Comparative efficacy and safety of first-line maintenance therapies in advanced ovarian cancer: A biomarker-stratified Bayesian network meta-analysis of 16 phase 3 trials.

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Background: The integration of poly(ADP-ribose) polymerase inhibitors (PARPi), immune checkpoint inhibitors (ICI), and anti-angiogenics has transformed first-line maintenance for advanced ovarian cancer (AOC). However, optimal regimens across homologous recombination deficiency (HRD) and BRCA mutation (BRCAm) profiles remain undefined. This network meta-analysis (NMA) evaluates the comparative efficacy and safety of emerging combinations against established standards. Methods: A systematic literature search identified Phase 3 randomized controlled trials evaluating first-line maintenance in AOC. Progression-free survival (PFS) log-hazard ratios and grade 3 adverse event (AE) rates were extracted. Bayesian NMAs were conducted, stratified by BRCAm, HRD-positive (HRd), and HRD-negative/proficient (HRp) status. Treatments were ranked using Surface Under the Cumulative Ranking (SUCRA) probabilities. Results: Sixteen phase 3 trials involving 11,482 patients were included. In the BRCAm network, PARPi monotherapies dominated efficacy, with olaparib (SUCRA 92%) and senaparib (SUCRA 88%) demonstrating superiority; adding ICI therapy (rucaparib+nivolumab) showed no synergistic benefit and ranked lowest (SUCRA 12%). In the HRd network, olaparib+bevacizumab achieved the highest probability of maximizing PFS (SUCRA 94%), outperforming triplet ICI combinations (durvalumab+olaparib+bevacizumab; SUCRA 78%). In the HRp network, individualized-dose niraparib (SUCRA 85%) and triplet therapies (SUCRA 74%) provided the most significant PFS advantages over baseline bevacizumab. Safety analyses revealed individualized PARPi dosing based on baseline body weight and platelets drastically improved tolerability rankings (SUCRA 62%) compared to fixed-dose administration (SUCRA 18%), mitigating severe hematological AEs. Conclusions: PARPi monotherapy remains the optimal frontline maintenance strategy for BRCAm AOC, as ICI combinations offer added toxicity without commensurate survival benefits. For HRd patients, combining a PARPi with an anti-angiogenic yields the highest efficacy. Across all subgroups, individualized PARPi dosing is critical for optimizing the therapeutic index.