Niraparib Found to Improve Progression Free Survival in Women with Advanced Ovarian Cancer

Niraparib (Zejula, GlaxoSmithKline) has been found to improve progression free survival (PFS), regardless of biomarker status, as a monotherapy for women with first-line platinum responsive advanced ovarian cancer. The results were from a phase 3, randomized, double-blind, placebo-controlled study.¹

The PRIMA study was presented at the 2019 European Society for Medical Oncology congress and simultaneously published in The New England Journal of Medicine. Treatment with niraparib resulted in a 38% reduction in the risk of disease progression or death in the overall study population compared with placebo.¹

In a Specialty Pharmacy Times Peer Exchange series, experts R. Wendal Naumann, MD, and Michael Birrer, MD, PhD, discussed the trial and its implications. According to Naumann, the trial enrolled patients who would be considered high risk: those who had residual disease after primary surgery and were assigned up to 3 years of niraparib based on the study design. Participants who had a response to chemotherapy were randomized at the end of their treatment.²

“[This process] showed a benefit actually in the intent-to-treat group as well as the homologous recombination deficiency [HRD]-positive group,” explained Naumann in the Specialty Pharmacy Times Peer Exchange series.²

According to a GlaxoSmithKline press release, results were driven by a clinically meaningful reduction in risk of progression in women with BRCA mutation tumors (60% risk reduction), homologous recombination (HR)-deficient (HRD) BRCA wild-type tumors (50% risk reduction), and HR-proficient tumors (32% risk reduction).¹

In an interim analysis of overall survival (OS), niraparib demonstrated an encouraging trend toward improvement in OS relative to placebo. In the HR-deficient subgroup, 91% of women on niraparib were alive at 24 months versus 85% for placebo.¹

“When [the researchers] did the subanalysis, it showed a benefit in the HRD-negative group. All of the magnitude of that benefit was relatively small. The hazard ratio is 0.68 and that translated to a median of about just under [3] months of benefit. But we do see a tail in that group,” said Naumann.²

Niraparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, PARP1 and PARP2, which play a role in DNA repair. In vitro studies suggest that niraparib’s cytotoxic effects may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, apoptosis, and cell death.³

“I think the BRCA-mutated patients, the HRD patients are going to see these drugs earlier, and I think the wild-type patients, or the HR-proficient patients, may see [bevacizumab] instead and maybe get their PARP later on, because the impact is a little bit less,” Birrer said.²

In the Specialty Pharmacy Times Peer Exchange series, the experts also discussed the PRIMA study’s findings compared with the recent VELIA study, which examined another PARP inhibitor, called veliparib. This therapy was examined versus chemotherapy alone, in combination with chemotherapy during treatment, and veliparib with chemotherapy followed by maintenance therapy.⁴

“I think the HRD issue was looked at, but I think it’s important to understand that the HRD cutoff, the loss of heterozygosity [LOH] score was actually lower [in the VELIA study] than it was in the PAOLA and PRIMA trials. The HRD-positive group in the VELIA trial may not have been as HRD-positive as it was in the PRIMA and PAOLA trial,” Naumann said.⁴

In the VELIA study, when researchers separated out the BRCA wild type, HRD-positive in a subgroup analysis, the intent-to-treat population did not show a statistical benefit.

“[T]he HRD cutoff, which is interesting because of its impact on this trial [has] an impact on the other trial, which in PRIMA there are probably HRD-like patients in what’s called HR [homologous recombination] proficient because the cutoff was so high. It just gets complex,” Birrer said.⁴

The experts also noted that veliparib did not result in a statistically significant reduction in potential dose reductions in curative chemotherapy.

Niraparib is not currently approved in the first-line ovarian cancer maintenance setting. The safety profile demonstrated in PRIMA did not differ from the established safety profile, with the most common adverse events being anemia (31%), thrombocytopenia (29%), and neutropenia (13%).

References

• Phase 3 PRIMA trial of Zejula® (niraparib) is the first study to show a PARP inhibitor significantly improves PFS, regardless of biomarker status, when given as monotherapy in women with first-line platinum responsive advanced ovarian cancer [news release]. Published September 29, 2019. https://www.gsk.com/en-gb/media/press-releases/phase-3-prima-trial-of-zejula-niraparib-is-the-first-study-to-show-a-parp-inhibitor-significantly-improves-pfs-regardless-of-biomarker-status/. Accessed February 7, 2020.
• PRIMA Trial Overview. Specialty Pharmacy Times Peer Exchange Series. Published January 13, 2020. https://www.pharmacytimes.com/peer-exchange/the-role-of-parp-inhibitors--in-ovarian-cancer/prima-trial-overview. Accessed February 7, 2020.
• About Zejula. Zejula website. https://www.zejula.com/en/hcp/about. Accessed February 7, 2020.
• New PARP Inhibitor: The VELIA Regimen. Specialty Pharmacy Times Peer Exchange Series. Published January 19, 2020. https://www.pharmacytimes.com/peer-exchange/the-role-of-parp-inhibitors--in-ovarian-cancer/new-parp-inhibitor-the-velia-regimen. Accessed February 7, 2020.