Practical Use of PARP Inhibitors in Ovarian Cancer

Bradley J. Monk, MD, FACOG, FACS:Let’s start to synthesize this. We have 7 approvals for PARP [poly ADP ribose polymerase] inhibitors; 3 in treatment: olaparib, rucaparib, and niraparib just in October of 2019. We have 3 platinum-sensitive maintenance approvals: NOVA for niraparib, Study 19 or SOLO-2 for olaparib, and ARIEL3 for rucaparib. So 3 and 3. And then we have frontline SOLO-1 maintenance only inBRCA. That’s where we are today.

And then soon we’re going to have frontline maintenance beyondBRCA. So we’ll probably have 10 FDA approvals of PARP inhibitors. And then also we’ll get the combinations, which we’re not going to talk about today. We also have the 3 bevacizumab approvals. Frontline, we just talked about it; platinum-resistant, which is really a trial with single-agent chemotherapy; and then OCEANS and GOG-213 with platinum doublets. That’s what people look at as chaos. Let’s bring order.

Thomas J. Herzog, MD:OK. That’s good.

Bradley J. Monk, MD, FACOG, FACS:So here’s how we do it. When you see a patient with newly diagnosed advanced ovarian cancer you have 2 decision points.

Thomas J. Herzog, MD:Right.

Bradley J. Monk, MD, FACOG, FACS:In the beginning, and then at the end of 6 cycles. I think you have to look at these 2 decision points, and they’re connected, because what you did with the first decision point informs the second decision point. Can we agree—I’m not sure we can, let’s try it—that at the first decision point when you start a patient on chemotherapy, you’re probably not going to have the HRD [homologous recombination deficiency test result] back. There are some people who think, “I’m going to get it back; it takes a week.” Listen, the pathologists are not going to release the tissue that quickly. Then it takes time to process the specimen and you are motivated to get your patient on effective treatment. So at the first decision point, let’s go through the choices. Chemotherapy alone. Chemotherapy with bevacizumab. And if veliparib gets approved, chemotherapy with veliparib. How do you make that decision? First decision point: chemotherapy, chemotherapy/PARP, chemotherapy/bevacizumab. How do you make that decision?

Thomas J. Herzog, MD:For me, chemotherapy alone is becoming less attractive.

Bradley J. Monk, MD, FACOG, FACS:Yes.

Thomas J. Herzog, MD:And I think that pushes you toward the other 2. There are still patients who are frail, who might now have a lot of bowel involvement, what have you.

Bradley J. Monk, MD, FACOG, FACS:Stage II patients, early.

Thomas J. Herzog, MD:High hypertension. Other patients who are not as high risk. But as you know, if the disease is outside the ovary, these patients are all at pretty significant risk.

Bradley J. Monk, MD, FACOG, FACS:Right, and they need maintenance.

Thomas J. Herzog, MD:They do.

Bradley J. Monk, MD, FACOG, FACS:Either with bevacizumab or with PARP inhibition.

Thomas J. Herzog, MD:That’s right.

Bradley J. Monk, MD, FACOG, FACS:And I say you have been making the decision to use bevacizumab or not since June of 2018. You’re comfortable making that decision?

Thomas J. Herzog, MD:Yes.

Bradley J. Monk, MD, FACOG, FACS:So if you decide to use bevacizumab, you’re probably not going to stop it, OK?

Thomas J. Herzog, MD:Well that’s where—and you’ve taught us this, Brad—that coupling between decision point 1 and decision point 2 is much firmer than what people want to admit.

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

Thomas J. Herzog, MD:It’s very true. And take us through that because I think it really illustrates how if you start going down 1 road, the momentum will keep you going on that road.

Bradley J. Monk, MD, FACOG, FACS:The momentum will keep you going. If you start veliparib, it’s a second decision point; assuming she doesn’t progress, continue it. If you start bevacizumab, you’re going to continue it in the maintenance phase. And if she’sBRCAor HRD-positive, you’re going to layer olaparib. That’s pretty simple.

Thomas J. Herzog, MD:Right.

Bradley J. Monk, MD, FACOG, FACS:And if you are chemotherapy alone, then at the second decision point you can either add olaparib alone if she’sBRCA, or niraparib if she’s not.

Thomas J. Herzog, MD:Correct.

Bradley J. Monk, MD, FACOG, FACS:Or even if she is.

Thomas J. Herzog, MD:Correct.

Bradley J. Monk, MD, FACOG, FACS:What do you think about that?

Thomas J. Herzog, MD:You’ll see varying uses then, right? I’m probably going to use more niraparib based on PRIMA than you will because of that, because I don’t use as much bevacizumab.

Bradley J. Monk, MD, FACOG, FACS:Right.

Thomas J. Herzog, MD:But still trying to figure out about that combination and for which group; we’ll get some more subgroup analyses and it’ll be fun to flush all this out. I think there will be more clarity as we move forward, but we’ll never be able to get around the fact that these have different eligibility criteria, and it will be hard to really tease out. But I do think there are some questions about all these trials that we will hopefully answer with some additional publications and get a better understanding. The other thing is going to be the label. The label guides a lot of things. So what will that label look like for niraparib, for example?

Bradley J. Monk, MD, FACOG, FACS:It’s got to be all comers cause all the subsets are positive. One of the things I’m excited about though in the HRD-negative group is that although the PFS [progression-free survival] is short, because the prognosis is so poor, the survival data are maturing very quickly. So we’ll probably have the overall survival for the HRD-negative patients by the time it’s approved. And if there is a survival benefit, maybe that will be interesting and persuade people.

Thomas J. Herzog, MD:Again, that group has had an impressive hazard ratio of 0.68.

Transcript edited for clarity.