RTP On Demand: Current and Future Role of PARP Inhibitors in the Management of Ovarian Cancer (Video Program) - Video 12Clinical implications of the ENGOT-OV16/NOVA trial results: Niraparib maintenance therapy for platinum-sensitive, recurrent OC
8:17 minutes.
TRANSCRIPTION:
DR BIRRER: It’s of course out now in The New England Journal of Medicine, which tells you how high-quality it is. But this study has been going on for a while. It’s taking patients who have essentially platinum-sensitive recurrence, and they get treated. The tumor shrinks, disappears, and then they go on a maintenance phase with this PARP inhibitor, which, in the Phase II trial and in the Phase I trial, there was all the evidence that we could tell that this was going to be a very active PARP inhibitor. So the biochemistry is very clear. Now I think we have clinical data to support that. But what was astonishing about the data was just the impact. If you look at the prolongation of PFS — actually, before I say that let me just define it a little bit more. They did take a big effort to try to divide patients down into their genomic makeup. And there were patients who had germline mutation of BRCA1 and 2. There were patients who had wild-type germline BRCA1 and 2, but had the gene mutated in the tumor. We call that somatic. And then they used this tool to identify a whole other group of patients who had neither of those. The BRCA1 and 2 were completely normal but, based on this tool, had what looked like HRD. So you can see there are buckets of patients. And when you looked at the impact of the PARP inhibitor in this trial compared to control, the hazard ratio — and this is a measure of how beneficial it is — was just very impressive. The hazard ratios were down into the 0.2, 0.18, 0.25 range, basically pointing out that patients who got this drug had a huge benefit versus patients who didn’t. Now the question is, who benefits the most? And I think this is the interesting issue, which is, clearly, germline patients benefited. No doubt. We pretty much expected that. The somatic mutations behaved like the germline. This is now the second data that tells us this. The ARIEL studies using rucaparib had also revealed this. And this is very important, because we now know, if a patient has a mutation in the tumor but not in their germline, they’re still going to benefit. But the third part was really interesting, which is when they took this HRD group that was measured by their tool, they benefited less than the other groups, but they still benefited. But if you took out all of those patients and you were left with the final group, normal BRCA status, no HRD based on the tool, they even benefited. In fact, it was a hazard ratio of 0.58, with a p-value of 0.02. Now you could argue a little bit about the p-value, but they’re still benefiting. So I think it’s a great study. And my prediction is they’re going to go forward for FDA registration, I think, for all patients, for everyone, and probably not use their genomic tool. But we’ll see. They’re gearing up right now to do that. It also tells me a second thing, which is, although we think we’re really smart and we got all these — we understand the science and the genomics — the truth is we don’t really quite get it yet. Their HRD tool probably is not as accurate as — well, we know it’s not as accurate as it should be. And that’s partly because we still don’t quite understand what causes homologous recombination defects in these tumors. DR LOVE: If it turns out as you are guessing or thinking might happen, that you’re going to use PARP inhibitors regardless of HRD or BRCA, yes, you might want to know BRCA for other reasons, but therapeutically, maybe you won’t need to use it. DR BIRRER: Yes. Well, I mean, it’s possible. I’d be disappointed if that happened, but it may in certain circumstances. Because I think, as you point out, family issues are going to be incredibly important for that patient population. But the second issue is, even though we might give PARP to everybody, we still know HRD status, certainly BRCA1 and 2 mutation, is a very strong prognostic factor. And that’s something I like to tell my patients, say, “Lookit. You’ve got this mutation. It’s not great news for your family, but we know how to handle this. But also recognize your tumor is going to be exquisitely sensitive to chemotherapy.” A lot of BRCA tumors and the patients undergo 6, 7, 8, 9 cycles of different things with complete responses because these tumors are on the edge of dying because of their DNA repair abnormality. You just need to push them over. DR LOVE: Yes. And in a weird way, I was kind of thinking maybe it’s going to evolve the way PD-1 is and checkpoint inhibitors in lung cancer. At the same ESMO meeting, there was the big first-line study in patients with high PD-1s. And maybe we’ll end up using BRCA and HRD in ovarian cancer to figure out clinically when to use it. DR BIRRER: Hmm. DR LOVE: I mean, do you think that — I guess the initial approval is going to be — this was in platinum-sensitive recurrence? DR BIRRER: Correct. DR LOVE: So would you like to use it in platinum-resistant disease? Would you like — DR BIRRER: Yes. DR LOVE: Would you like to use it up front? DR BIRRER: That’s the million-dollar question. I think moving these things all the way up front is a flawed approach. And the reason I say that — I’ve been a big critic of this — if you try to combine PARPs with chemo, it’s extremely difficult. They are very myelosuppressive. Not surprising. So when this has been tried, what happens is you have to dose reduce the platinums and the paclitaxel and everything else you’re giving to try to get the PARP inhibitor in. So that’s a problem. In addition, if you’re treating at day zero and your patients are living, median, 5 years or 6 years, then I would ask, do we need to worry about MDS and leukemia if we have that kind of follow-up? Because, remember, the trials to date have been later in the course. And so I’m not so sure we have the safety profile that far out. So I think up front I’m not a big fan of, but it begs the question, because you could bring them in as maintenance up front. DR LOVE: That’s what you would think, normally. DR BIRRER: Yes. DR LOVE: When I said “up front,” I meant as maintenance, really. DR BIRRER: Yes, not in combination. Yes. DR LOVE: Yes. DR BIRRER: And I think that’s — I think what’s going to happen right now, if I see it, is that olaparib is at 3 lines or greater. Rucaparib, in front of the FDA, is going to be for somatic mutations, 2 lines or greater. So in fact they’ve kind of got a little edge there. But niraparib is going to be — in the platinum-sensitive queue for maintenance — will be in front of all of them. So I think the natural reflex would be if, let’s say, they all get approved, based upon the NOVA1 data, would be — I think you’re going to see a lot of people using it in that context. Now, do you use it on — perhaps you might segregate out the somatics and the germlines and pick them, because they get the best, the most benefit, and then bring it in later on, on the wild types, later in the course of disease, because you could give it anytime. You might see some partitioning like that. But the other question is, do we know what causes resistance? Answer is pretty much no. We do know there are reversion mutations in BRCA1 and 2. But it begs the question that, if you treat a patient early in her course, they get a response, they do well, but then the tumor comes back. Two years later, they’re still alive and they’re getting treated. Could you re-treat with PARP inhibitors? Don’t know the answer to that. |