Experts Discuss Rationale for PARP Inhibitors Niraparib, Bevacizumab

In a Directions in Oncology Pharmacy^TM Peer Exchange series, experts R. Wendal Naumann, MD, and Michael Birrer, MD, PhD, discussed the PRIMA trial, the rationale for using poly (ADP-ribose) polymerase (PARP) inhibitors, and the indications for niraparib (Zejula, GlaxoSmithKline) and bevacizumab (Avastin, Genentech) with ovarian cancer treatment plans.

PRIMA Trial Overview

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

According to Naumann, the PRIMA trial enrolled patients who would be considered high risk: those who had residual disease after primary surgery 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.

“[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.

Niraparib is an inhibitor of 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.

According to Naumann, the hazard ratio was 0.68 for participants who received the niraparib treatment, translating to a median of just under 3 months of benefit. Despite the benefit, the question for Maurie Markman, MD, and Naumann became when to counsel based on HRD testing.

“The BRCA-mutated do the best as a group. The HRD-positive, non-BRCA-mutated do second best. And whether it’s HRD-negative or proficient, it still show[s] a statistically significant improvement with treatment compared to the control. Whether it’s .3, .5, or .7 hazard ratios, it’s somewhere in that range,” said Markman.

To Birrer, it becomes an issue of when a patient should receive a PARP inhibitor, which he believes relates more to a sequence and timeline. The patients with HRD will see these drugs earlier, whereas the “wild-type patients” or HR proficient patients may see BEV instead and may get their PARP later on moving forward.

Reference

• About Zejula. Zejula website. https://www.zejula.com/en/hcp/about. Accessed February 7, 2020.