Drs Coleman and Monk discuss what led to the recent withdrawal of several indications for PARP inhibitors in the treatment of advanced ovarian cancer.
Robert L. Coleman, MD, FACOG, FACS: We talked about why we got to PARP inhibitors in the frontline setting, because they came from the second-line setting. Initially, it was because of treatment, so we used these in biomarker-positive type patients as therapy. We showed we could shrink tumors, and we said, hey, listen, this is a great strategy to use in maintenance therapy because many patients who are getting induction chemotherapy don’t have complete responses [CRs], so maybe we can further reduce the burden of disease as a maintenance strategy. We were able to show in the ARIEL3 [study] that when we had patients who had measurable disease after chemotherapy, we could shrink tumors with a response rate. But then we had all of this retraction information, long-term follow-ups, post-marketing commitments, and trials that were done after these approvals that were trying to demonstrate what the potential benefit was long term. What happened last year?
Bradley J. Monk, MD, FACOG, FACS: There’s this theory, and it sounds worse than it is, that all PARP inhibitors induce platinum resistance, and you might be hurting patients. My response to that is, look, the most efficient way to develop platinum resistance is to give platinum. No one would ever say don’t use platinum, but now the FDA is saying, don’t use PARP in the recurrent [setting]. It’s a broken narrative. But these long-term end points, particularly in randomized trials, SOLO1 in treatment with olaparib, and ARIEL4 in treatment rucaparib, there were so many imbalances and the hazard ratios were broad. In my humble opinion, and I’ve heard you say, so I think our opinion is that they’re overinterpreted. Also in ARIEL3, our study with maintenance with rucaparib, and in a study that I participated in, NOVA, with niraparib, those indications have been removed in platinum-sensitive maintenance, except for BRCA.
The kicker is 2-fold; one, the Europeans don’t agree with this. You can look on PubMed, we just wrote a paper in the International Journal of Gynecological Cancer because this is an international issue. The EMA [European Medicines Agency], the European regulators say, what are you talking about, FDA? You can’t sort that out. So the hypothesis remains there and untested. We emphasize it too much in the United States because olaparib is still here. We’re concerned about the regulatory environment, but olaparib, study 19 in platinum-sensitive recurrent ovarian cancer, the response is still there. As long as they have a platinum response, PR [partial response] or CR, and they have, from SOLO2, BRCA. So if you see a patient who is PARP naive and responds to second or greater lines of platinum, I don’t want people saying, “I wish I could use niraparib, but it’s been withdrawn and over. I wish I could use ARIEL3, rucaparib.” Just use olaparib and stop your whining, right?
Robert L. Coleman, MD, FACOG, FACS: Exactly. The patient population that is ending up in recurrence without having seen a PARP inhibitor is vanishing. But the ones who will end up there are the ones who have HRD [homologous recombination deficiency].
Bradley J. Monk, MD, FACOG, FACS: They need it the most.
Robert L. Coleman, MD, FACOG, FACS: Exactly, I agree with you. Somebody reached out to me last week and said, I’ve got this patient, she’s HRD test positive, and she hasn’t seen a PARP, and I want to use it as a therapy because this is what they wanted to do. I said, you know what? You’re right, it does shrink tumors. We have data that this is the case, and it can be used as a maintenance strategy, you’re right. Olaparib does not have a restriction. But I think we forget that these drugs were developed in a situation where we were trying to shrink tumors, and we could do it with these drugs. They definitely have activity. What happened with the QUADRA [trial] and niraparib? It kind of got caught up in the sweep. They said, OK, listen, none of these drugs should be given in the recurrent [setting]. And I know we didn’t even have a formal post-marketing study with QUADRA, but maybe we should remove its indication as well.
Bradley J. Monk, MD, FACOG, FACS: As the last author of QUADRA, now you’re picking on me. QUADRA got hit in the crossfire. It was…whatever.
Robert L. Coleman, MD, FACOG, FACS: You mentioned something that’s important, and I think people believe this. We’re still sorting out what is the effect on patients who are on PARP with their potential response to subsequent platinum. I think there is some biology that would support this, but we have to think about this a bit differently than just prior exposure. In the recurrent setting, these patients who were treated on PARP inhibitors as a maintenance strategy were treated until progression.
Bradley J. Monk, MD, FACOG, FACS: That’s right.
Robert L. Coleman, MD, FACOG, FACS: In that scenario, depending on when you start your clock, those patients who have progressed during PARP probably have some mechanisms for induced platinum resistance, as you mentioned, just by using platinum. What do you think about that?
Bradley J. Monk, MD, FACOG, FACS: I’m completely aligned.
Transcript edited for clarity.