Niraparib Maintenance Shows Continued PFS Improvement in Ovarian Cancer

Paul D. DiSilvestro, MD

Director, Program in Women’s Oncology

Women & Infants Hospital of Rhode Island and Care New England Health System

Division director, Gynecologic Oncology

Department of Obstetrics and Gynecology

Warren Alpert Medical School of Brown University

Providence, RI

(Read Part 1 here)

Targeted Oncology^TM: What results were seen in the PRIMA trial (NCT02655016) of niraparib (Zejula)?

DISILVESTRO: [The PRIMA trial] was investigating niraparib versus placebo as maintenance. Patients could [enroll if they were treated in the] neoadjuvant setting. There were complete or partial responders, and their HRD [homologous recombination deficiency] status was followed but they were not required to be HRD-positive going into the trial. The primary end point was going to be PFS [progression-free survival] in the HRD-positive as well as the intention-to-treat [ITT] population along with some other key outcome data.

When we look at the data, it showed that there was a significant reduction in PFS in both the HRD-positive as well as the ITT populations.¹ Another thing that came out of the PRIMA study, based on some data determined from NOVA [NCT01847274], was this idea of fixed versus individualized dosing. In the PRIMA study, individualized dosing was allowed. The benefit was seen regardless of the individual 200 or 300 mg daily dosing. That was reevaluated in the PRIME study [NCT03709316]. That was another study in which individualized dosing was utilized. And, again, a benefit was seen across the different treatment profiles in terms of HRD status utilizing individualized starting dosing.

If we look at the PRIMA original outcomes in the ITT population, there was a 5-month benefit overall. In the HRD population, there was approximately an 11.5 month benefit with a 57% reduction in the risk of progression.¹

The breakdown within the HRD group showed there was a slightly longer benefit in the BRCA-mutated arm but with a more profound hazard ratio, with a 60% reduction in the risk of progression or death in the BRCA subgroups.^1,2 If we look at the homologous recombination proficient subgroup alone, that benefit was only about 3 months.

For PFS by subgroup, there was a couple of different findings [where the upper bound of the hazard ratio] crossed that bar of 1.00, mainly patients with stage IV disease and those whose homologous recombination status was not determined, but for the most part every different strata benefitted from niraparib.¹

What are the most recent developments from this trial?

There was a recent presentation at the European Society for Medical Oncology Annual Meeting in 2022 that updated the long-term PFS.³ There were some minor changes in the overall numbers. But, in terms of the hazard ratios for reduction of risk of progression or death, they’re relatively similar except if you look at the HRD population overall. There was a bit of a longer PFS but ironically a higher hazard ratio, although there was clearly a benefit in this population.

The overall survival [OS] data is not yet mature. There was an initial presentation in 2020 but the event rates were low, and, at this point, they have not made any definitive conclusions for OS for PRIMA.

What is known about the safety of this maintenance regimen?

We learned a lot about safety with niraparib. We were aware of the anemia, nausea, and thrombocytopenia but also…there was one case of myelodysplastic syndrome in the niraparib arm after 9 months of niraparib treatment, which makes you wonder if…that’s related to chemotherapy as opposed to niraparib.²

There was the PRIME study that looked at the individualized starting dosing. This was primarily performed in China and this randomly assigned patients to niraparib versus placebo but allowed for the utilization of the individualized starting dosing. When we look at the HRD-positive outcome, for PFS, the hazard ratio was 0.39 or a 61% reduction in the risk of progression, and overall there was a statistically significant benefit with a reduction in progression of 32%.⁴ If you look at the individualized starting dose, [it appears] similar in overall in terms of rates of leukopenia, but there was a reduction in some of the adverse events as it relates overall in terms of thrombocytopenia, anemia, and neutropenia. Utilizing the starting dose as described, it still maintains a statistical significance.

_References:

_{1. González-Martín A, Pothuri B, Vergote I, et al; PRIMA/ENGOT-OV26/GOG-3012 Investigators. Niraparib in patients with newly diagnosed advanced ovarian cancer. N Engl J Med. 2019:381(25):2391-2402. doi:10.1056/NEJMoa1910962}

_{2. González-Martín A, Pothuri B, Vergote I, et al. Niraparib therapy in patients with newly diagnosed advanced ovarian cancer (PRIMA/ENGOT-OV26/GOG-3012 study). Ann Oncol. 2019;30(suppl_5):v851-934. doi:10.1093/annonc/mdz394}

_{3. González-Martín AJ, Pothuri B, Vergote IB, et al. PRIMA/ENGOT-OV26/GOG-3012 study: Updated long-term PFS and safety. Ann Oncol. 2022;33(suppl 7):S789. doi:10.1016/j.annonc.2022.07.658}

_{4. Zejula. Prescribing Information. GlaxoSmithKline; 2020. Accessed January 18, 2023. https://bit.ly/3TiRyei}