Advanced Ovarian Cancer: Recent Advances and Unmet Needs - Episode 10
Bradley J. Monk, MD: We now we have a PARP inhibitor 2 years later, December 19th, 2016, called rucaparib, again with accelerated approval from a trial with 106 patients, a 54% response rate, and a 9.2-months duration of response. So, what people do is say, “Well, olaparib is 34%, rucaparib is 54%, so rucaparib must be better.” Is that not true?
Matthew Powell, MD: Well, there are obviously some patients on the olaparib trial who had 14 prior lines of therapy, so it’s a different patient population.
Gottfried E. Konecny, MD: You can’t compare that. I think what the ARIEL2 study did was really look at PARP activity in all platinum-sensitive patients, and the entire ARIEL2 study with 500 patients included patients that had…
Bradley J. Monk, MD: So, ARIEL2 is the phase II of rucaparib. Keep going.
Gottfried E. Konecny, MD: They included BRCA-mutated patients, be it somatic or germline. They included patients with 1 prior line of therapy, 2 prior lines of therapy, 3 prior lines of therapy, and who were platinum-sensitive or platinum-resistant. So, it clearly shows that the response rate was inversely correlated with the number of lines of therapy. The more lines you have, the higher the response rate. So, you can’t do cross study comparisons. You can’t say olaparib had a 30% versus a 50% or an 80% response rate. It depends on the number of prior lines, and it depends on the platinum-sensitivity status.
Bradley J. Monk, MD: Here’s what you taught the world: the predictors of PARP sensitivity are the molecular signatures. You told us that BRCA, LOH (loss of heterozygosity), molecular signature, platinum sensitivity…
Gottfried E. Konecny, MD: Yes, the better the platinum response, the better the response to PARP therapy.
Bradley J. Monk, MD: And the number of lines of therapy. Matt says, “Well, number of lines of therapy,” so those 3 things—molecular signature, platinum-sensitivity, and number of lines of therapy—predict activity. That’s a good take-home message.
Robert L. Coleman, MD: And I would say there are other key points. So, one is that ARIEL2 validated this non-BRCA HRD signature. That’s one thing, and the other was that we hadn’t had much data on germline versus somatic, but in the ARIEL2, we were able to show—and now also in the NOVA trial—that the somatic alterations are the same, or seem to perform the same.
Bradley J. Monk, MD: The rucaparib label includes not only germline, like olaparib, but germline and somatic. And olaparib is 3 prior regimens, but rucaparib is now 2 prior regimens. So, with the rucaparib approval, we got a line earlier and we got somatic. Tell us what the toxicities are, Matt, of rucaparib.
Matthew Powell, MD: Rucaparib has similar toxicities, as Katie mentioned, with olaparib. Perhaps there are slight differences, but again, they were different patient populations, more heavily pretreated. You’re still going to have the nausea. You’re still going to have issues with anemia and fatigue. And I think with nausea, the take-home message—again, it was born out in the trial that looked at the TWiST—is the nausea happens early, and usually the patients do well later. It’s the fatigue that tends to get us later, or the anemia. So, dose reductions and dose delays are very important for these patients.
Robert L. Coleman, MD: Thank you for that. So, to summarize those 2—olaparib, rucaparib toxicities…
Katie Moore, MD: I think there’s a difference.
Bradley J. Monk, MD: I’ll get to that, but I want to summarize: 1.) is GI, nauseas, diarrhea, and dyspepsia; 2.) is bone marrow, we talked about some platelets and anemia; and 3 is the fatigue.
Gottfried E. Konecny, MD: But aren’t you surprised when you do these trials and you read the papers that, at average, between 40% and 60% of the patients on every trial with a PARP inhibitor ended up with a dose reduction?
Bradley J. Monk, MD: That’s right.
Gottfried E. Konecny, MD: Did we start out too high?
Robert L. Coleman, MD: Yes, that’s a good question.
Bradley J. Monk, MD: But these are fixed oral doses. So, when you have all different sizes and shapes of patients and you give them all the same dose, it’s not going to be right for some. We could do a digoxin level, right? Give them a dose and do their level. But it’s more practical just to monitor them closely, like you just said, and when appropriate, do a dose delay and let them get better.
Gottfried E. Konecny, MD: Despite a dose reduction, you still see the demonstrated efficacy. You’re not compromising the activity. Stay on the drug, but you’ve got to dose reduce.
Robert L. Coleman, MD: That’s right, and we learned that long ago. When we were doing olaparib 100 mg versus 400 mg, we saw that there’s a broad therapeutic window. We have room to tweak it in the patient, to personalize it.
Bradley J. Monk, MD: Thank you for that. The next study to come out of rucaparib is ARIEL3. So, you talked to us about ARIEL2, which is a phase II trial, and that helped inform the level. Now, ARIEL3 is a— tell us, Rob. You were the PI.
Robert L. Coleman, MD: Again, it’s a phase III trial that looks very much like the others. It’s a study that is looking at platinum-sensitive patients, or patients responding to a platinum with a partial or a complete response, and then they’re randomized to placebo or rucaparib.
Bradley J. Monk, MD: Platinum-sensitive and a maintenance drug.
Robert L. Coleman, MD: Correct, just like the NOVA trial, just like SOLO-2, with the exception of a broader patient population. And so the analytical plan—and we can maybe talk about this a bit—essentially, what it’s doing is looking at the germline patients, the HRD patients, and the broader population in a way to help us understand how these drugs work in all of those situations.
Gottfried E. Konecny, MD: I think the development is that they are prospectively validating this assay of HRD.
Bradley J. Monk, MD: In the nongermline.
Gottfried E. Konecny, MD: In the nongermline. They’re also in negotiation with the FDA, so at the end, maybe there will be a companion diagnostic that you can use to test this HRD. It will get approved, as opposed to the niraparib data, where you do have an HRD assay, but it’s not an official companion diagnostic and it’s not tied to the HRD status. And ARIEL3 will be very informative regarding that prospective evaluation.
Robert L. Coleman, MD: And then, as I mentioned before, in ARIEL2, we did see that it was a discriminator between those potential patient populations.
Transcript Edited for Clarity