Background
Phase III RCT (ENGOT-OV16/NOVA). 553 patients with platinum-sensitive recurrent ovarian, fallopian tube, or primary peritoneal cancer with complete or partial response to most recent platinum-based chemotherapy. Enrolled irrespective of HRD/BRCA status. Two independent cohorts prospectively stratified: germline BRCA-mutated (gBRCAm, n=203) and non-germline-BRCA (n=350, further subdivided by HRD status). Randomized 2:1 to niraparib 300 mg QD maintenance vs placebo. Niraparib is an oral PARP1/2 inhibitor.
Interventions and follow up
Arm A: Niraparib 300 mg QD maintenance until progressio
Arm B: Placebo
Primary endpoint: PFS in gBRCAm cohort, then non-gBRCA cohort
mFollow up: 16.9 month
Arm B: Placebo
Primary endpoint: PFS in gBRCAm cohort, then non-gBRCA cohort
mFollow up: 16.9 month
Results
PFS — gBRCAm cohort: 21.0 months (niraparib) vs 5.5 months (placebo), HR 0.27 (95% CI 0.17–0.41), P<.001
PFS — non-gBRCA HRd: 12.9 vs 3.8 months, HR 0.38 (95% CI 0.24–0.63), P<.001
PFS — non-gBRCA HRp: 6.9 vs 3.8 months, HR 0.58 (95% CI 0.36–0.92), P=.02
PFS — non-gBRCA overall: 9.3 vs 3.9 months, HR 0.45 (95% CI 0.34–0.61), P<.001
PFS — non-gBRCA HRd: 12.9 vs 3.8 months, HR 0.38 (95% CI 0.24–0.63), P<.001
PFS — non-gBRCA HRp: 6.9 vs 3.8 months, HR 0.58 (95% CI 0.36–0.92), P=.02
PFS — non-gBRCA overall: 9.3 vs 3.9 months, HR 0.45 (95% CI 0.34–0.61), P<.001
Adverse events
Main adverse events: Grade ≥3 thrombocytopenia: 33.8% — the major dose-limiting toxicity. Grade ≥3 anemia: 25.3%. Grade ≥3 neutropenia: 19.6%. Hypertension grade ≥3: 8.2%. Nausea (mostly grade 1–2): common. PALT/ALT elevations: observed. After this trial, individualized starting dose (200 mg for lower body weight/platelet count) was established to reduce thrombocytopenia (used in PRIMA).
Conclusions
Niraparib significantly improved PFS across all patient subgroups regardless of BRCA or HRD status, with greatest benefit in gBRCAm (HR 0.27), clinically meaningful benefit in non-gBRCA HRd (HR 0.38), and modest benefit even in HRp patients (HR 0.58).
Key Limitations
Key Limitations: The 300 mg fixed dose caused high rates of thrombocytopenia (33.8%) requiring dose reductions in ~75% of patients — this led to the individualized starting dose in PRIMA. OS data immature. The HRp subgroup benefit (HR 0.58, 3.1-month absolute median PFS gain) is modest — clinical benefit in HRp patients is debated. No crossover to PARP inhibitor, complicating OS interpretation in later analyses. No biomarker predictive of response beyond BRCA/HRD.
Clinical Context
NOVA is the foundational trial for niraparib in platinum-sensitive recurrent ovarian cancer across all biomarker groups (FDA approved 2017). The individualized starting dose approach (PRIMA) significantly reduced hematologic toxicity. In patients with prior PARP inhibitor exposure (first-line maintenance), efficacy of retreatment PARP inhibitor is substantially lower. Rucaparib (ARIEL3) is an alternative for BRCA-mutated or HRd platinum-sensitive recurrent OC.
References