PARP Inhibition’s Role in Recurrent Ovarian Cancer

Bradley J. Monk, MD: I’m going to transition now to recurrent disease. As Dr Moore said, these patients do develop recurrence, and there are a number of opportunities. We have six PARP inhibitor indications in recurrence. I’m going to ask our panelists to go through each of the PARP inhibitors in no particular order, and to talk about the maintenance opportunity after platinum-sensitive response, as well as treatment. I’m going to start with Tom Krivak, and maybe you could talk about niraparib and what the indications are for niraparib in recurrent ovarian cancer.

Thomas C. Krivak, MD: In 2016 in The New England Journal of Medicine, there was a study of niraparib with two cohorts, a germline cohort and a nongermline cohort. This study was looking at platinum-sensitive recurrent ovarian cancer with platinum-based chemotherapy and then PARP maintenance. We saw a significant benefit with a hazard ratio of 0.27 in the BRCA-mutated group, and a P value of less than .1.

For the subgroup analysis going into the nongermline-mutated patients, they broke it down and looked at BRCA somatic mutations, HRD [homologous recombination deficiency], and HR [homologous recombination] proficiency. When looking at the BRCA somatic mutation patients, there are very similar outcomes with the platinum-based chemotherapy followed by PARP maintenance with niraparib.

In breaking down the patients who had HRD, they looked at the somatic patients with HRD, and then broke out the HRD, excluding the somatic patients. There was an improved PFS [progression-free survival] and a hazard ratio of 0.45. Going to the HR-proficient patients, there was an improvement of about three months in that group.

It was a nice trial in that we saw a really nice prolonged response in our BRCA-mutated patients, responding to platinum-sensitive recurrence. As we’re trying to build on our biomarkers, this was a nice trial because of the exploratory analysis of HRD, the Myriad Genetics, Inc test. I think we could debate the absolute benefit of three months in the HR-proficient group—what I used to call the triple-negative group, negative BRCA somatic, negative BRCA germline, and HRD-negative—which is one of the most complex patients to treat due to quick recurrence.

I think that built on the OCEANS trial, which looked at bevacizumab. Now we’re looking at this using ENGOT-OV16/NOVA and niraparib for platinum-sensitive recurrent ovarian cancer. 

Bradley J. Monk, MD: The beauty of that, as Katie Moore said, is that we had the integrated biomarker with platinum sensitivity. We underemphasized the HRD testing, but HRD testing is much more valuable in frontline if you decide to do it. But NOVA was the first platinum-sensitive maintenance opportunity, and then tell us about QUADRA.

Thomas C. Krivak, MD: NOVA expanded the indication. It went from BRCA mutations to all-comers. NOVA was well designed because of safety nets to look at certain baskets of patients. QUADRA, this is Katie’s trial, and it’s odd for me to be talking about Katie’s trial because she’s done so many good trials, had heavily pretreated patients, both HRD and BRCA patients. It screened about 700 patients and enrolled about 463. Patients who had a BRCA mutation, regardless of platinum-sensitivity, in the fourth-line could receive niraparib as treatment, so going from maintenance to treatment. If a patient was HRD-positive, that patient had to have platinum sensitivity. The study had some very nice numbers with respect to who responded and who didn’t respond. The platinum-sensitive BRCA patients were probably around 40%, and platinum-resistant patients were right around 25% to 30%. When looking at the HRD folks, it was around 25% to 30%. To me, the study extended out how we can use niraparib and changed the indication going from a maintenance drug, even though I consider maintenance to be treatment maintenance in most of these cases, to actual treatment.

Katie’s done a ton of good trials, and this was another great trial to add to the options for our patients with recurrent ovarian cancer.

Bradley J. Monk, MD: The beauty of QUADRA, and thank you Katie Moore for doing that, is that it showed us the 3 predictors of PARP activity: platinum sensitivity, molecular signature, and number of lines of therapy. We’ve leveraged those in PRIMA and PAOLA, so that was great. We also have rucaparib, Tom Herzog, so tell us about rucaparib and what that offers to our patients.

Thomas J. Herzog, MD:We have two indications for rucaparib currently. Unlike the other PARPs, it’s approved for recurrent disease for those patients who have had three- lines of prior therapy. It’s one line earlier than four lines and beyond, it’s three lines and beyond. Those, of course, are patients who have mutations.

And then it has an indication based on the phase 3 ARIEL3 data, where Robert Coleman, MD, presented this at ESMO [the European Society for Medical Oncology annual meeting] in 2017, and then it became approved in 2018. Jonathan Ledermann, MD, and Robert Coleman were co-PIs [principal investigators] on this particular trial. The randomized phase 3 trial was similar to NOVA, but there were some differences. But what was remarkable to me was how close the control groups were in these phase 3 trials. These were high-grade serous or endometrioid, greater than or equal to two prior lines of platinum, and had to have a CR [complete response] or a PR [partial response] to the penultimate platinum that they had right there.

They also had to normalize their CA-125 [cancer antigen 125], which is interesting. They didn’t have a size limit on their residual disease, which was a little bit different. They had 564 patients randomized 2:1 either to the rucaparib or to the placebo. They also had the step-down statistical analysis, first looking at their BRCA mutation group, with a hazard ratio of 0.23. Then they went to the HRD group, with a hazard ratio of 0.32. Their HRD was measured by Foundations Medicine, Inc, LOH [loss of heterozygosity] greater than 16%. They then went to the intent-to-treat population, with a hazard ratio of 0.36 as you get out there.

The medians change, and you can see the same effect where if we look at the LOH low population, it was still positive, but the difference in the medians was 6.7 versus 5.4 months. So very much what we’ve seen in these first-line trials, with a different PARP, but very interesting safety profile, pretty much in line with what we’ve seen with rucaparib from the Study 10 and ARIEL2, which formed their treatment label.

Transcript edited for clarity.