PARP Inhibition in Ovarian Cancer: What's Next?

Thomas J. Herzog, MD:The other thing that’s interesting though is this whole concept of, can we cure more of these women with these drugs? Whether it’s veliparib, whether it’s niraparib, whether it’s olaparib, and we’ll have other data with rucaparib in the frontline setting with the ATHENA trial.

Bradley J. Monk, MD, FACOG, FACS:That’s right.

Thomas J. Herzog, MD:If we look at the curves on SOLO-1, they’re very impressive in terms of what we have, the PFS [progression-free survival] data. We’re going to get a look at the OS [overall survival] data very soon. And I think people are really fascinated by that, because we hopefully helped the FDA understand that because of the difficulty with crossover treatments and so many other active treatments, achieving an OS in ovarian cancer with a disease course that runs as long as 6, 7, 8 years is nearly impossible. However, if we’re able to effect that change in the frontline setting where they never have any other drug, we will see an OS, and that’s the hope.

Bradley J. Monk, MD, FACOG, FACS:That’s right. And you talked about combination. The idea is that maybe in this HRD [homologous recombination deficiency]-negative group, I/O [immune-oncology] can make PARP [poly ADP ribose polymerase] better. In the HRD-negative group, bevacizumab and PARP do not seem to synergize or even have an additive effect. And so we have ATHENA, which is switch maintenance with rucaparib and nivolumab. But we also have durvalumab, the DUO-O trial; OV43, pembrolizumab; and FIRST, dostarlimab. So we’ll have all these I/O PARP combinations, these other 4 trials, probably in about 2 years.

The study that’s next will be bevacizumab I/O, and anti-VEGF I/O has been very transformational in renal cell and lung cancer and these other opportunities in endometrial cancer, where you saw pembrolizumab/lenvatinib is also approved. So I’m excited about bevacizumab/atezolizumab, which is the next frontline trial to report.

Thomas J. Herzog, MD:It’s all about combinations, right?

Bradley J. Monk, MD, FACOG, FACS:Particularly in the HRD-negative group.

Thomas J. Herzog, MD:Exactly.

Bradley J. Monk, MD, FACOG, FACS:That’s the unmet need.

Thomas J. Herzog, MD:Well, we know that the PARPs are so dominant if you have homologous recombination deficiency. So if you are positive for that measurement then you will certainly benefit from a PARP; or not certainly, but the chances of you benefiting are significantly high.

Bradley J. Monk, MD, FACOG, FACS:The other thing that you’ve taught me is that pretty soon most patients with ovarian cancer are going to be PARP exposed, so that the next unmet need is how to overcome PARP resistance, and do you have any thoughts on that?

Thomas J. Herzog, MD:Well, first of all, we need PARP-after-PARP data, which are cooking. We have some small series that have come out but nothing that’s big enough for us to really change practice with some reassurance that you can certainly give PARPs. Do you give a different PARP, how does this work? Are there some differences between these PARPs? These are all things that need to be ferreted out.

Bradley J. Monk, MD, FACOG, FACS:Or add another drug to it.

Thomas J. Herzog, MD:Exactly. Combinations, exactly. I think there’s a lot to digest there. The resistance area is very complex. There are at least 10 different resistance mechanisms that have been hypothesized. Now whether all these are actually in play is hard to know. But we do have data on these reversion mutations, which is a very interesting phenomenon. Liz Swisher, MD, and her group at the University of Washington have done a fair amount of work on this looking at the patients who have aBRCAmutation that is an unstable mutation that over time reverts to a functional gene, whereby they are essentiallyBRCAwild-type and would not have the same benefit from PARP inhibition.

Bradley J. Monk, MD, FACOG, FACS:But as you said, there are other mechanisms too.

Thomas J. Herzog, MD:Exactly, and we don’t know. Does that scarring that occurred still make them more sensitive to a PARP? I think there are a lot of assumptions that just because there was a reversion, they would have no activity from a PARP; we need more data on that.

Bradley J. Monk, MD, FACOG, FACS:Well, this has been a lot of fun, buddy. I appreciate it. I want to thank you, Dr Herzog, for this insightful discussion. And thank you to our audience for joining us during thisTargeted Oncology^TMpresentation of PARP inhibition. Thank you, and so long for now.

Thomas J. Herzog, MD:Thanks for having me, Brad.

Transcript edited for clarity.