Emerging Therapies in Recurrent Ovarian Cancer

Bradley Monk, MD, FACOG, FACS: You and Katherine Fuh, [MD, PhD,] at your institution, [the Washington University School of Medicine], are working on this pathway that many of our listeners may not have heard about. It’s called AXL. Tell us about that.

Matthew Powell, MD: Yes. It’s quite exciting. When Katherine was a graduate student, she was involved with the discovery of this pathway, and we now have a drug to help drug this pathway. It’s coming full circle. AVB-S6-500 is the drug. We’re combining that with either liposomal doxorubicin or paclitaxel. This inhibits the GAS6/AXL-mediated signaling, which is a growth factor pathway involved in both endometrial and ovarian cancer. We’re really quite excited about this. It’s a fairly tolerable combination, and results are yet to come.

Bradley Monk, MD, FACOG, FACS: Shannon, I know you guys have a spore. You do all sorts of early phase development, so I want to ask you an open-ended question. At [The University of Texas] MD Anderson [Cancer Center], you’re so good at clinical trials, and so many of your patients go on trials in platinum-resistant recurrent ovarian cancer. What are some of the agents that you’re excited about at MD Anderson?

Shannon N. Westin, MD, MPH, FACOG: To Mike’s point, we’re getting better at being more selective. We have a number of trials that are looking at overcoming PARP resistance, but not just slapping together 2 things randomly; we’re starting to select what pathways might be important in the development of PARP resistance, whether that’s innate PARP resistance or adaptive. We found a lot of interesting results with combinations around PARP and PI3 kinase-directed agents, and PARP and MEK-directed agents.

It’s been exciting to see populations that we wouldn’t expect to respond to PARP Inhibitors getting a benefit there. We’ve also had the opportunity to start developing some agents that target, either directly or indirectly, TP53, which in high-grade serous ovarian cancer is arguably the holy grail. If you could use that against the tumor, then you could have a benefit. We’ve had some interesting results around B1 as well as some drugs that seem to reactivate TP53.

Bradley Monk, MD, FACOG, FACS: It’s exciting that we can talk about frontline and then novel drug development. I know, Leslie, you work on a drug with a lot of people, but you’re very passionate about this VB-111. It’s a gene therapy? Tell us about that.

Leslie Randall, MD, FACOG: VB-111 is interesting. It’s first-in-class, and it has this dual activity. In one respect it’s an antivascular gene therapy. It’s also like an antiviral therapy to the drug, and it delivers a second cytotoxic hit to the cell. It’s interesting. There’s a trial looking at it in combination with weekly paclitaxel. This is a randomized phase 2, weekly Taxol [paclitaxel] with or without VB-111. This is a different way of targeting a very targetable active drug, antivascular, a great target in ovarian cancer, but hitting it in a very different way with this drug.

Bradley Monk, MD, FACOG, FACS: Yes, the challenge with these is that they’re large studies but with very little information. For that particular trial, I was struck by the interim analysis that was, incidentally you sit on our publications committee, and do press releases. Dr Randall does so many things, and she’s a cervical cancer doctor too, although we’re talking about ovarian cancer.

Leslie Randall, MD, FACOG: That’s why I can’t remember the words half of the time.

Bradley Monk, MD, FACOG, FACS: You’re great. The interim analysis for this study, which is called OVAL, was positive. It was prespecified, and it’s in the public domain, so I invite you to look at that. Thank you, Leslie, for your passion on that.

Then, Matt, magnets, really? Magnets can cure cancer? Come on man, tell us about that.

Matthew Powell, MD: Yes, this is cool stuff. INNOVATE-3, which is also what we call GOG-3029, is using alternating electrical fields to disrupt cancer cell growth. It’s cool stuff, and when we first heard this presented, we were like, “That seems crazy,” but for glioblastoma and brain tumors, it’s working. It has pretty impressive data. This is a randomized phase 3 trial with weekly paclitaxel and using these electrical fields to disrupt tumor growth. Neat stuff.

Bradley Monk, MD, FACOG, FACS: Yes. You strap on this magnet, and it changes the electrical fields. The vest doesn’t move, but the electrical fields change. Like you said, “Really?” Then they got 2 indications in glioblastoma multiforme, and then they got it in thoracic mesothelioma. This is a collaboration with our ENGOT [European Network of Gynecological Oncological Trial Groups] colleagues, and then you say, well it disrupts the spindles, and if you add weekly paclitaxel to it, then there’s a synergy. Think of that. Antibody drug conjugates, magnets, gene therapy that gets an immune response as well as an antivascular oncolytic virus, and then some combinations with PI3K and even a TP53 target.

The last study that I want to highlight is one that I’m particularly passionate about, called MOONSTONE. In fact, Leslie, you’re the PI [primary investigator] for it. You tell us about MOONSTONE.

Leslie Randall, MD, FACOG: Yay, thank you for talking about MOONSTONE. It’s an exciting trial. MOONSTONE is a combination, and I agree with Shannon 100%. PARP inhibitors are great drugs. How do we make PARP inhibitors better?

This trial is niraparib in combination with the dostarlimab that we talked about in frontline ovarian cancer, a PD-1 inhibitor. It’s based on the preliminary data from TOPACIO. The TOPACIO trial was a breast and ovarian cancer trial that looked at niraparib with pembrolizumab in that population and showed an 18% response rate in the ovarian cancer cohort. Interestingly, there was a 65% disease control rate, and most of the responses were in biomarker-negative populations. Here, we’ve been talking about how biomarkers guide treatment in the platinum-sensitive population. Here, we have a resistant population, both BRCA wild type and PD-L1 negative having responses to this combination. The thought is that the PARP inhibition upregulates the PD-L1 expression, so it induces the susceptibility to the checkpoint inhibitor that you would not have seen had you not given the PARP inhibitor.

MOONSTONE is the follow-on, single arm, phase 2, open label with a registrational intent for that combination. Hopefully that will be successful, and that’s ongoing.

Bradley Monk, MD, FACOG, FACS: Yes. Again, thank you for your hard work.

Transcript edited for clarity.

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