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Welcome to CME on ReachMD. This activity, entitled “Keeping Pace in Women’s Cancers: Ovarian Cancer—From IO to PARP” is provided by AGILE and is supported by an independent educational grant from Merck.
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Here is Dr. Floor Backes.
Dr. Backes:
Immunotherapies have changed how a number of different cancer types are managed because they have significantly improved the quality of life and survival of so many patients. But what is their role in ovarian cancer? And how do we determine their use in the PARP era? Welcome to our discussion on Keeping Pace in Women's Cancers: Ovarian Cancer—From IO to PARP. I'm Floor Backes, and I'm joined today by Dr. Robert Coleman. Welcome to the program, Robert.
Dr. Coleman:
Thanks so much for having me. This is great. I just wish we could be face-to-face, but nonetheless, happy to be with you virtually.
Dr. Backes:
The focus on ovarian cancer, as with many other tumors, is finding predictive biomarkers. Where are we today in that area, Robert?
Dr. Coleman:
Predictive biomarkers are specifically focused on aligning a therapy or an intervention on the basis of some characteristic and expecting only that group to do better. So with respect to predictive biomarkers of ovarian cancer, we've had very few. It's just been this last maybe, I don't know, maybe 5, 6 years where we've started to understand the role of the homologous recombination or DNA damage response alterations, factors like MSI [microsatellite instability] status within the tumor, tumor mutational burden, that these joined a very limited number of other biomarkers that we have had experience with, for instance, estrogen and progesterone receptor in endometrial cancer. And so as we think about what's happened in the last, like, 5 or 6 years or so when the PARP inhibitors have started to come on the scene. We recognize that these BRCA1/2 mutations we found in tumors were aligned with an intervention that's targeting that that specific pathway, the PARP inhibitors, which we're going to talk about. We now know that we can broaden that particular character to homologous recombination deficiency. So even in wild-type for BRCA in the tumors, that these agents seem to have some merit. And then as we expand into the immunotherapy, understanding MSI-high status, tumor mutational burden. And these factors now have also been aligned with specific therapies. And of course, we have approvals that have been based on that. So as we look at this and spreading this information around the world, we're starting to see this uptake in more targeted therapies using targeted agents. But the key to this, the key for all of the success is understanding the background or the underlying component of what a predictive biomarker is.
Dr. Backes:
Yeah, and I think one of the other biomarkers that we also hear mention of a lot of times is the PD-L1 as a biomarker. And while that may be a reasonable biomarker in some other diseases, we've just not seen that similar success in ovarian cancer. We still have a long way to go. PD-L1 status does not seem to really predict if patients are going to respond to immunotherapy, at least not for ovarian cancer.
Dr. Coleman:
I think our approach is focused pretty strongly around the BRCA and tumor assessment. So we generally will get now – because you can almost do co-testing most diagnostic kits, so you get both tissue and blood. And I think that's going to be important when we try to decide how we're going to utilize that information. But at least we do understand what the somatic and germline status of the patient is. Obviously, germline data is also important for doing risk assessment for familial members as well as the patient herself. And you know, when you started to think about, well, where do these drugs work relative to their own predictive biomarker? Well, MSI and TMB are ones that we now have linked therapeutic agents across multiple different tumor types, including ovarian cancer. So the question is, and I question myself on this as well, you know, maybe we should be adding it like we do with endometrial cancer, at least to get that assessment done at some point along the journey.
So, Floor, the next big question is, you know, what do you do with these test results? I think there's been significant progress with the use of PARP inhibitors in platinum-sensitive recurrent ovarian cancer. What do the latest data tell us?
Dr. Backes:
Yeah, we have a lot of data now available, very exciting data in the platinum-sensitive recurrent ovarian cancer. We recently had results from the SOLO-2, the NOVA trial with niraparib, ARIEL3 with rucaparib, and all of those showed similar decreases in risk of cancer progression or recurrence with the use of the PARP inhibitor versus placebo maintenance. And all of those also showed activity across – for all comers, but specifically for those patients – or higher and longer progression-free survival for those with the BRCA mutation or who showed evidence of homologous recombination deficiency.
But now, more recently, we've had the long-term data from the ASP, from the from the SOLO-2, that was presented at ASCO last year, and the overall survival for these patients who received olaparib maintenance in the recurrent setting versus placebo and who had a BRCA germline mutation, they had a 13-month overall improvement or improvement in overall survival. And so our median overall survival went from 51 to 38 months, which is remarkable to have that in the recurrence setting. And now that we've seen that in a recurrence setting and have taken all these PARP inhibitors to the frontline, I'm very excited about the results that we've seen there. SOLO-1, for example, which was olaparib compared to placebo for patients with the BRCA mutation, either germline or somatic mutation. And while they only took the study intervention, so olaparib or placebo, for 2 years, it showed a huge improvement – 3 ½ years at 5-year follow-up in progression-free survival. So I'm really encouraged by these things that we're now seeing. And with this long and the flattening of the curves, that hopefully we'll see that translate also into overall survival and that we're actually curing more patients, which is something, really, that we've been waiting for, I think, for a long time in ovarian cancer and haven't really been able to do.
Dr. Coleman:
Yeah, I would totally agree with you. I think what is really remarkable with that longer follow-up we saw in SOLO-1 is – just as you mentioned – that the tails of the curve don't come back together. And we have seen that with other biologicals, particularly with bevacizumab in all of the trials, essentially, that have been run with that agent. But with 5 years and still seeing a 28% difference between the curves, that's just, to me, very remarkable.
Is there a patient population in the platinum-sensitive space where we don't, for instance, use PARP, or you have to make a decision between PARP and bev? Because bev has also proven the same in the same situation.
Dr. Backes:
Absolutely. Now when you are choosing your PARPs, how do you select which drug is the right drug for the right patient?
Dr. Coleman:
I love it. Yeah. We've gone through this question so many times. I think what I’ve come to understand is that many, many people get comfortable with the drugs. I think from an efficacy standpoint, we aren't nuanced enough to see that there's a big discriminator between them. So it gets down to how you manage the adverse events and how your patient actually tolerates different regimen schedules. But ultimately, it's how do you work well with your patient to make sure that the patient can stay on effective dosing of the drug for the longest duration of time, because we know that that's the key. But I think that many people should get comfortable with one, know how to dose modify it, know what toxicities to look out for, and know when they come. And so then they just feel comfortable with knowing that the efficacy signal will be basically consistent between the 3.
Dr. Backes:
Yeah, and I think for myself, also, if I have a patient with difficult-to-control hypertension, I'll typically try and avoid niraparib, or very high cholesterol I’ll try, or LFT - problems with their LFTs [liver function tests], I'll try to avoid rucaparib, but those are just some of the main things. Otherwise, I agree with you. They're very similar, but every patient can respond differently to each of the drugs, which kind of keeps it interesting for us for sure.
For those just joining us, this is CME on ReachMD. I’m Dr. Floor Backes, and I'm here today with Dr. Robert Coleman. We're discussing the emerging perspectives in the management of ovarian cancer.
So, Robert, let's turn our attention to immunotherapy in ovarian cancer. We know that single-agent immunotherapy has not given us the returns we are hoping for. So is there still a role for immunotherapy in this space.
Dr. Coleman:
I do think that the secret sauce for immunotherapy probably is there for ovarian cancer, but I think the mistake we made was adopting what we were seeing in melanoma, lung cancer, and others directly into ovarian cancer. Essentially kind of making that discrimination between tumors that are driven by high mutational load, high new antigen exposure, versus those tumors that are associated with high numbers of copy number alteration. Ovarian cancer is a high copy number alteration tumor. It doesn't mean that we shouldn't stop looking, because I do think that the benefits that we've seen in some unusual responding cases, both with immune checkpoints such as CTLA-4 and PD-1, PD-L1, but in certain tumor types, we've seen these really long tumor control situations in recurrent patients where we wouldn't have expected it, and they may have stopped therapy but still had good long-term tumor control. So these kind of unusual responders, I think, are telling us that there is a way to educate the immune system to a specific tumor where you can get long-term disease control.
So I mentioned earlier about, you know, TMB and MSI status because in ovarian cancer, we're talking 3% to 5%, maybe, of the tumors that fall into this kind of disease category. And I think this is probably also one of the big detriments to the phase 2 experiences that we've had with the immune checkpoint in ovarian cancer with kind of an all-comer design, is that we really – we check their PD-L1 status, which isn't a great biomarker. We didn't check the MSI status, which is a good biomarker. So we really don't have a great kind of annotation of our current experience to date. But I think we're starting to learn, and as we continue to evaluate ways to improve this by targeting other inhibitors, I think obviously there’s been a lot of interest in some of these other factors, like OX40, TIGIT, and some of these other components that can help increase the awareness of the immune cells in the tumor microenvironment and also kind of decreasing the inhibition effects that can be there.
Dr. Backes:
Yeah, I agree. I think basically what I'm hearing you say is how do we make these tumors more immunogenic, or how do we make it more susceptible to the immunotherapy? And we've done a lot with the single agents, but I completely agree that we can’t just look at one active agent, and we need to combine them. We'll probably need to combine them with other things. And we've seen some good responses when we combined it with antiangiogenic treatment, like you mentioned, with the CTLA-4 agents. TIGIT, that's under study now in solid tumors and not specifically necessarily in just ovarian cancer quite yet. But I'm sure that that is going to come up. And you mentioned a couple of other ones, OX40, and there’s many more. I’ve seen the trials with rucaparib and nivolumab; DUO-O with durvalumab, bevacizumab, and olaparib; FIRST with niraparib plus dostarlimab, you name it. There's lots of different combinations, pembrolizumab with the olaparib. And so I think over the next couple of years, we're going to know a lot more. Is immunotherapy here really to become a big player, or should we find different avenues and maybe focus more on tumor vaccines or T cell therapy here, things like that?
Well, this has certainly been a fascinating conversation. But before we wrap up, Rob, can you share one of your take-home messages with our audience?
Dr. Coleman:
Well, I guess my one take-home message is to remember what I mentioned about the predictive biomarker, and it's going to be super important, I think, for us going forward. And to add on to what you mentioned about the trials that are coming in the frontline setting because, as you mentioned, in addition to chemotherapy, we have 3 strategies that we're trying to look at. We're looking at PARP inhibition. We're looking at immunotherapy; we’re looking at anti-angiogenesis. These 3 agents, we think, have a very important role to play.
Dr. Backes:
Yeah, I couldn't have said that any better. I fully agree with you. And that was a really nice summary. And then, as you mentioned before, finding that biomarker that would predict who may respond to immunotherapy early. And if they don't have that biomarker, how can we make the tumor more immunogenic and less immunosuppressed? Then, yeah, we're going to make some great strides in ovarian cancer. So lots of work still to do.
Dr. Coleman:
Absolutely.
Dr. Backes:
Well, unfortunately, that's all the time we have today. I want to thank our audience for listening in and thank my colleague, Dr. Robert Coleman, for sharing his valuable insights. It was great speaking with you today, Rob.
Dr. Coleman:
Thanks so much for having me, and this was really enjoyable. Thank you again.
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