PARP Inhibition in Ovarian Cancer: BRCA-Mutated and Beyond - Episode 2

Current Landscape of PARP Inhibition in Ovarian Cancer

Bradley J. Monk, MD, FACOG, FACS:We’ve been in this for 5 years. It’s hard to imagine that our first PARP inhibitor got approved in December 2014. Tell us about that first FDA approval.

Thomas J. Herzog, MD:It was very interesting because I think with olaparib, I don’t think the pharmaceutical company was even sure they had the data that were going to make this happen. To my understanding, the agency even prompted them to say, “Hey, have you ever thought about…”

Bradley J. Monk, MD, FACOG, FACS:Treatment rather than maintenance.

Thomas J. Herzog, MD:Exactly. This was a trial that Dr Bella Kauffman reported on, a relatively small trial that had different cohorts: prostate, breast, and ovarian cancer. And with ovarian cancer, you’re correct. It’s the family of cancers with primary peritoneal, fallopian tube. I think the numbers were quite small, but they saw a response rate that was quite impressive. Unlike what you would normally see, we were able to leverage an alternative pathway toward approval, if you will, in an accelerated approval based on the relatively small data set. Of course confirmatory trials needed to be done and so forth.

Bradley J. Monk, MD, FACOG, FACS:There were 137 patients, and there was a 34% objective response rate. On December 19, 2014, it received a treatment indication, just like you would use chemotherapy.

Thomas J. Herzog, MD:Right. And that was for fourth line and beyond.

Bradley J. Monk, MD, FACOG, FACS:Fourth line and beyond, 3 prior lines. Thank you for that.

Thomas J. Herzog, MD:That’s right.

Bradley J. Monk, MD, FACOG, FACS:Then rucaparib comes along, treatment again, adds somatic to germline because it’s probably the same and gets a 54% response rate. Does that mean rucaparib is a better PARP inhibitor?

Thomas J. Herzog, MD:No, these are different patient populations. We’re going to do a lot of non—cross-trial comparisons, but we’ll be talking about where it’s probably OK to do some comparisons and other areas where it’s not. I think the cleanest data are probably in the platinum-sensitive maintenance setting. If you look at all the PARPs in terms of the similarity between those trials, it starts diverging in the treatment trials. ARIEL is very complicated. With ARIEL2, there’s part 1, there’s part 2, different inclusion criteria, and so forth. They narrowed inclusion criteria as it went further, and that probably boosted the response rate there. But it is a very active PARP inhibitor as well, and that got approval for third line and beyond.

Bradley J. Monk, MD, FACOG, FACS:That’s right. So there are 2 treatment indications: olaparib fourth line and beyond, rucaparib third line and beyond. You can’t really compare the efficacy, but the toxicities I think we’re becoming more familiar with. And then on October 23, 2019, we got the third treatment indication for the third PARP inhibitor, and that trial is called QUADRA because it’s fourth line.

Thomas J. Herzog, MD:Fourth line and beyond, right.

Bradley J. Monk, MD, FACOG, FACS:Tell us about QUADRA.

Thomas J. Herzog, MD:Well, this is a study where Kathleen Moore is the PI [primary investigator]. The study is, as you said, a treatment using niraparib, and what was very interesting is it confirmed a lot of what we’re starting to understand, that there’s more than just platinum sensitive versus resistant.Platinum refractorymeans the cancer is growing resistant to primary treatment with platinum, a very poor prognosis group. Then we have the group that recurs between 0 and 6 months. We call those patients platinum resistant, and then we have the patients beyond 6 months, and we label those as platinum sensitive. This is a continuous variable, meaning the further out you are, the more sensitive you are.

Bradley J. Monk, MD, FACOG, FACS:To chemotherapy and PARP inhibition.

Thomas J. Herzog, MD:Correct. That’s what we learned early on when we started looking at subgroups from rucaparib data, from olaparib data, and it was really well shown in the QUADRA study. So what do we look at in terms of trying to figure out if you’re going to respond in the recurrent setting? We look at the histology, which is surrogate for maybe you have HRD [homologous recombination deficiency] if you’re serous, for example. We then look at the question of lines of therapy because that’s important. As you have an increasing number of prior lines, your response rate drops. Then we also look at the molecular signature, and that gets into QUADRA looking at HRD, which was really important, as well as mutational status.

Bradley J. Monk, MD, FACOG, FACS:And platinum sensitivity.

Thomas J. Herzog, MD:That’s right.

Bradley J. Monk, MD, FACOG, FACS:So histology, molecular signature, the number of lines of therapy, and platinum sensitivity. You can see your patient. You taught me this. I’m just parroting what you’ve taught me over the years. You can see your patient and integrate that and say, “You have a 50% chance of responding” or “You have a 20% chance of responding.” The worst prognosis would be a platinum-resistant patient, maybe 1 who doesn’t haveBRCAthat’s heavily pretreated. The beauty of the niraparib approval on October 23, 2019, is what you also said: it’s beyondBRCAHRD. It’s the first HRD approval. I think that means we have to start testing for HRD now.

Thomas J. Herzog, MD:Well, as you see when we start talking about some of the data from ESMO [the European Society for Medical Oncology Congress] 2019, that comes into question as well. There’s going to be more pressure to test than what there was previously. But getting back to what we were talking about, I think there’s a subgroup in QUADRA that really illustrates nicely that allBRCAmutations are not created equal because those other variables greatly influence response. So I think there were, what, 63 patients who wereBRCAmutated, right?

Bradley J. Monk, MD, FACOG, FACS:But there are the 3 categories that you talked about.

Thomas J. Herzog, MD:Exactly.

Bradley J. Monk, MD, FACOG, FACS:Refractory, resistant, and sensitive.

Thomas J. Herzog, MD:Some of them were platinum sensitive.

Bradley J. Monk, MD, FACOG, FACS:And that works really well.

Thomas J. Herzog, MD:Right, 39% response rate. And if you were platinum resistant, that dropped down to 29%. If you were platinum refractory, 19%.

Bradley J. Monk, MD, FACOG, FACS:But they’re allBRCA.

Thomas J. Herzog, MD:All BRCA, so you’d expect them to respond the same, but it does matter in terms of lines of therapy and so forth.

Bradley J. Monk, MD, FACOG, FACS:Such a take-home message.

Thomas J. Herzog, MD:An interesting caveat out of that is of those who had HRD, all of them were platinum sensitive essentially.

Bradley J. Monk, MD, FACOG, FACS:Because HRD also means platinum sensitivity and also PARP sensitivity.

Thomas J. Herzog, MD:Right. And those patients had a 20% response rate, so close to the platinum-refractory group if you look in the HRD. Many people look at this as, I think, a very broad label. In actuality, it’s probably not. Right, Brad? If you look at it, if you’re platinum sensitive, you can have HRD. If you’re platinum resistant, HRD [shakes head no].

Bradley J. Monk, MD, FACOG, FACS:Yes, so technically with the new niraparib treatment label…

Thomas J. Herzog, MD:If you’reBRCAmutated, you’re all good.

Bradley J. Monk, MD, FACOG, FACS:All good. But only HRD platinum sensitive.

Thomas J. Herzog, MD:Correct, and I think that’s a nuance that may get missed. The label has just come out, so people need again to synthesize these data.

Transcript edited for clarity.