RTP On Demand: Current and Future Role of PARP Inhibitors in the Management of Ovarian Cancer (Video Program) - Video 11PARP inhibitors as maintenance therapy for platinum-sensitive, relapsed OC
7:05 minutes.
TRANSCRIPTION:
DR MATULONIS: It’s an exciting study because it really does expand the use of a PARP inhibitor to other populations of patients besides those who have underlying BRCA mutations. But I think, also, this is not a surprise because this kind of a trial really distills a patient and a cancer that is previously sensitive to platinum, continues to be in response to platinum, and is a high-grade type of cancer. So we really have taken the essence of all of the characteristics where a PARP inhibitor should work. So the fact that you see this improvement in progression-free survival of niraparib versus placebo in all of the 3 predefined patient populations makes sense. DR LOVE: Well, it might make sense, but there’s one number in particular that I really want to ask you about. But before we get to that number, maybe you can just talk a little bit about the setting and the design of the study. DR MATULONIS: Again, it was a study that was modeled after Study 19, but a Phase III — again, as an attempt at a registration trial. So taking — DR LOVE: The Study 19 being the olaparib maintenance study. DR MATULONIS: That’s correct, because we had already known about that study. That had been presented, and it was positive. This was taking patients up front who were platinum sensitive, previously in receipt of platinum, had at least 4 cycles of platinum-based chemotherapy, had either a CR or a PR via investigator assessment to platinum, and were then BRCA-tested up front. And then they were put into 2 groups, either those patients who had a germline BRCA mutation versus not — so, 2 separate populations — and then randomized to either niraparib versus placebo in those 2 main populations. DR LOVE: And the duration was indefinite? DR MATULONIS: The duration was indefinite. That’s correct. The patients were followed via CAT scan. And that’s how we made the assessment of disease progression. DR LOVE: And just to clarify in terms of the prior olaparib maintenance study, which you actually ran — that was just BRCA, correct? DR MATULONIS: No. That was also high-grade serous cancer. DR LOVE: And I think it was a randomized Phase II? DR MATULONIS: It was a randomized Phase II, 1 to 1. That’s correct. DR LOVE: And you saw a dramatic benefit, correct? DR MATULONIS: Correct. In Study 19, there was a benefit between olaparib versus placebo. And that difference in progression-free survival was a little under 4 months or so. But then there was a retrospective analysis looking at the patients who had either germline BRCA or had a somatic BRCA mutation. But it was a preplanned retrospective analysis. And that’s where you saw that 7-month improvement in progression-free survival between olaparib versus placebo, so further distilling those patients. DR LOVE: Right. But I guess that wasn’t enough to get it approved in that setting in the United States. DR MATULONIS: Right. That was the ODAC meeting that I presented at. And that was just terrible. That was an awful ODAC meeting. There was — even though that was just a few years ago, I think that, because it was the first trial and that PARP inhibitors were newish at that point — now, PARP inhibitors are used and more studies being run. It’s shown efficacy in other cancers besides ovarian cancer. The mechanism of action is understood, et cetera. So I think it’s a — we’re in a different time in 2016-2017 compared to 2014. DR LOVE: But if I remember correctly, if I’m thinking of the right cancer, it is approved in Europe? DR MATULONIS: Olaparib is approved in Europe based on Study 19 results. That’s correct. DR LOVE: For maintenance? DR MATULONIS: For maintenance. That’s correct. DR LOVE: But not in the — in the US, it’s just, like, fourth-line advanced disease. DR MATULONIS: Yes, you have to have received 3 lines or more of prior chemotherapy. And the SOLO-2 results were just announced. SOLO-2 is a recapitulation of Study 19, except that patients had to have a germline BRCA mutation or a somatic BRCA. And they just had a press release which basically showed that the patients receiving olaparib versus placebo had an improved progression-free survival that was better than was seen in Study 19. But that is a different trial than the NOVA study, the niraparib, where you’ve broadened that patient population to now not just include germline or somatic BRCA but high-grade serous or high-grade endometrioid cancer. Up front there was a randomization between underlying germline BRCA versus nongermline. And then the patients who were gBRCA-negative were then retrospectively tested through an HRD assay, a homologous recombination deficiency assay. And that’s the assay that looks at different components of how one could define a cancer that was HR deficient. DR LOVE: But it’s not just BRCA genes, right? DR MATULONIS: No. It’s basically looking at scarring that occurs to the DNA that is representative of a cancer that has underlying homologous recombination deficiency. DR LOVE: Okay. So let me tell you my number that I’m so fascinated by. You mentioned the fact that in all 3 of these groups there was an advantage. But, again, I’m always thinking hazard ratio. So for germline — I like that gBRCA. I haven’t heard anybody say that. I like that abbreviation. So with the gBRCA patients, the hazard ratio for progression was 0.27. Then the nongermline BRCA with the HRD positivity, hazard ratio 0.38, again kind of the same ballpark, similar-looking curve, maybe not quite as impressive. But the thing that really blew my mind was the germline-negative and HRD-negative patients. And the hazard ratio was 0.45. That’s the one that kind of surprised me. DR MATULONIS: Yes. Again, I think that it really just says to you that PARP inhibitors have activity in platinum-sensitive, recurrent high-grade cancers, because of the — you're really distilling out, pulling out patients who have this homologous recombination deficiency phenotype, because they’re responding to platinum, but also genotype as well. |