PARP inhibitor-based first-line maintenance therapy for newly diagnosed advanced ovarian cancer across molecular subgroups: an updated systematic review and network meta-analysis.

Background: PARP inhibitor-based maintenance has become central to first-line treatment of newly diagnosed advanced ovarian cancer. With expanding therapeutic options, treatment selection increasingly relies on BRCA mutation and homologous recombination deficiency (HRD) status. The 2026 NCCN Guidelines emphasize biomarker-directed maintenance; however, comparative evidence across molecular subgroups remains limited. We conducted an updated network meta-analysis to compare efficacy and safety of PARP inhibitor-based first-line maintenance strategies. Methods: We searched major databases and conference proceedings to 1 April 2026 for randomized controlled trials evaluating first-line maintenance in newly diagnosed advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. Eligible interventions included PARP inhibitor monotherapy, PARP inhibitor plus antiangiogenic therapy, antiangiogenic monotherapy, and placebo. Primary analyses focused on progression-free survival (PFS) in BRCA-mutated and HRD-positive populations; secondary and exploratory analyses covered intention-to-treat, HRD-positive non-BRCA-mutated, and homologous recombination proficient populations. Safety outcomes included grade ≥3 adverse events and treatment discontinuation. A frequentist random-effects model was applied. Results: Seven trials involving 3,930 patients were included. PARP inhibitor-based maintenance significantly improved PFS versus placebo, with the strongest benefit in BRCA-mutated and HRD-positive populations. PARP inhibitor monotherapy also significantly improved PFS in the HRD-positive non-BRCA-mutated population, supporting clinical relevance of HRD status beyond BRCA mutation alone. Benefit in the intention-to-treat population was smaller than in biomarker-selected populations. Evidence of benefit in the homologous recombination proficient population was inconsistent. Indirect comparisons showed no statistically significant superiority of one active regimen over another. Within the connected network, no statistically significant incremental PFS benefit was established for adding antiangiogenic therapy to PARP inhibition; this comparison was limited by the restricted evidence base for combination therapy and the inability to incorporate PAOLA-1 into the primary network because of network disconnection. No statistically significant evidence indicated that frontline bevacizumab exposure modified the relative PFS benefit. Sensitivity analyses yielded results consistent with the primary analysis. PARP inhibitor monotherapy increased grade ≥3 adverse events versus placebo; comparative safety of combinations remained limited. Conclusions: This network meta-analysis supports biomarker-directed PARP inhibitor-based first-line maintenance in advanced ovarian cancer, with the greatest PFS benefit in BRCA-mutated and HRD-positive populations. No active regimen demonstrated statistically significant superiority within the connected network. The incremental benefit of adding antiangiogenic therapy to PARP inhibition remains uncertain because connected-network evidence for combination strategies was limited and PAOLA-1 could not be incorporated into the primary network. These findings should not be interpreted as evidence against the clinical value of olaparib plus bevacizumab or combination maintenance strategies in general. Treatment selection should integrate molecular status, prior bevacizumab exposure, safety, treatment availability, and patient preference. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420261382266.