Expert Views on Therapy for Ovarian, Fallopian, and Peritoneal Cancers - Episode 10

Rucaparib for Ovarian Cancer

Transcript:Bradley J. Monk, MD: The next approval of another PARP inhibitor, probably, is going to be rucaparib, which has a PDUFA (Prescription Drug User Fee Act) date on February 23rd. So, it’s exciting now that we have another PARP inhibitor, rucaparib, that has been filed with the FDA. Their filing is in the public domain. In fact, their data set was presented at ESMO 2016 by Dr. Kristeleit. Why don’t you share with us what was presented at ESMO 2016 and hopefully submitted to the FDA for accelerated approval?

Kathleen N. Moore, MD: So, Dr. Kristeleit presented, at ESMO 2016, a combination study including patients who were in ARIEL2 part 1 as well as something called Study 10, which was another rucaparib study that Clovis carried out. They were particularly interested in looking at those patients who had a germline or a somatic BRCA mutation and had received greater than 2 lines of prior chemotherapy. And so, when they looked at that group, what they found were actually pretty remarkable outcomes. They had a median progression-free survival that was 12 months, and they had an overall response rate that was about 71% with side effects that were just class effects of PARP inhibitors. Again, going back to Dr. Coleman’s comment, when you compare that to historical controls, so to speak, or historical data looking at third-line and beyond chemotherapy, it’s a fairly remarkable progression-free survival: 1 year.

Thomas Herzog, MD: And response rate.

Kathleen N. Moore, MD: And response rate. And so, that data are what informed the FDA submission with, as you mentioned, PDUFA data in February of 2017. So, we’re anticipating another approval in that population.

Bradley J. Monk, MD: One of the exciting parts about rucaparib is that they have prospectively studied a molecular signature kind of like HRD, and that was recently published in ARIEL2. I think, Rob, you were a coauthor on that. Tell us about that, what I call the “LOH (loss of heterozygosity) tests.” What is that?

Robert L. Coleman, MD: Homologous recombination deficiency, as we talked about before, can arise from a number of different things. The most obvious situation is BRCA mutation and some of the other genes. Interestingly, not all of the genes can lead to the same kind of synthetic lethality, as we talked about before, with giving a PARP inhibitor and the defect. So, rather than going through and trying to pick off which genes are actually the vulnerable ones—which is still ongoing work, I’m not saying we’re giving up on that—it was easier just to look across all of the genes.

Bradley J. Monk, MD: The effects.

Robert L. Coleman, MD: To see whether or not these specific tumors showed up with lots of what we call “genomic scars.” So, we know that the machinery is defective. We don’t know exactly where it is, but we know it’s defective and that’s enough. This trial was really set up to take that information and interrogate it separately from the BRCA mutations, which we knew from somatic because the germlines showed up in the tumor that way. And so, that was the interesting part of this trial, that we’re moving away from the known into a little bit of the unknown. We’ve had a hint of this all during that olaparib work that had been done for the previous 6 to 7 years, where we had seen responses in patients who did not carry a germline mutation. So, we knew there was something going on in the tumor that made these particular tumors vulnerable. And so, the ARIEL2 trial that we had worked on was specifically looking at the nongermline patient population.

Bradley J. Monk, MD: We had genomic scarring, and it validated that the rucaparib was more effective in those patients with high LOH or genomic scarring.

Robert L. Coleman, MD: Correct.

Thomas Herzog, MD: So, telomeric imbalance and large-scale transitions, what do they add versus LOH? Can you look at just LOH?

Bradley J. Monk, MD: Let’s take that question. That test is not commercially available. The commercially available test is not only LOH, but is also a combination of telomeric imbalances and large-scale transitions. So, now we have 2 tests. One’s commercially available and that one is attached to niraparib, and we’re going to talk about that. And as I just said, I used it in my olaparib patient and it’s now available. Is there a difference between those 2 HRD molecular tests, Rob?

Robert L. Coleman, MD: We don’t know. The LOH is done and the 2 tests are done differently. Gordon Mills, at the SGO last year, did a very nice analysis of the 2 assays, but the benchmark was not PARP sensitivity. It was platinum sensitivity. And they do line up pretty well, but there are false-positives and negatives on both of them. I think it’s yet to be determined which one is a better test. I think, ultimately, the work still needs to continue because even in ARIEL2, which has a pretty good LOH assay, there was a person who was BRCA wild-type, low LOH, who had a complete response. So, we’re still trying to sort out how to do this.

Transcript Edited for Clarity