plusbo the patients? Who have reversed in placebo, how many of them did receive a crossover a perpendicular, what other treatments were given so it's impossible to trace anything in this this population and and and that makes it very difficult to to trust on the on the results of this Overall survival data which is presented, which we have today, which 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 the the slide, from sear, from not to cancer, institute, the Surveillance, epidemiology, and end results. The 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 the shows gradual Increase probably Due to Better Surgery Centralization and so on and after Introducing of Perpetrators in 2,012. You see a steep increase in the prevalence of of 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? So what we have done is we have prolonged, their, their their good, 3. Time, 2 subsequent subsequent progression, and subsequent Therapy and that means that all the symptoms they may have we have prolonged prolonged that intensively so this is a huge Achievement. And this is not being shown in overall survival. Probably because the the data, collection, the the cause of past progression, long progression, free survival. Now the long past progressions survival, and that we have small sample size for apparent cancer. If you don't have a luxury lack in breast cancer to to trans and 10,000 patients. So it is impossible for us to come up to a conclusion on overall survival. So so I, think the 0 Grade of Pfs 2 is telling us that it's it's working, and you, increase the Pfs, too. As well, and on top of that today. I presented the data on overall survival of the Chinese study, the Norah Trial. So Noa trial was much similar to Nova trial that these are the patients who had platinum, sensitive Relapse, they were either Bracket Mute, or Bracker, Wild Type and these patients upon response, received either Narrative or Placebo they are those some differences from Nova Trial one of the Differences, that individualized do thing was given to all patients, and while in Nova tried, we learned how to treat what thoseages should be, given and the second difference is that in Nora trials all most if not all patients have received Treatment, at the first relapse because the so in in Nova Trial. There are quite a mix of patients with 2 relapsing, 3, 4 relapses, and and so on so these are the differences between the 2. But you, can see that hazard ratio is very positive in whole population. With has 0 point 3. 2. And when you look at the subterraneous, according to the bracka Status in the G Bracker, you see, a has a ratio of point 2, 2, and a non g bracket has a ratio of point 4. 0. These results were already presented by Dr. Wu, and are published in analyza on college in 2,021 and today, I presented the data on Overall Survival so there Overall survival data should have been analyzed with 50% Maturity however, because of the all the issues With right, now all the Addressed in the community, in the in in us, and in in 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 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 Bra commute population were crossed in the placebo arm were crossed over to 2 to another part inipter and even in the non G Praka in the placebo group 36% of the patients crossed over to a per Centimeter and they were multiple other chemotherapies were given to these patients. So when we look at the it, population overall survival the hazard ratio, is 0 point 8, 2, that means that there is a trend towards efficacy of narrative when we adjust this and remove the patients who had received subsequent part benefits so this is the gesture Analysis you see, the has a ratio of point 6 9 which is quite comforting, they're telling us that that there is a strong trend towards the efficacy of when they're rebound overall survey when we look at the subgroup analysis of overall Survivor in the G Praker on the left, you see the unadjusted overall survival on the right, to see that just to the world survival which is which is adjusted after censoring the patients who have over crossed over and you see that has it Ratios are point 7 6 and point 8. 8. So there is trend towards postivity. When we look at the overall survival sub group analysis in the non G Bracker Population again in an adjusted group, you see, the has a ratio of 0 point 8 5 and in adjusted it is point 6, 2 so I think all these Results, tell Us. That there is a trend in overall survival towards the benefit of their opera, and knowing that Nova Trial registration of past Progression, Therapies is so incomplete that we have to but in this this trial is helped a lot, not because of their business, of the data and telling Us that that the narrative given in the in the patients who have relapsed as maintenance, therapy, is helpful So I will take you directly to the to, the, to my conclusion slides, and to discuss further. So I think he takeaways from this very short presentation is that 3 factors make it impossible to interpret the results none. Of the now without Nora Trial, the other Nanoseconds 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 receive part especially in the also in the Placebo situation, substantial post-progression, Crossover, to a Part Manipulated therapy has a good as you saw in all trials and OS was unknown analytical endpoint, in These studies. So in these studies, the OS Analysis is underpowered, and there are issues with crossover to parole, inhibitors in the control arm as a consequence with the current data these studies, are just not able to demonstrate Difference, between the control arm and the experimental Hence the Data, from nova and aerial 3 simply does not simply to do not support, a demonstration of lack, of efficacy in terms of overall survival and there comes the neurot data the robustness of neurodate, study, makes it, possible, to see the favorable trend I think it is Important to understand what we can see, after seeing that data from the first line, that we see now overall survival benefit. Nora study had, mostly, if not all, the patients with Second Relapse, and you see, a positive outcome also in our own survival, what it tells us probably is that we have to push a Use of part Manipators, up. Front and but but there we should also remember if a patient has not received part manipeter upfront, and has platinum sensitive relapse has responded to thermy, the Platinum Therapy Noah Trials. Keeps us a very strong evidence that we shall treat these patients with part benefits upon relapse, in the maintenance, Setting. So so I think it it just came right in time. So the other takeaways is that although the incidents of varying cancer has in has decreased the prevalence has increased. Unprecedented in the recent years, probably due to the introduction of Parameter Maintenance, therapy in the Platinum Sensitive Relapse Setting. We are seeing, unprecedented improvement in the outcome of our patients, and also after Introducing part of inhibitors in first line, we probably are curing some of our patients so the use of Power, benefits as maintenance, platinum in therapy, in platinum Sensitive Relapse leads to a significant benefit in progression, free survival, all Part nice Patients responding to subsequent platinum-based therapy should be considered a 4 maintenance therapy, with a bar inipter, 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 date information which we cannot rely upon and reaches. The information we can rely upon. So we cannot rely on the myths on that information which is and not helping us against the the the reality, the the the data, the real data which is on pfs, and the robust data of nora Trail, and other studies, so I will stop here and I would like to thank you for for going to 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 to to ask any questions. If you have. I don't know if you had time to attend the the session earlier today, the s more virtual planner, we also had a very nice discussion there with Isabelle, Rico Quad, and Antonio Konzales I think this is a very very, positive thing that we can. We can already now share. By the help of Itcs, the data with all of you. And so any questions. Okay, that's so thank you very much for that. Hi! I was wondering you know, the FDA is taking a an approach that there's probably somewhat different from the Ema, and would love to hear your Comments on that in terms, of how this is being viewed in in Europe as opposed to the us. That's a that's a great question. And that is the reason why I pushed where I was very much involved in Nora trial, I post that we have to look at the data already now on OS. While it was 44% maturity and that helps us a lot. So, but when I please forgive me if this is rude way to say it, but when I look at the way and European Medicine agency evaluate Odac, evaluate the E-mail oak, which calls Sag a scientific advisory group, evaluate, the fe case, of a drug. They just don't stick to some specific hazard ratio, 1 point, 0 one or 0 point 9 9. The same, but for us, it's for clinicians are the same, but for the for the some regulators they say, Oh, if it is 1.0, one it's a decremental effect, if it's your point 9 9 that's good enough so so this is wrong, way, to Put it. And I. I feel that the the European agency is very pragmatic. They look at the holistic value of the of the drug with the what Fee, what what benefit patients are receiving for for and where they're very important they take into account not only overall, survival, but all but the Primary, endpoint Progression. Free, Ser Survival. Pfs, 2. The the 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 to our patients who are part naive, can continue to benefit from Park at the time, of relapse However, FDA has taken a very Well. Very different. Approach. They looked only at the hazardous of OS without looking at the holistic value of the of the of of the Parameters in these population. And this is really sad, and I hope if Eba will come European medicine agency will come with that conclusion, that that will help probably the patients in Us, as well, because I'm sure, that you neither your societies SEO Kog and patient at this, group will go, back to FDA and discuss That why, you know the other major agency has taken a different decision than then, if they can reconnect. So this is this, 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 a an important point. You know. We we went to the the Svm went to the FDA, a number of years ago to Educate on how important it was to use Pfs as an endpoint, because the last is just UN Obtainable in most cases in in the Upfront setting for a grand cancer and even in recurrent of Married cancer, particularly for platinum sensitive, because of the long Post Treatment to survival times, that people have and it. These these trials cannot be powered to, to to do that Dev armstrong, ask a question about if you think that there is any problem with secondary humil, human logic, malignitudes and mile Or Dysplasia, that might contribute to the OS data and the maintenance part inhibitor Setting new York could Well, that's that's a great question. That's a great question. Let's start from the from the trials, in the Platinum, Sensitive Relapse. There, if you look at the Brackam Mut population, so so what has happened? These patients have received multiple lines of platinum therapy, which also increased Mds, Aml risk and they have received part 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 be showing solo to 8%. So it has doubled but when it comes to the non cheap racker cohort, we don't see that serious increase there's a very very little increase we saw in nora trial, only 2 patients who have been reported to have one. Mds, and one Aml. And very few patients in the Nova Trial in the Known G. Praker Group. So I think that is quite comforting still. That I this is not probably adding to the soil detrimental effect. The the the depth, differences, about one and a half, percent, between the 2 groups. And when we go to upfront you don't see this we have now long term Data of Both Solar One and Paula, one and and and premature. It seems very comfort comfortable, that we don't see that that that increase it stays at about 1% all the time. So I don't believe that this is the reason why we, see the true the invite. We don't see Benefit and Overall Survival in Nova, Trial. It's clear that that the amendment was made, that patients who want to get unblinded. There excluded from the study, and then that means that we don't have any day down, but they receive past progression. So it's difficult to take make any any any decisions on subsequent, the efficacy, endpoints. Yeah, so that actually leads into the next question of You know, I think there's been some discussion about the issue in the upfront setting of Stopping, the Park Inhibitor, whether It's 2, years, or 3 years depending on the Study, and and do you think that there would be benefit to continuing it or detriment to continue it is that what we should be doing? I obviously, we we stopped it in 2 years, in in solo, one and and it turned on very well, but you know I who knows and somewhat of an arbitrary decision. I, think, yeah. But but could it put pressure on the timber to become flatten and resistant? Is the question Yeah, I, think tha, this is a this is a great, a a great question, because we may, because in platinum resistance in some and we have seen well, 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, these are 2 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 relapse and the statistics shows that these patients are prone to dye, so there it was difficult to stop treatment before progression of disease. But now I think we are mature enough to do such stress. And look at it. If this is the case, at at some point, we have to stop the therapy, or or to the break, or whatever. But but these trials have to be touched the initial trials, which are performed. Study 19, Nova, aerial 3 could not answer that question because all of these trials have given treatment until progression of disease. Oh, you are mute Sorry, Mike Bootman, brought up the the point basically the concern over loss of Drugs to patients, which which you address, but but do you think that the in may and the FDA could could actually engage in Conversations directly would that be helpful I I know the Fta set in on the meeting They are, they are they are in, in, in, in, in a, in a discussion, together, and so in well, I I I'm not allowed to hear publicly say that but FDA was present, in the discussions, while emma was discussing these issues, so I think they will the take home message for them will be something good, that that may may help FDA to maybe Britain, or change their, their, their their stand, but they're we we really need your health, from Sio, from gog, from from from from a patient that okay, C. Groups, everybody should should should work to to make them understand why it is difficult to to use overall survival in ovarian, cancer because of the long Path past Progression I think one more thing, what we need to do next, stress now, we are talking, about it that we have to control subsequent therapy. At least this Pfs 2 until Pfs, 2. We have to design trials, where we try to design what is patient going to receive. Once, they progress, at least to till Pfs. 2. That will give us a lot of knowledge Or at least at least track it because these patients fall out of the trial. So we don't always know what. Some, yeah, that's a hard one Yes, absolutely so I think is it so important to understand what treatment they are receiving when they are progressing and all this we have to get it very nicely, richested in future that we have learned the hard way and and and we have to work on that in our future so so I i keep my fingers. Crossed. I think we would know the outcome from from from Europe, in Medicine's agency in a day or few, in a week, and then Let's see how FDA is going to to react on that hopefully they Will go Back to their Yeah, I hope hopefully. Hopefully, but thank you for that excellent presentation. And I really appreciate your time and expertise Thank you and it again, thanks to itcs that we can discuss this very important topic today, and I really hope that we can be able to give this very important treatment treatment over patients, the patients who are still part, naive they must receive bar inhibitor at the time of relapse Thank you. Thank you and Merry, Christmas Thank you.

overall survival data

PARP inhibitors

platinum-sensitive relapsed ovarian cancer

clinical trials

maintenance therapy

progression-free survival

interpretation