PRIMA: Frontline Niraparib Maintenance Therapy in Ovarian Cancer

Bradley J. Monk, MD: In germline and somatic BRCA mutations, maybe two-thirds or three-quarters of those are germline. We want to go beyond BRCA, and clearly PARP inhibitors work beyond BRCA: we’ve shown that in the recurrent setting. There’s now a third study that was also published in the New England Journal of Medicine by Antonio González-Martín called PRIMA. Tom, tell us about PRIMA and what the opportunity is here beyond BRCA.

Thomas J. Herzog, MD: It is also known as GOG-3012, right? We can’t forget that. This compared maintenance niraparib with placebo, and niraparib was given as maintenance for 36 months in this trial after patients completed primary chemotherapy. Eligible patients had stage III with gross residual disease after primary surgery or had stage IV disease, and this trial included patients who had neoadjuvant chemotherapy as well. Both serous and endometrioid histologies were included in this trial, importantly, and to be eligible, you had to have a response, either partial [PR] or complete [CR], to previous chemotherapy.

Brad, you’ve shown this with your weights-and-plates work in the past in terms of impact, especially on thrombocytopenia, for those patients who had a platelet count less than 150,000 permm3 or who weighed less than 77 kg. You actually reduced the dose. That happened about two-thirds of the way through this trial. That’s important in terms of interpreting some of the toxicity data.

The patients were randomized 2 to 1. There were 733 patients who were randomized in total. Importantly, they used hierarchical step-down in terms of the statistics. They actually did stratification based on whether you received neoadjuvant chemotherapy or not, what your HR [homologous recombination] status was, and whether you had CR or PR. Those were the 3 stratification factors. The primary end point in this was homologous recombination deficiency [HRD], and we can get into discussing what exactly that is and what that means. But the primary end point was the HRD population. If that was positive, then they were able to go on to the other populations, and the second population they looked at was the entire intent-to-treat population. That’s important to understand. The primary end point that they used within these groups or cohorts was progression-free survival [PFS] as determined by BICR: they had radiological blinded independent central review to determine if you actually had progression or not.

In their first assessment for the group that had HRD, they found a significant improvement in the median. The PFS was 21.9 months for the group that received niraparib and was 10.4 months for the group that had placebo. The hazard ratio was very impressive, 0.43, so there was a 57% reduction in the hazard of either relapse or death. If you look at it in the intent-to-treat population, it was still impressive: 13.8 versus 8.2 on the medians, with a hazard ratio of 0.62. That’s in all comers who were in this study. The phase 3 patients had to have residual disease, so they were a fairly difficult group. When you’re looking at the medians, you have to be cognizant of what the patient population was.

Then there were a number of subgroup analyses that were looked at as well, getting back to what Katie just talked about. If you look at the BRCA group, you’re down into the 0.3 range. If you break it out—Brad, you had data at the SGO [Society of Gynecologic Oncology] Annual Meeting this year looking at BRCA1 versus BRCA2, and BRCA1 showed a slightly higher hazard ratio of 0.39. It was a little lower, 0.35, for our BRCA2 population. If you pull out the BRCA and look at just the HRD, the hazard ratio is still impressive, 0.5. That’s interesting. If you look at your HR [homologous recombination] proficient patients, you still had a positive hazard ratio. It did not cross 1, and the hazard ratio was 0.68, that’s very impressive in terms of what you’re seeing with this data. Now, the medians were not very different. The difference was about 2.7 months, so you’d have to include that in how important you think that difference is.

I don’t think there were any significant new safety signals from this trial. We continued to see anemia, nausea, and thrombocytopenia—the big 3—largely as grade 1 and 2 events. But we still saw 28% nausea that was grade 3 or higher. In terms of thrombocytopenia, the amount definitely dropped down a little, but we still saw a significant amount of grade 3 or higher events that were present at about 29%. We still saw some of those safety signals that were the same.

What does this mean, Brad? It means you have a patient population where you could argue you could use a PARP in any of these subpopulations. I’d love to hear about these subgroup analyses that really aren’t powered and what they mean. I think people have different interpretations of what that means and how they’re going to apply it clinically. But I do think many people are going to look at these data and say, why wouldn’t I use it on everyone?

Bradley J. Monk, MD: I wanted a comprehensive answer, and that was comprehensive. The impact of this study deserves a comprehensive assessment as you just provided. I’m not going to debate yet—we will—whether HRD testing should be performed.

Transcript edited for clarity.