Future Outlook of Advanced Ovarian Cancer Treatment

EP: 1.Overview of Advanced Ovarian Cancer

EP: 2.Role of Biomarkers in Advanced Ovarian Cancer

EP: 3.Role of PARP Inhibitors in Advanced Ovarian Cancer

EP: 4.Advanced Ovarian Cancer: Updated Indications for PARP Inhibitors in Second- and Later-Line Settings

EP: 5.Advanced Ovarian Cancer: Current Treatment Landscape in Second- and Later-Line Settings

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EP: 6.Future Outlook of Advanced Ovarian Cancer Treatment

Transcript:

Bradley J. Monk, MD, FACOG, FACS: This has been an organic and exciting conversation. Maybe we can talk about something, because when you and I had planned this, it didn’t happen. A wonderful day on November 14th was, for the first time in 9 years, we got a medication approved, the first antibody-drug conjugate, which you’re very passionate about being one of the global PIs [principal investigators], SORAYA (NCT4296890) and mirvetuximab. Tell us a little bit about that. Then I want to spend the last few minutes talking about MIRASOL (NCT0409855).

Robert L. Coleman, MD, FACOG, FACS: That sounds good. We should talk about some of the other exciting ones coming, as well. SORAYA was a “phase 3 trial” that was looking to evaluate the efficacy of mirvetuximab, which is an antibody-drug conjugate that is linking soravtansine analog to folate receptor alpha. This is a drug that’s had a long history of development. It went through a phase 3 [trial] that used a different methodology; I think you mentioned what the cutoff for this expression is, but it had a different methodology. It was rebranded with a different methodology to provide better predictive value for folate receptor expression. As an antibody-drug conjugate, at least in this setting, you want this alignment of tumor cells that are coded with the target antigen so that we can hit it with the antibody-drug conjugate, and it can then bring the chemo warhead into the cell.

This trial was done in FR [folate receptor] alpha high-expressing tumors, it was looking for objective response, it demonstrated over 32% response rate, and the duration of that response was almost 7 months. We just reported at SGO [Society of Gynecologic Oncology] this year that the overall survival is over 15 months, which is nice to see in a patient population that’s seen up to 3 prior regimens. These patients received bevacizumab before, and over half of them received a PARP inhibitor. [This is] what we would consider a contemporary platinum-resistant cohort of patients with prior exposure demonstrating a remarkable objective response rate. This was persuasive, as you mentioned, receiving accelerated approval in November, and as we just heard, we have the positive results from the MIRASOL trial, do you want to dig into that?

Bradley J. Monk, MD, FACOG, FACS: Yes. You call it a phase 3 because it was a pivotal trial and you’re right, but it was a single-arm trial and the FDA is concerned about these dangling approvals that we’ll get accelerated approval and it will sit around for a long time. That happened on November 14th and then on May 3rd, the confirmatory trial, which was the same cohort of 1 to 3 priors, but it did not require bevacizumab vs physician’s choice chemotherapy. The shot was heard around the world. This is the first trial ever in platinum-resistant recurrent ovarian cancer to show a survival advantage. We’re not talking about a little survival advantage, we’re talking about an improvement of about 4 months, a hazard ratio of 0.65. The PFS [progression free survival] benefit, which was also positive in this 453-patient randomized phase 3 trial, and the OS [overall survival] was about the same as the PFS and, although there were 1 to 3 priors, half or 47% had 3 priors. These are patients who have seen a lot of bevacizumab and a lot of PARP. This will not expand the indication, because we already have it, but it’ll confirm it. It’ll improve if there are any reimbursement problems. I don’t think there are in the US. Remember the shot was heard around the world, so this will bring this medication to every country.

Robert L. Coleman, MD, FACOG, FACS: I think you’re right. What’s reassuring about this trial is that although the patient populations were slightly different, the trend for objective response, PFS, OS, very aligned. If people were looking for confirmation, this is right on target, so very important. Nothing new about the safety signals. We have a good understanding of how to give this and predict when, for instance, the ocular toxicity occurs and how we mitigate that, but it also provides us, as we’ll see when the results become fully disclosed, of how chemotherapy performs, provides the need. People always ask, “Why do we keep looking for new drugs?” Because we need it. This is setting a new standard for us and we’re hopeful that with the coming trials, we’ll be able to potentially expand on this success.

Bradley J. Monk, MD, FACOG, FACS: Three commonly used medications, liposomal doxorubicin, topotecan, and gemcitabine, have a response rate of 10% or less. The accelerated approval was based on 31%. Now, as we learn how to give the medication better, the phase 3 randomized trial is 42%. Not only is it better, but the adverse reactions vs chemotherapy were less.

Robert L. Coleman, MD, FACOG, FACS: Don’t you love seeing that? I love seeing a more active, less toxic drug. It’s awesome.

Bradley J. Monk, MD, FACOG, FACS: It’s awesome, but I just had to get that out there because it’s practice-changing, it’s game-changing, it’s standard-of-care changing and I’m so happy for the investigators and the patients, most importantly.

Robert L. Coleman, MD, FACOG, FACS: Absolutely. As you mentioned, it’s so unprecedented. We’re excited to be able to have something new in the space, but let’s talk about it briefly because we’re about to close, what are you excited about as we look forward? Because now this was in a patient population that was narrowly defined with respect to its biomarker expression in the tumor. We know that screen fail rate in the trial was around over 60%. We’re seeing slightly less higher rates, but this is going to be a defined population. What do we have coming that you’re excited about for the rest of them?

Bradley J. Monk, MD, FACOG, FACS: Three things. Number 1, other ADCs [antibody drug conjugates]. You mentioned UpRi [upifitamab rilsodotin], which is against NaPi2b. Their pivotal phase 3 trial will report later this year, shortly after ASCO [American Society of Clinical Oncology], probably. I’m also interested in combinations in earlier lines of therapy. Mirvetuximab can be added to bevacizumab in the frontline platinum-sensitive maintenance, that’s called GLORIOSA [NCT05445778]. We can’t give up on PARP inhibitors. PARP inhibitors work in HRD [homologous recombination deficiency] test negative; we talked about it. But there are trials where immunotherapy might make PARP work even better, with or without bevacizumab. Those trials are now starting to read out; there’s 4 of them, and more than 5,000 patients. I have new ADCs, earlier lines of therapy, and novel combinations, including ADC-bevacizumab and PARP-IO.

Robert L. Coleman, MD, FACOG, FACS: We also have tumor treatment fields. That will be coming this year, so we have all these new things. We’re focusing on biology. I think you emphasized it nicely in the beginning of this conversation that the information that we can gain from the tumor can help us annotate what kinds of treatments we could potentially have options for in the recurrent setting. Now that we’ve learned about how PI3 kinase pathway aberrations can be leveraged, and the gamut of other events that can happen in the tumor microenvironment that we can target, there’s a lot of hope for the future. Hopefully we’ll continue to expand this space and find new therapies, and ultimately be able to change and improve upon some of those subgroups in the frontline setting where we still need effective and active therapies. That’s exciting. It’s been a great conversation, Brad; thank you for your insight on this space. Your passion for clinical trials, as you just mentioned; I saw you pounding the fist. That was great. Put [patients] on them because that’s our best opportunity.

Bradley J. Monk, MD, FACOG, FACS: That’s our best opportunity.

Robert L Coleman, MD, FACOG, FACS: Absolutely, and we’re so pleased. For all of you who are listening in, thanks for joining us. Please consider clinical trials; you have access to them. I know I speak for Brad; reach out to either of us if you have questions about this or how we can potentially help you find appropriate trials for your patients. Brad, any closing comments?

Bradley J Monk, MD, FACOG, FACS: Just thank you for your support and everything you’re doing. It’s a lot of work, and I appreciate the audience. Thank you. So long for now.

Robert L Coleman, MD, FACOG, FACS: So long. Thanks.

Transcript edited for clarity.