Naumann on Navigating the FDA Approval of Niraparib in Ovarian Cancer

R. Wendel Naumann, MD

On April 29, 2020, the FDA approved niraparib (Zejula) for maintenance therapy in adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to frontline platinum-based chemotherapy, representing the second PARP inhibitor to receive regulatory approval in this setting. The approval, though a welcome addition to the armamentarium, has raised questions regarding proper patient selection, according to R. Wendel Naumann, MD.

“We’re beginning to have more decisions to make in terms of how we treat patients in the up-front setting. When the SOLO-1 data came out in 2018, we started using [olaparib (Lynparza)] for maintenance therapy [in patients with BRCA mutations]. Now, [we can give niraparib] to all-comers,” said Naumann.

The regulatory approval for niraparib, which is indicated for all-comers, is based on data from the phase 3 PRIMA trial, which showed a progression-free survival (PFS) advantage with the PARP inhibitor in women with BRCA mutations (HR, 0.40), HRD-positive tumors (HR, 0.43), and HRD-negative tumors (HR, 0.68).

As PARP inhibitors continue to expand in their role in the up-front setting, Naumann explained that the field will have to determine the downstream effects on the use of bevacizumab (Avastin), which has historically been reserved for high-risk patients, as well as on PARP inhibitors in the recurrent setting.

In an interview with OncLive, Naumann, a gynecologic oncologist at Levine Cancer Institute, Carolinas HealthCare System/Atrium Health, discussed the FDA approval of niraparib in ovarian cancer and the impact on the current treatment paradigm.

OncLive: Could you discuss the data from the PRIMA trial that led to the FDA approval of niraparib?

Naumann: The PRIMA study evaluated niraparib in patients who had a complete or partial response to up-front platinum-based chemotherapy. These patients had a high risk of recurrence. The investigators enrolled all-comers and then they looked at the results according to HRD status and BRCA status.

As expected, patients with BRCA mutations did exceptionally well with niraparib maintenance. Additionally, all-comers benefitted with niraparib, even the homologous recombination deficient (HRD)-negative patients. The hazard ratio for the HRD-negative group was 0.68. The PRIMA trial enrolled patients for up to 3 years after they had finished chemotherapy. We know. [platinum sensitivity] is sort of an in vivo HRD test, so it’s not surprising that everyone benefitted from these agents. Now, [the benefit in that population] did not translate to a large difference in outcomes—–the median improvement [in PFS] was only about 3 months in HRD-negative patients––but [some of those patients] will benefit from niraparib.

[These data] speak to the fact that our HRD testing is probably not very good, and we can’t always separate out patients who are not going to respond [to these agents] based on HRD testing. However, as we determine who [should receive niraparib], HRD testing is still going to play a role. We have to sort out who is going to have more benefit [with niraparib] and weigh the toxicity versus the benefit of these drugs when we’re discussing these results with patients.

Could you shed light on the way to optimally dose niraparib?

[That information] came from the NOVA trial. In the NOVA trial, patients received 300 mg of niraparib, and we did see a fairly significant amount of thrombocytopenia at that dose level. The investigators looked at subgroups who had the highest risk of thrombocytopenia, and [the dosing] was based on weight and platelet counts which is a reasonable approach. The baseline dose is probably a little higher for everyone, but [PARP inhibitors] are generally well tolerated agents.

Could you discuss the safety profile of niraparib?

The safety profile [of PARP inhibitors is pretty similar], though there are some subtleties. It’s important to watch blood counts, particularly platelet counts, as well as neutropenia. Anemia can also be an issue. However, [PARP inhibitors are] relatively safe, overall. We do have some concern about the possibility of myelodysplasia with these types of agents because they do inhibit DNA repair. Though, we have not seen a marked difference [in blood counts] even in patients who have been on these agents for a while.

How will the approval impact the paradigm?

We were already testing everyone for BRCA. However, I don’t think, particularly since the PRIMA data was released at the 2019 ESMO Congress, that a lot of people have thought about and talked to patients about these agents.

We also have data from the PAOLA-1 trial with the combination of olaparib and bevacizumab, which was presented at the 2019 ESMO Congress. The patients in that trial did much better compared with bevacizumab alone; this wasn’t a placebo-controlled trial. Now, we have to ask, “Do we give maintenance, and if we do, what therapy do we choose?” Bevacizumab has been approved since 2018. High-risk patients would go on bevacizumab, and now we’re choosing to put patients with BRCA mutations on PARP inhibitors first.

The big questions are, “How is [the approval] going to impact treatment in the second-line and third-line settings when these drugs are traditionally used? When is it appropriate to go back to a PARP inhibitor, and when are we going to use bevacizumab?

We have to weigh the risks and benefits, and even the potential costs of these agents in terms of the return on investment. We also have to consider recurrence. If you can only use bevacizumab 1 time, is it more prudent to give it up front, or is it more prudent to wait and hold it for recurrence? Those questions are going to have to be sorted out in the next couple years. Then, we’ll have to consider how [the approval] is going to impact our second-line trials that are ongoing.

González-Martín A, Pothuri B, Vergote IB, et al. Niraparib therapy in patients with newly diagnosed advanced ovarian cancer (PRIMA/ENGOT-OV26/GOG-3012 study). Ann Oncol. 30(suppl 5; abstr LBA1). doi: 10.1093/annonc/mdz394.052.