Bradley J. Monk, MD, FACS, FACOG: Let’s talk about 1 of the other determinants, which is adverse-effect profile. Tell us about the adverse-effect profile of veliparib, and we’ll go back and forth between the adverse effects of veliparib and niraparib.

Robert L. Coleman, MD, FACOG, FACS: Do you want to talk about it just in the maintenance setting, or are you talking about it during chemotherapy?

Bradley J. Monk, MD, FACS, FACOG: I’m talking about when I use it in the clinic. It doesn’t have to be that complicated. When you talk to your patient, there are adverse effects to medications, and you’re going to talk to them about what they are.

Robert L. Coleman, MD, FACOG, FACS: OK. If we’re at the point that you want to have that conversation, you’ve then cleared chemotherapy, right? The point of discussing adverse effects starting at first-line therapy is that you’re talking about the interaction between chemotherapy and its adverse effects in combination with the adverse effects that you get from the PARP inhibitor. We were happy to see in VELIA that the adverse-effect profile was not much different on chemotherapy. There was a little more thrombocytopenia and higher-grade thrombocythemia that was seen with that.

Bradley J. Monk, MD, FACS, FACOG: In the combination?

Robert L. Coleman, MD, FACOG, FACS: In the combination. Once we transitioned over into the maintenance phase, it was very much what we saw. It may have been even a little less from the hematologic standpoint than we’ve seen in the other trials that have used these agents.

Bradley J. Monk, MD, FACS, FACOG: Is that because they’d all been dose reduced by the time they got to the maintenance phase?

Robert L. Coleman, MD, FACOG, FACS: Actually, they were dose increased, right? We started at 150 mg, then we transitioned to 300 mg, and then we went to 400 mg.

Bradley J. Monk, MD, FACS, FACOG: If you had a dose reduction in the combination phase, did you go immediately to this?

Robert L. Coleman, MD, FACOG, FACS: Yes, and we learned as we were doing the trial that it was hard to do.

Bradley J. Monk, MD, FACS, FACOG: It’s not related.

Robert L. Coleman, MD, FACOG, FACS: Yes, and we learned that the chemotherapy effects actually persist a bit. We built in this 2-week transition phase in which we stepped up the dose, and then 2 weeks later, we stepped up the dose as long as it was tolerated. If they didn’t tolerate the 400 mg, we went back to the 300 mg and kept it there, but we transitioned that step so that we could get back up to the full dose.

Bradley J. Monk, MD, FACS, FACOG: Again, that’s very different, right? You taught us that you have to either make the decision in the beginning to start BEV [bevacizumab] or PARP inhibitors, and after the chemotherapy, decide if it’s going to be a maintenance strategy as in PRIMA. Tell us about the adverse-effect profile of niraparib.

Kathleen Moore, MD: From a nonhematologic standpoint, it’s very similar to the other PARP inhibitors with very common but low-severity nausea, fatigue, and vomiting. About 25% can get dyspepsia and diarrhea. It’s very similar. Niraparib has the unique toxicity. It’s not very common, but about 15% can get hypertension. It’s not incredibly high grade, but you can get it. About 10% of patients can have tachycardia or palpitations because of the serotonergic impact of niraparib.

Bradley J. Monk, MD, FACS, FACOG: None of that is seen in veliparib, right? No adrenergic effects?

Robert L. Coleman, MD, FACOG, FACS: No, we didn’t see that.

Bradley J. Monk, MD, FACS, FACOG: Keep going.

Kathleen Moore, MD: That’s something unique to niraparib. They’re very manageable, and you can counsel patients regarding them. From a hematologic standpoint, it is a little more toxic than the other PARP inhibitors, especially veliparib, although the individualized dosing is way better. However, it’s still a little higher. You see a little more grade 3 neutropenia. You see a bit more grade 3 thrombocytopenia. It’s about 6% of patients with the other PARP inhibitors. Here, it’s about 13% when you do the adjustment.

Bradley J. Monk, MD, FACS, FACOG: Tell them about the individualized dosing and what that is.

Kathleen Moore, MD: Originally, niraparib started at a 300-mg flat dose once daily and had notable difficulty with thrombocytopenia related to weight, which is 77 kg. If you were lower than 77 kg or you had baseline platelets less than 150,000, then you were at much higher risk—about 40%—of having this severe thrombocytopenia. If you have either of those, you start the niraparib dose at 200 mg. When that was adjusted—and you presented this data at SGO [Society of Gynecologic Oncology Annual Meeting on Women’s Cancer]—in the PRIMA study about halfway through, you can really see a dramatic difference in the hematologic profile between the 2 phases of the study.

It looks similar now to olaparib and rucaparib. It’s just a smidgen higher, but I don’t think it’s to an extent that’s clinically relevant. We’ll see. I think that breakdown is coming. It wasn’t presented at this meeting. It was just the overall toxicities. We still saw about 30% of patients with grade 3 or higher thrombocytopenia, but I think once we see the breakdown, we’ll see that go down.

Bradley J. Monk, MD, FACS, FACOG: There’s been a lot of anxiety about starting at 200 mg.

Robert L. Coleman, MD, FACOG, FACS: Yes.

Bradley J. Monk, MD, FACS, FACOG: I try to teach people that the most common dose is 200 mg, anyway.

Robert L. Coleman, MD, FACOG, FACS: It’s 200 mg, anyway.

Shannon N. Westin, MD, MPH: That’s right.

Bradley J. Monk, MD, FACS, FACOG: The dose intensity is only on the first cycle, because you’re going to get to 200 mg in most patients at the second cycle. You’re going to do it 2 ways. You’re going to figure it out based on the weight and platelet count, or you’re going to suffer the brain damage of thrombocytopenia and get there. The relative dose intensity over many cycles is similar.

Robert L. Coleman, MD, FACOG, FACS: I just wanted to point out that I really like this concept. This was an adverse event we didn’t anticipate when we first started. We went back and looked back at the pharmacokinetics and pharmacodynamics of the drug. We had some of that data, learned about the volume of distribution, learned about how the concentrations might be in the bone marrow, and learned about how that be mitigated by adjustments. We set up a strategy for it, which retrospectively looked as if it might work, and then prospectively validated it. That’s really good stuff.

Transcript Edited for Clarity