Hello, everyone, and welcome to this webinar dedicated to how current maintenance therapy is changing the ovarian cancer treatment and what's the future. Next slide, please. I'm Ketalu Russo. I'm a GYM oncologist working at the Fondazione Policlinico Gemelli in Rome and Catholic University, and I'm so happy to chair this webinar, which is in part sponsored and supported by Immunogen. Before we get started, I want to mention a few housekeeping items for all of you. Please know that a recording of this webinar will be available in the coming days on IGCS Education 316 Learning Portal within only one business day. 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. Next slide, please. It's my great pleasure and honor to welcome our panelists. We have Rob Coleman. So please, Rob, can you introduce yourself? Yes. Thank you so much. So Rob Coleman, I'm a GYN oncologist in Houston, Texas. I practice out of the Texas office there in the Woodlands, and I also serve as the chief medical officer for Vanium Group. It's good to be there. Thank you for joining. We are happy you are with us. The second speaker is Dr. Mansur Mirta. Mansur, can you please introduce yourself? Yeah, thank you, Keita, and thank you for having me here with these great colleagues and friends. I'm chief oncologist in Rijkshospital, that is Copenhagen University Hospital in Denmark, and I'm also medical director of NSGO Nordic Society of Gynecologic Oncology in Denmark. So looking forward to it. Thank you for being with us. And finally, we are joined by Dr. Tashama Myers. We are so happy to have you with us. Can you introduce yourself? Hi, I'm Tashana Myers. I'm the division chief of gynecologic oncology at Baystate Medical Center, and I also serve as the medical director over clinical trials for our health system. Thank you for having me. We are very happy you are here. So let's get started. As part of the registration for today's webinar, all the attendees were asked to answer some questions. Today, we will share the results of the pre-recorded questions, and we will discuss the results with our panelists. I'm excited as we are discussing these results, because these are part of our art in maintenance treatment in first and second line. We will discuss the criteria for choosing treatment and also what are the unmet needs in patient journey and what will be the future, potentially future treatment option. So let's move to the first question, please, in the next slide. This is the history of a 64-year-old woman with stage 3c optimally resected ovarian cancer, which was HD positive, but with the BRCA mutation negative tumor. So the typical gray zone of HD positive, BRCA negative patient. What is the preferred maintenance strategies in first line? So it's very nice to see that for 54% of our colleagues, PARP inhibitor was the main strategy of treatment. 30% of them answer the combination of PARP plus BEV, according to Paola Wan. 12% of patients or colleagues suggest bevacizumab single agent in this patient, and up to 5% no maintenance at all. It's important to comment on this data. Rob, can I ask you your comment about no maintenance or bevacizumab maintenance? Yeah, thank you so much. I always love when we do polls like this because I think it reflects, obviously, what options are available to our colleagues all over the world. And I think that's kind of, this is how people actually deal with what their current situation is. And I think it's important to see that essentially 85% of the respondents to this question chose a PARP in one way, one form or another. But then there's this other cohort of patients, of respondents who the 15% or so that did not have PARP on there as an option. And so that could reflect regulatory guidelines and it could reflect opportunities. But I think we all recognize the desire to have something effective after primary therapy because 95% of our respondents picked something. So I think this is a very good reflection of the very much difficulty, the very hard situation we have in patients who have essentially resection of all optimal, of all the visible disease and have a great response to chemotherapy. And then know that the probability for recurrence is so high that we want to do something. And that has really driven the whole concept of maintenance therapy for years. But having something effective has been a struggle. But I think those are kind of some of the key, my first kind of key high points on this data. Oh, that's very important, the necessity to underline how much is important to provide maintenance treatment according to the availabilities we have in this moment. Mansoor, one million questions. You know, since three years, we discuss if PARP inhibitor alone or the combination of PARP plus BEV in this population. And also our colleagues, as you see, are quite split among these two options. In a patient with the complete optimal resection, what would be your first option for this patient? So first of all, thanks, Keta. I agree with what Rob just said. I would say that my goal here would be to see that each and every patient gets PARP, either as a single agent or in combination. That's a B thing. I want to see a patient with PARP, and I do understand some 15% of the patients may not receive it because of some regulatory issues probably. When it comes to the combination, as you know that we still need to define how much was the role of addition of bevacizumab, we do not have that arm in the Paola trial to answer that question. We try to indirectly find a way to say that they are doing better than the solo one and all that. But the evidence is needed in that. I would say if patient had stage four disease or any residual disease, I would give the combination. If it is patient is without any residual disease, I would give PARP alone in this setting because we have great data, both from solo one and from Prima trial on single agent, and in Paola we also have 4-HAD-positive population, the combination, and for the Pracabute. So that would be my preference. It may differ. It may vary. Now we saw the results of ICAN-8B trial, although PARP was not part of that trial, but still it gives more data on the positive efficacy of bevacizumab in stage 3 and 4 patients, in all patients. And indirectly, if you're comparing, I would say that I would be more prone to combination than single agent. However, we do not have first-line evidence. From a scientific point of view, what you say makes a lot of sense. Unfortunately, as you know, we do not have patients without residual tumor in Prima trial and this led to some regulatory restriction. In Italy, for instance, we cannot use, in a situation like this, we cannot use PARP-inhibitor as a single agent. Tashana, do you have the similar restriction in US or you can choose treatment regardless residual tumor? We can charge treatment regardless, but I do view these patients differently. I think this patient who has deemed to be favorable prognostically with the optimal resection is different than the residual disease, is different than the 4A. And so I do think that we should modify the treatment and it should be escalated for those with a slightly worse prognostic indication. Fully agree with you. Let's move to the next slide, please. Thank you. So this patient have received PARP-inhibitor in first line, either alone or in combination with Bevacizumab. So considering your prior selection, what you would offer to this patient as maintenance strategy if this patient with HRD Brachial type tumor recur 11 months after the completion of chemo receive another platinum-based chemo and respond to another platinum-based chemo? And here we have several options. Probably the question was misleading for the colleagues. Here we have a lot of options, 20% of our colleagues who suggest Bevacizumab, 23% PARP. Well, 25% would offer the combination in second line of PARP plus Bev. And there was 22% of patients, very interesting, who would offer a trial with an antibody drug conjugate maintenance. So Rob, starting again with you, how to interpret this? Yeah. So, yeah, and we'll get to a slide that we put together to kind of match what the first choices were or second choices were. But I think, so in general, I think it was a bit surprising because if you think about this in real time, if you, so to take away the individual level, if we have a patient who was given a PARP, which as I said, 75% of the, or 85% of the respondents in the first line said they would give a PARP. And then this patient essentially progresses during the PARP inhibitor. So they were on either PARP alone, or they were on PARP plus Bev, and they progressed. So then the patient comes back in the office at 11 months and they're like, okay, well, what are you going to do now? Well, okay, so we're going to start you back on chemotherapy and we'll use that chemotherapy as kind of an index to see whether or not you still have homologous recombination deficiency. And so if they respond again, people are saying, well, let's try it again, but we just don't have the confidence that that actually is true. We know that patients that progress on PARP inhibitors do develop many mechanisms that essentially translate into poor response to PARP again, even in the presence of platinum response. So I think that, that to me was a kind of a surprising number. And I, you know, when you always have a clinical trial option, if that is really in front of you in this kind of patient, I would jump on it. I mean, that would be a hundred percent, you know, cause I think, I think that's about a valuable option and something that we should do. But I think, I think you're right. I think, I think not knowing exactly what the first choice was and how that influences the second choice is kind of what is, you know, I think we should, you know, it would be neat to see. Absolutely, Mansoor, 25% of our colleagues would suggest the reintroduction of PARP at the time of recurrence. What are the evidence on this point? So this is, this is, I agree. This is a strange answer, either they haven't understood or I don't know how the practice is going on. Let's put it this way, 15% of the patients were PARP naive in this population and 85% of the patients are progressing under PARP therapy, either alone or in combination. So it doesn't make any sense to give PARP after PARP to these patients, either as a single agent or in combination with Bevacizumab. Actually, we have absolutely no evidence of combining PARP plus Bevacizumab in the patients who have received PARP before, we have some information from our NOVA about the combination, but otherwise we have nothing serious available in that sense. So I do not understand that 50% of this population is getting PARP again, while 85% had received PARP earlier, especially the combination makes no sense. And I completely agree with Rob, there are several trials ongoing, recruiting these patients who are not PARP naive, and they are being randomized to receive some sort of PARP combinations versus something else and all that. We are running a trial with a cancer therapeutic vaccine plus a checkpoint inhibitor plus PARP in this population. That is a clinical trial setting and that is what I'm going to do with this patient. If not, the patient who had received PARP plus Bevacizumab earlier, then first line, in my country, I won't be able to give any maintenance therapy. In US, you would be able to retreat them with Bevacizumab, right? Correct. And if those patients who have received PARP before, Bevacizumab will be the only choice for me in my country to treat them. So this doesn't fit to anything when I see that 50% of the patients are receiving PARP out of clinical trial, outside the clinic. What is evident is that when we choose treatment in second line maintenance setting, we have always to consider what patients have received in first line. And so we have to consider what are the limitations in prescription because the strategy of Bev after Bev, we have demonstrated it works, it reduced by 52% the risk of progression. Unfortunately, there are some limitations in the prescription and also in Italy, we cannot use it. Tashana, 23% of our colleagues suggest a trial with an antibody drug conjugated. Personally, I think... In maintenance setting. In maintenance. Yeah. Yeah. Exactly. And I'm strongly convinced that this new class of agent are probably among the most interesting class of agent we are using in this moment in oncology, but do you have a trial on this? There is something moving with this gene? Absolutely. Absolutely. I think, you know, this is an unmet need and I do understand, you know, PARP inhibitors were dramatic, radical, and I think some of the enthusiasm, people wanted to extrapolate, right? We go back to platinum agents and so could we possibly, and the data doesn't suggest. So I would suggest we have a trial in this space because this is an unmet need. The trial that we currently have is Gloriosa. It is looking at an ADC targeting folate receptor, folate alpha receptor. And what is interesting about this is that we already have an approval. We already know the target population where there's efficacy. We already have a valid test to find these patients. And the inclusion for those criteria are PARP, people who've had PARP exposure, people who've had Bevacizumab, right? So that would be 85% of the people that you're seeing in the frontline. It is for first line recurrence, platinum sensitive disease. and then patients are stratified by their PARP exposure, by their response, either complete, partial, or stable disease, and then by their exposure to bevacizumab. It's a two-arm trial. You will either have mervituximab in combination with bevacizumab or mervituximab by itself. Again, it's for folate alpha receptor. What I would suggest to patients, to clinicians, is that screen your patients early. This is going to be a drug that you will either use for their platinum-sensitive recurrence or the already approval of platinum resistance. It's important to know this, just like HRD status, as it's going to help dictate their care. Oh, this is very important, also considering what Rob say about the cross-resistance between PARP and platinum. And during ESGO last week, we saw the results of mervituximab in terms of efficacy, according to prior PARP, and the drugs works very, very well in PARP-pretreated patients. So this is a very important and interesting trial, and we will join the trial also in Europe, but we have some issue in this moment with the test according to the IVDR regulation, but we will solve and join the trial with you for our patient. Next slide, please. Oh, Rob, when this was for you, do you want to comment on that? Yeah, so what we tried to do on this slide, and I really appreciate Ashley for putting this together, but basically, we actually broke it down on a per-respondent basis. So going across on the rows, were the choices that were made with respect to the primary treatment. So no maintenance, you can see there were three individuals out of 60, whatever it is, 67, who chose no maintenance. That's where that percent came from. So if you look at that group, you can see that in the patients who had recurrence, of those, everybody picked something. So out of those three people who didn't use maintenance in the frontline setting, they used something in the second-line setting. So Bev or PARP, and you can see how that was set up. So to Minter's and to Shanna's point, if you look down at the people who chose a PARP inhibitor in the frontline setting, you can see, so 56 out of the 67 chose a PARP, either alone or with Bev or Susan, but when they recurred and responded again, you can see that five of those respondents basically said they would choose nothing in the next line of therapy. And that may be, again, that they don't have the availability. But just as surprising is that 15 people out of those 56 respondents would pick a PARP combination. So people who got PARP alone in the first line, nine out of those 15 people would choose Bev and PARP in the next line of therapy. So you can kind of see that there's a little bit of, it's kind of hard to like put the data together, but you can see how it's kind of all over the place. So of those 56 that chose a PARP inhibitor in the frontline setting, you can see that, what is it, 17 plus 11. So 28 of those individuals chose PARP again. So PARP after PARP. So very, very, very kind of interesting to see. And again, not having the information to know why they chose what they chose, I think that would really bring some color, even more color to these decisions, but kind of interesting to see that. So I fully agree. Maybe they misunderstood this question. I, it's very difficult for me to understand that. Well, one thing, Mansoor, I think you mentioned it, or somebody mentioned it, that, you know, if they're, you know, once the, we know that we don't have a dynamic biomarker for HRD proficiency or deficiency, right? So the HRD test was positive in this case, and the patients then, I guess, progressed on their treatment, but they were given platinum again and responded. And so people may be thinking, well, hey, listen, that's, this is a functional biomarker because it's DNA damage, you know, repair. And from the OREO trial, we have at least some evidence that there might be some benefit there, but it's not, it's not very strong. And when we've done, when we looked at patients who've actually progressed on a PARP inhibitor and started to annotate them molecularly, we find a very high percentage of reversion mutations and other, you know, factors that could, could limit the efficacy of a second exposure. Actually, actually there's many of these patients will not fit for OREO trial because- Right, that's right. The patient was in 11 months, right? That's right. Yeah, you're exactly right. And also- I hate to say that. And if I can add, probably we have also to consider what is the trade-off between the advantage of PARP reintroduction, according to the OREO that you mentioned, Rob, and the toxicity we pay. In second line, in the severely pretreated population, leukemia, myelodysplastic syndrome, particularly in BRCA mutant patient, as was this patient, no, sorry, this was wild type, but anyway, rises the incidence of leukemia and myelodysplastic syndrome is up to 6 to 8%. So probably the trade-off between the two months increase in PFS we reported in the OREO and the toxicity should be considered in the decision to reintroduce in PARP also. Next slide, please. Here we have another patient, another situation. This is a patient, stage 3C, optimally resected, HRP, the dark side of the moon, the patient with the worst prognosis. I like the statement, dark side of the moon. Exactly, exactly. What our colleagues suggest for this patient in terms of maintenance therapy, about 39% of them suggest Bevacizumab, 31% of them PARP-inhibitor, about 20% of our colleagues suggest the combo of PARP plus Bev, and still 15, 1.5% of our colleagues were not prone to suggest any kind of maintenance treatment. So, Rob, starting again with you, what about this choice? What about, for instance, PARP plus Bev in an HRP patient? Yeah, so, you know, in the US, what I will say is that the PALO-1 trial essentially addressed this question in a tech-to-treat population. So the study, without knowledge of HR proficiency or deficiency or even BRCA status, the trial was positive. And so that would support this if patients were started on Bevacizumab during chemotherapy, that they could add a PARP inhibitor if they hadn't progressed. That would support it. The regulatory decision in the US, as I'm sure it is in many parts of the world, don't support that. So if you look at PALO-1 and you cut out the HR-proficient and BRCA patients, or excuse me, the HR-deficient tumors and the BRCA tumors, that group of HR-proficient tumors didn't really seem to have a major effect, but in a non-analytical way. And I emphasize that. So the indication in the US is that it doesn't support using a PARP-Bev combination in patients who have tumors that are HR-proficient. So it wouldn't be an option in the US. In addition, part of this is also predicated on whether or not you started Bevacizumab to begin with. So if you have a patient who's stage three C-optimal and you have the information on the BRCA status and the tumor status, that they're proficient, you need to make a decision whether or not you're gonna use Bev because that's gonna define everything downstream. So if like for us, for me, I'm a Bev user, so in this kind of patient, I would have started them on Bev and of course would have then continued on Bev because I don't have the option to give a PARP inhibitor in the maintenance setting. Mansoor, this is a provocation for you. I am a Bev user as Rob, but you are probably more prone to use a PARP in this population. So this again, I think we can break down these four answers into different way. No maintenance. I may have had patients with no maintenance until I went to ASCO, but after seeing the data on ICANN 4B and seeing the overall survival benefit, I will have difficulty not giving any maintenance to these patients. So I would rather much give Bevacizumab to these 15% of the patients which are no maintenance. These are probably the patients upfront surgery, no residual disease, and these are the patients who did not receive maintenance. When it comes to Bev, probably we are, so what we are doing is we are trying to figure out where patient stands and we are giving Bev to all of our patients, even though I would like to give PARP inhibitors to some of these patients, but we are not because we are not allowed to do that by the regulators. So we have only one option, but otherwise that was the option of PARP or Bevacizumab in this population, because if you look at the data, probably you see the similar data, but now you have, I would say the data from ICANN 8B has superseded the data that we have from Prima trial because we are still waiting for the overall survival data for Prima trial. So I think I'm now getting more prone to Bevacizumab because of the ICANN 4B and until we see the overall survival data of Prima. If this again shows overall survival benefit, then we still have the two options, but I definitely do not understand the last option of combination because we do not have any data that that is beneficial. So yes, fortunately we do not decide on Bevacizumab any of these until we have the BRCA test and HRD test and we get it done and have an answer, if not on the cycle number two, then at the latest cycle number three. So we can take a decision and it's not late to add Bevacizumab if we need it or PARP is after six cycles. So this is our strategy. So we try to get upfront the genetic profiling so we can decide on the treatment. Dr. Shalala, in an ideal world in which you do not have any limitation in prescription as probably is your real situation, what do you choose in an HRP patient? Bevacizumab or PARP inhibitor? Looking at what Mansoor said, we do not have yet overall survival data, but we have 3.5 years follow-up data. What is your choice? I think we have to treat without emotion. I know we think that ovarian cancers deserve to see PARP inhibitors, but we have to use the data. And so my belief is that we give Bevacizumab in this clinical setting when this woman recurs, if she does and her biology declares itself, if she is platinum sensitive, she will have an opportunity to see PARP at that time and the efficacy will be established in that setting. So I feel comfortable not giving PARP in this clinical situation and reserving it when the efficacy is higher. I can agree honestly, completely with you. In second line, in this situation, we have two proof of platinum sensitivity, if the patient recurrence platinum sensitive and if patient experience another response to platinum. And as Rob said, this is the best predictor of PARP response so I could not agree more with you. Next slide, please. And this is the specular situation. So if this patient, HRP, recur 11 months after completion of chemo, she receive another platinum-based chemotherapy treatment, what option in the maintenance strategies we can offer? Again, Bevacizumab is the preferred choice for 27% of our colleagues, PARP for 23% of them, again, the combo for 12% of our colleagues, no maintenance, 11%, and Tashana, your trial again for 25% of our colleagues. So I think this trial is very famous in the world. So we will recruit very fast. Who wants to comment on that? Next slide, Rob is for you, probably you. Okay. Can you go back? I just want to mention one thing. So I feel uncomfortable with the 23% of the 24% of the population, the one who are not getting any maintenance and the one who are receiving combination of PARP plus Bevacizumab. I agree for all other options which are set. I still believe that there will be patients who have not received maintenance upfront or who have received PARP so they can get Bev or they have received Bev and they could get PARP, but combination, I don't understand. So my, you know, I would say that no maintenance or combination should not be an option, but 24% of the patients are getting one of the two. May, I don't know if Rob, you want to comment? Well, you know, I do think that it may be again, such, you know, health ministry restrictions on that. Yeah. So in other words, so some of the no maintenance, we'll see this in the next slide. Some of the no maintenance option people were the no maintenance. Sorry, Robert. Oh, go ahead. Can we have the next slide, please? Yes, this facility. So you can see, if you look at the no maintenance in the recurrent, so that the first column there, there's eight people that chose no maintenance. So three of those people had no, chose no maintenance in the frontline setting. So you can see almost half of them probably just didn't have it as an option as well. But you can see there, to your point, you know, these people are very, they're not curable. So having some option for them, you know, is valuable. And it looks like in this patient population of HRP tumors, that four out of our eight people who chose no maintenance in the frontline setting decided, hey, I might as well give them something. So again, you know, it is kind of hard to sort through that. But I think, again, you can see in this table that there's a lot of reuse of PARP in, you know, in an HRP in the frontline setting with progression while on it, still wanting to use some kind of PARP in the second line setting after platinum response. So very high numbers. As you mentioned, Minster, a little surprising. But again, 25% of our colleagues would choose your trial, Tashana. Are you still, the trial is open in US? Absolutely, open and recruiting. And what I would say, the incidence of positivity, at least based on the platinum resistance studies, were 35 to 40%. So there's gonna be a significant portion of patients that are fully receptor alpha positive. And so this is just adding options. We're not trying to take away options. We assume that the more favorable patients have already seen a PARP, have seen Bev. And so this is going to be applicable in real world for this second, first recurrence platinum sensitive. Very, very good. Unfortunately, we are at the end of our webinar. This is all the time that we have today. Thank you, Rob, Mansoor, Tashana, for your time, insights, and expertise. And thank you also to ImmunoGen for supporting this webinar. Thank you for all the attendees. And you were a lot. And I just want to remember you that the recording of this session will be available on IGCS Education 360 Learning Portal by the end of the week. We wish you good to continue healthy and safety. Thank you for attending. And thank you, Keta. Thank you, Keta. Thank you. Thank you. Great, great discussion. Great session. Thank you, everyone. It's good to see you. Good to see you. Bye, bye-bye. Bye-bye.

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maintenance therapy

ovarian cancer

treatment options

PARP inhibitor

Bevacizumab

clinical trials

trends

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preferences

PARP inhibitors