Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer

Abstract

BACKGROUNDNiraparib is an oral poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP) 1/2 inhibitor that has shown clinical activity in patients with ovarian cancer. We sought to evaluate the efficacy of niraparib versus placebo as maintenance treatment for patients with platinum-sensitive, recurrent ovarian cancer. METHODSIn this randomized, double-blind, phase 3 trial, patients were categorized according to the presence or absence of a germline BRCA mutation (gBRCA cohort and non-gBRCA cohort) and the type of non-gBRCA mutation and were randomly assigned in a 2:1 ratio to receive niraparib (300 mg) or placebo once daily. The primary end point was progression-free survival. RESULTSOf 553 enrolled patients, 203 were in the gBRCA cohort (with 138 assigned to niraparib and 65 to placebo), and 350 patients were in the non-gBRCA cohort (with 234 assigned to niraparib and 116 to placebo). Patients in the niraparib group had a significantly longer median duration of progression-free survival than did those in the placebo group, including 21.0 vs. 5.5 months in the gBRCA cohort (hazard ratio, 0.27; 95% confidence interval [CI], 0.17 to 0.41), as compared with 12.9 months vs. 3.8 months in the non-gBRCA cohort for patients who had tumors with homologous recombination deficiency (HRD) (hazard ratio, 0.38; 95% CI, 0.24 to 0.59) and 9.3 months vs. 3.9 months in the overall non-gBRCA cohort (hazard ratio, 0.45; 95% CI, 0.34 to 0.61; P<0.001 for all three comparisons). The most common grade 3 or 4 adverse events that were reported in the niraparib group were thrombocytopenia (in 33.8%), anemia (in 25.3%), and neutropenia (in 19.6%), which were managed with dose modifications. CONCLUSIONSAmong patients with platinum-sensitive, recurrent ovarian cancer, the median duration of progression-free survival was significantly longer among those receiving niraparib than among those receiving placebo, regardless of the presence or absence of gBRCA mutations or HRD status, with moderate bone marrow toxicity. (Funded by Tesaro; ClinicalTrials.gov number, NCT01847274.)

Missed therapeutic and prevention opportunities in women with BRCA‐mutated epithelial ovarian cancer and their families due to low referral rates for genetic counseling and BRCA testing: A review of the literature

“…Myelodysplasia is a rare but usually fatal complication and occurred in 1.4% and 1.1% of patients receiving niraparib or placebo, respectively, in the NOVA study (niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer). 68 Olaparib and rucaparib have US regulatory approval in those with known BRCA mutations as monotherapy in third or greater relapse (ie, knowledge of BRCA mutation status is required to ensure access to these drugs).…”

“…176,177 Approval on a worldwide basis is more common as maintenance therapy after successful retreatment with platinumbased therapy in those with sensitive disease (defined as EOC relapsing 6 months after completing prior treatment).Three randomized studies of maintenance PARP inhibitor therapy have been published, and a fourth has just been presented at a conference. 68,[178][179][180][181][182] Study 19 was a randomized phase 2 study comparing maintenance olaparib versus placebo after successful second-line chemotherapy for platinum-sensitive, HGS EOC. It was not powered for overall survival (OS), and there was a 20% rate of crossover to olaparib, which will confound OS analysis.…”

“…The current data are too immature for an OS analysis. 68 US Food and Drug Administration approval was granted in March 2017 and did not require a BRCA mutation to be present. However, because these drugs are still very expensive, it is likely that many jurisdictions will limit their use to those with a BRCA mutation, because this is where the absolute benefit is the greatest.…”

“…[64][65][66][67] Tumor testing will identify germline BRCA mutations, somatic BRCA mutations, and also homologous repair deficiency (HRD) (see the section below on PARP inhibitors), from either phenotypic DNA patterns or specific gene profiles, all of which predict for a greater PARP inhibitor effect. 68 As an additional benefit, this tumor testing could be used as a preliminary step in identifying those women with EOC who potentially carry an inherited BRCA mutation. Only those women with mutations in the tumor, of which 75% are germline and 25% are somatic, would then need formal germline testing.…”

BRCA mutation genetic testing implications in the United States

“…BRCA1-or BRCA2-deficient ovarian tumors are particularly responsive to PARPI [117e119]. In a recent randomized phase 3 trial among patients with platinum-sensitive, recurrent ovarian cancer, the median duration of PFS was significantly longer among those receiving niraparib (PARPI) than among those receiving placebo, regardless of the presence or absence of BRCA mutations [120].…”