Background
Randomized, double-blind, placebo-controlled phase 3 (N=666). Advanced/metastatic squamous or nonsquamous NSCLC without known targetable driver alterations, after 1L platinum-based chemotherapy + pembrolizumab. Tested whether adding the PARP inhibitor niraparib to pembrolizumab maintenance improves outcomes; primary analysis restricted to patients with CR/PR to induction (n=401).
Results
Interventions and follow up: Arm A: Niraparib 300 mg PO daily + pembrolizumab 200 mg IV q3wk, as maintenance
Arm B: Placebo + pembrolizumab 200 mg IV q3wk
Primary endpoint: PFS by BICR in the CR/PR population
mFollow up: 34.3 vs 33.5 mo (OS follow-up; data cutoff Feb 2025)
Results: PFS (CR/PR, BICR): 5.55 vs 5.55 mo (HR 1.00; 95% CI 0.79-1.27; 1-sided P=.502)
PFS (ITT): not formally tested (hierarchical testing stopped after primary endpoint failure)
OS (CR/PR and ITT): not formally tested
Time to CNS progression: not formally tested
Arm B: Placebo + pembrolizumab 200 mg IV q3wk
Primary endpoint: PFS by BICR in the CR/PR population
mFollow up: 34.3 vs 33.5 mo (OS follow-up; data cutoff Feb 2025)
Results: PFS (CR/PR, BICR): 5.55 vs 5.55 mo (HR 1.00; 95% CI 0.79-1.27; 1-sided P=.502)
PFS (ITT): not formally tested (hierarchical testing stopped after primary endpoint failure)
OS (CR/PR and ITT): not formally tested
Time to CNS progression: not formally tested
Adverse events
Grade ≥3 TRAEs (niraparib arm): predominantly hematologic: anemia, thrombocytopenia, neutropenia (rates NR in abstract)
New safety signals: none
New safety signals: none
Conclusions
Adding niraparib to pembrolizumab maintenance did not improve efficacy in biomarker-unselected advanced NSCLC (PFS HR 1.00). Definitively negative phase 3 that effectively closes the PARP-inhibitor-plus-IO maintenance strategy in unselected NSCLC.
Key Limitations
Biomarker-unselected population (no HRR/BRCA enrichment) despite a DNA-repair-targeted mechanism; primary endpoint confined to CR/PR responders, limiting generalizability; hierarchical testing stopped at the first endpoint, so all secondary endpoints are descriptive only; added hematologic toxicity without any efficacy gain.
Clinical Context
Consistent with the negative olaparib-plus-pembrolizumab maintenance trials (KEYLYNK-006/-008): PARP + PD-1 maintenance is now repeatedly negative in unselected NSCLC. Standard of care after 1L chemo-immunotherapy remains pembrolizumab ± pemetrexed maintenance. No regulatory implications.