Recent Developments in Management of Gynecologic Cancers - Episode 4

PARP Inhibitor Trial Updates


Bradley Monk, MD, FACOG, FACS: I think we all want to use PARP inhibitors in non-BRCA-mutated patients. The problem is, we have no evidence that in the frontline setting in patients who respond, that there’s activity. So we stand before the threshold of 3 trials that are going to inform that. Krish, tell me a little about DELIA, the study that we call GOG-3005, and why that study is important.

Krishnansu S. Tewari, MD: That study is important for several reasons. One is it’s going to introduce us hopefully to a new PARP inhibitor that we don’t have a label for, veliparib. And it will show us whether combining chemotherapy with PARP inhibitor in the frontline setting is going to be tolerable and efficacious. So that’s a very important trial that we hope to report on this year.

Bradley Monk, MD, FACOG, FACS: That’s interesting. We heretofore have not really been able to add PARP inhibitors to chemotherapy, but there’s a phase I study that informed this phase III. Tell us about that dose finding of veliparib in chemotherapy study.

Jubilee Brown, MD: Exactly. Actually, Deborah Armstrong is presenting that at ASCO [American Society of Clinical Oncology] 2019 Annual Meeting. That really evaluates the dose that’s acceptable, and that’s 150 mg. Interestingly, maintaining efficacy and the ability to add veliparib at 150 mg to chemotherapy gives us an option that we don’t have with any other PARP inhibitors.

Bradley Monk, MD, FACOG, FACS: Yeah, it’s exciting. So that’s 1 strategy with chemotherapy, and it also has an all-comer and an HRD [homologous recombination deficiency] sort of endpoint. Tom, tell me about PRIMA.

Thomas Herzog, MD: PRIMA is important because the primary endpoint is going to be the HRD population. To your point, where we are with SOLO-1, it’s only in those with BRCA mutation, either germline or somatic. This will greatly expand that, and we’ll also get a look at everybody. Very much like NOVA, it will be interesting to see what the data are, and if they’re similar, arguably we could have approval for all patients.

Bradley Monk, MD, FACOG, FACS: Wouldn’t that be great? And it’s niraparib, which some people argue is the best PARP trapper, the highest volume of distribution, the best—that’s controversial.

Thomas Herzog, MD: Well, those things are not controversial; it’s the question. I think those are true. I think the question is, how does that translate into clinical practice?

Bradley Monk, MD, FACOG, FACS: Exactly, into frontline PARP usage in a BRCA-like molecular signature, HRD or an all-comer.

Thomas Herzog, MD: Right.

Bradley Monk, MD, FACOG, FACS: Michael, you want to combine both of them, right? That would be your style. You’re a medical oncologist. You want to combine BEV [bevacizumab] and PARP. I mean, if PARP is so good and BEV is so good, why don’t we combine both of them in the frontline setting?

Michael J. Birrer, MD, PhD: I think it’s a great question. First of all, it solves the dilemma we have now, which is that everybody is arguing about BEV versus PARP, and if it turns out the combination is better, that solves that. As you know, there are trials addressing this, right?

Bradley Monk, MD, FACOG, FACS: Yeah, so PAOLA-1 does that. It takes the bevacizumab GOG-0218 and in the maintenance phase adds olaparib—so that’s 3 studies. And I think they’ll all be at ESMO [European Society for Medical Oncology]—the DELIA trial that you talked about, the PRIMA trial that you talked about with niraparib, and then the olaparib-bevacizumab.

Michael J. Birrer, MD, PhD: Right.

Bradley Monk, MD, FACOG, FACS: I talked about what happened in 2018: IP [intraperitoneal] chemotherapy, bevacizumab, and olaparib in mutated patients. We’re going to have a conversation soon about what happened in 2019 with the addition of veliparib to chemotherapy, the HRD niraparib endpoint, and olaparib-bevacizumab. I mean, we can barely keep up. How great is that?

Michael J. Birrer, MD, PhD: And we might add that at this ASCO, although it’s in recurrent setting, AVANOVA combines them also, which are interesting data.

Bradley Monk, MD, FACOG, FACS: Let’s talk about that. Tell us about AVANOVA. Go ahead.

Michael J. Birrer, MD, PhD: Again, it’s based on this concept that the combination would be more effective than single-agent PARP inhibitors, and there is biology behind that. If you make a tumor hypoxic, it does create a sort of a pseudo-HRD phenomenon. So that’s what drives it. It’s in a platinum-sensitive recurrent scenario area in the natural history. It’s accrued. It’s not a huge study. It’s about 90 patients, 49, 45 on each arm. And there’s a significant prolongation of PFS [progression-free survival] on the combination. The question is, is that additive or is that synergistic?

Thomas Herzog, MD: But it’s pretty big, right? It’s 5.5 versus 11.9 months, and I think the hazard ratio was 0.35, so it’s a significant.

Bradley Monk, MD, FACOG, FACS: The reason I wanted to discuss that is it adds anticipation to PAOLA-1. And it also shows that maybe, Tom, we don’t need chemotherapy frontline.

Thomas Herzog, MD: Well, that’s the interesting thing about that particular abstract to me.

Bradley Monk, MD, FACOG, FACS: Or even it’s in recurrence, right.

Thomas Herzog, MD: To do this chemotherapy-free and to get results that are that impressive. I mean, even the single arm did as well as chemo, and then the doublet really outperformed traditional chemotherapeutics.

Bradley Monk, MD, FACOG, FACS: Yeah, PARP, VEGF. It could also be olaparib-cediranib. It can be with bevacizumab. It looks as if it performs just as well as chemotherapy, so it’s a chemotherapy-free regimen. We give a lot of paclitaxel, and we talk every day we’re in clinic about alopecia and neuropathy.

Krishnansu S. Tewari, MD: Allergy.

Bradley Monk, MD, FACOG, FACS: Hypersensitivity, right?

Thomas Herzog, MD: And GY004 will give us a little more insight on the platinum-sensitive group.

Bradley Monk, MD, FACOG, FACS: Yeah, olaparib-cediranib.

Thomas Herzog, MD: Yeah.

Bradley Monk, MD, FACOG, FACS: Yeah, very interesting. Jubilee, we haven’t really begun to talk about I/O [immuno-oncology]. I think we’ve all come to the realization that ovarian cancer is a very cold tumor. The mutational burden is low. The tumor-infiltrating lymphocytes are there, but they’re probably immunosuppressed. PD-L1 [programmed death-ligand 1] expression is also inconsistent. Tell us about these frontline trials, though, that are trying to add I/O to either PARP or BEV or all 3.

Jubilee Brown, MD: Yeah. There are 3 trials that are ongoing now, and they all actually are answering different sort of tweaks. The ATHENA trial is a very interesting 4-arm trial that looks at platinum-sensitive patients.

Bradley Monk, MD, FACOG, FACS: Frontline.

Jubilee Brown, MD: Frontline, who get placebo, or nivolumab as maintenance, or rucaparib as maintenance, or both. So I think that will answer the first question of whether we can use either a PARP, or immuno-oncology, or both.

Bradley Monk, MD, FACOG, FACS: I like it.

Jubilee Brown, MD: In maintenance therapy. I think that’s 1 interesting trial, certainly. And then when we look at the FIRST trial, you know the FIRST trial has an interesting control arm because it’s the only 1 that doesn’t mandate BEV.

Bradley Monk, MD, FACOG, FACS: But allows it.

Jubilee Brown, MD: But allows it, right. So we’ll have an interesting control arm to look at. And then we’ll be able to evaluate both a PARP inhibitor, as well as immunotherapy together in that situation.

Bradley Monk, MD, FACOG, FACS: Is that going to be financially toxic? Figure it: BEV, niraparib, and dostarlimab.

Jubilee Brown, MD: Yeah, theoretically.

Bradley Monk, MD, FACOG, FACS: And maybe or just flat-out toxic, so we’ll see.

Michael J. Birrer, MD, PhD: That’s grade 4.

Bradley Monk, MD, FACOG, FACS: That’s grade 4.

Jubilee Brown, MD: Theoretically.

Bradley Monk, MD, FACOG, FACS: With a dollar sign, right—4 dollar sign?

Thomas Herzog, MD: Or euro.

Bradley Monk, MD, FACOG, FACS: Or euro.

Thomas Herzog, MD: Yes.

Bradley Monk, MD, FACOG, FACS: OK.

Jubilee Brown, MD: And then similarly we have the JAVELIN OVARIAN PARP 100 trial as well, and that follows a similar theme. But I think there are a couple of interesting tweaks to that, so bevacizumab is in the control arm for all those.

Bradley Monk, MD, FACOG, FACS: And I can just announce it’s in the public domain, that that trial has been closed, that Pfizer has decided not to pursue avelumab any further. It’s hard to keep up with these. We struggle keeping them straight. You’re doing a great job, by the way. I don’t know if you have this written down in your notes. Probably not, you’re so smart. And then the DUO-O and ENGOT ov43, which is olaparib with or without durvalumab or PEMBRO [pembrolizumab]. It becomes exhausting to figure out what the right combination is, and it’s a very competitive landscape that all the makers of—not all, certainly all the PARP inhibitor manufacturers are adding I/O, and as you said, maybe with BEV.

Jubilee Brown, MD: It will be interesting to see those results and see if that refines how we give the therapy.

Bradley Monk, MD, FACOG, FACS: And then isn’t there IMagyn050, right?

Krishnansu S. Tewari, MD: Yeah.

Bradley Monk, MD, FACOG, FACS: Tell us about that study.

Krishnansu S. Tewari, MD: IMagyn050 is looking at adding an anti—PD-L1 inhibitor, atezolizumab, to basically a GOG-0218 skeleton. That’s going to be an interesting readout, whereas we can then use frontline BEV with possibly anti–PD-L1.

Bradley Monk, MD, FACOG, FACS: Jubilee, it’s hard to be as good as you, but I’m going to try. I got BEV-I/O, IMagyn050. I’ve got BEV-PARP, PAOLA. I’ve got BEV-PARP-I/O in ov43, DUO-O, and FIRST and then pure maintenance in ATHENA. I mean, if I have trouble.

Michael J. Birrer, MD, PhD: Good job.

Bradley Monk, MD, FACOG, FACS: I know, right? Well, she tutors me.

Jubilee Brown, MD: No.

Bradley Monk, MD, FACOG, FACS: I don’t really want to get too much into the details other than to say that we have 3 categories of agents, anti-VEGF, which is all BEV; 3 PARP inhibitors, maybe soon to be 4 with veliparib; and then we have these checkpoint inhibitors, durvalumab, pembrolizumab, atezolizumab, and dostarlimab—4 checkpoint inhibitors. And all the permutations are in play.

Michael J. Birrer, MD, PhD: Even the regulatory components may actually utilize cross-trial comparisons, right? For instance, if PRIMA is positive and everybody is eligible for a PARP inhibitor, will AstraZeneca PLC take the data from PAOLA on the control arm and say, hey, as they did with Study 19.”

Bradley Monk, MD, FACOG, FACS: But the thing that has not happened is, if there’s 1 indication for a PARP inhibitor, and the insurance company says, “Well, that’s OK, we’ll pay for whatever PARP.” It’s not a plug and play.

Michael J. Birrer, MD, PhD: That’s right.

Transcript Edited for Clarity