Results from a phase III trial indicate that maintenance therapy with the PARP inhibitor niraparib is more effective than placebo in slowing the progression of recurrent platinum-sensitive ovarian cancer. Improved progression-free survival was seen regardless of the presence or absence of germline BRCA mutations, or of homologous recombination deficiency; however, patients who had these mutations or defective DNA repair did better.

Maintenance therapy with the investigational PARP inhibitor niraparib (Tesaro) significantly prolonged progression-free survival (PFS) in patients with recurrent platinum-sensitive ovarian cancer compared with placebo, according to results from the phase III ENGOT-OV16/NOVA study. The data were presented last month by Mansoor Mirza, MD, at the European Society for Medical Oncology's 2016 Congress in Copenhagen, Denmark, and simultaneously published in The New England Journal of Medicine.

The study enrolled 553 patients, who were separated into two cohorts: One included 203 patients with germline BRCA (gBRCA) mutations, and the other 350 non–gBRCA-mutant patients. Patients in both cohorts were randomly assigned to receive either niraparib or placebo as maintenance therapy. Compared with placebo, niraparib prolonged the median PFS by 15.5 months and 5.5 months in the gBRCA and non-gBRCA groups, respectively.

A subgroup analysis of non-gBRCA patients indicated that those whose tumors tested positive for homologous recombination deficiency (HRD) responded better to PARP inhibition than the cohort overall. Among these patients—identified using Myriad Genetics' myChoice test—niraparib reduced the likelihood of disease progression by 62%. However, a clinically meaningful reduction of 42% was also seen in HRD-negative patients. Mirza thinks the latter is due to defective DNA repair genes that myChoice did not detect. A better test is needed to show “a clear separation between responders and nonresponders,” he says.

Niraparib's main side effects were thrombocytopenia, anemia, and neutropenia, which were largely resolved with dose adjustments. Quality of life, as reported by the patients, was similar between the treatment and placebo arms.

“I have quite a few patients who come every month, get the drug, and lead their normal daily lives,” says Mirza, chief oncologist at Copenhagen's Rigshospitalet. “It's amazing, because these are patients with relapsed disease who have had multiple rounds of chemotherapy.” He adds that it's too early to determine if niraparib also improves overall survival, but at a median follow-up of 18 months, about 40% of study patients had not experienced disease progression.

PARP inhibitors are “clearly a viable new class of agents within the umbrella of DNA repair inhibition, and an important addition to our therapeutic armamentarium for ovarian cancer,” says Elise Kohn, MD, head of gynecological cancer therapeutics at the NCI's Cancer Therapy Evaluation Program in Bethesda, MD, who was not involved with this study.

Currently, the sole approved PARP inhibitor for ovarian cancer is olaparib (Lynparza; AstraZeneca), but only for patients with gBRCA mutations—a group that accounts for just 15% to 20% of cases. Mirza points out that the FDA granted olaparib accelerated approval based on the results of a nonrandomized phase II study; niraparib is the first PARP inhibitor to show benefit in a phase III trial. He hopes that the ENGOT-OV16/NOVA results will lead to niraparib's approval for patients with recurrent platinum-sensitive ovarian cancer, regardless of their BRCA or HRD status.

Mirza also suspects that PARP inhibitors can inflict synthetic lethality on a wider range of DNA repair–defective cancers, a hypothesis he'd like to see explored in more clinical studies. –Kim Smuga-Otto

©2016 American Association for Cancer Research.
2016
American Association for Cancer Research.