PARP Inhibitor Maintenance After First-Line Chemotherapy in Advanced-Stage Epithelial Ovarian Cancer

Abstract

This systematic review and meta-analysis investigates the association of first-line poly(adenosine diphosphate-ribose) polymerase inhibitor (PARP inhibitor) maintenance therapy with efficacy and safety outcomes among patients with advanced-stage epithelial ovarian cancer. QuestionWhat is the association of first-line poly(adenosine diphosphate-ribose) polymerase inhibitor (PARP inhibitor) maintenance therapy with survival outcomes in epithelial ovarian cancer, and how do outcomes vary across regimens and subgroups?FindingsIn this meta-analysis of 7 randomized clinical trials among 4013 patients with advanced-stage epithelial ovarian cancer responding to first-line platinum-based chemotherapy, progression-free survival improved in most subgroups but not in homologous recombination-proficient tumors, and no subgroup demonstrated a statistically significant overall survival benefit. Efficacy and toxic effects varied across agents.MeaningThis study found that first-line PARP inhibitor maintenance therapy was associated with a progression-free survival benefit in many patient populations; however, the lack of overall survival benefit, increased toxic effects, and variability across subgroups and regimens, suggest that treatment should be individualized. ImportanceFirst-line maintenance therapy with poly(adenosine diphosphate-ribose) polymerase inhibitors (PARP inhibitors) after platinum-based chemotherapy improves progression-free survival (PFS) in advanced epithelial ovarian cancer (EOC), particularly in patients with BRCA-variant or homologous recombination-deficient tumors. However, overall survival (OS) benefits remain uncertain, and toxic effect profiles emphasize the need for optimized patient and agent selection.ObjectiveTo evaluate the efficacy and safety of first-line PARP inhibitor maintenance therapy compared with chemotherapy alone in advanced-stage EOC, with subgroup analyses by BRCA and HRD status, up-front or interval surgery, chemotherapy response, and residual disease.Data sourcesMedline, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched from database inception to August 19, 2024.Study SelectionRandomized clinical trials and prospective 2-arm studies evaluating PARP inhibitor maintenance therapy in patients with advanced-stage EOC responding to first-line platinum-based chemotherapy were included.Data Extraction and SynthesisThe Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline was followed in reporting this study. Data were independently extracted by 2 reviewers. Random-effects models were used for meta-analysis. Risk of bias was assessed with Cochrane risk of bias and certainty of evidence with the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework.Main Outcomes and MeasuresPrimary outcomes were PFS and OS; secondary outcomes included high-grade adverse events.ResultsA total of 7 randomized clinical trials with 4013 patients with advanced-stage epithelial ovarian cancer responding to first-line platinum-based chemotherapy were included. PARP inhibitor maintenance was associated with improved PFS in the overall population (hazard ratio [HR], 0.57; 95% CI, 0.46-0.70; high certainty) and in all molecular subgroups except the homologous recombination proficient group (BRCA variant: HR, 0.40; 95% CI, 0.35-0.45; BRCA wild type: HR, 0.62; 95% CI, 0.44-0.86; homologous recombination deficient: HR, 0.44; 95% CI, 0.39-0.50; all high certainty). PFS benefits were consistent across surgical timing, chemotherapy responses, and residual disease; for example, surgical timing had HRs of 0.51 (95% CI, 0.31-0.84) for neoadjuvant chemotherapy and 0.54 (95% CI, 0.36-0.81) for primary cytoreductive surgery (all high certainty). No molecular subgroup showed a statistically significant OS improvement (high to low certainty). High-grade adverse events were more common in the PARP inhibitor group (HR, 2.40; 95% CI, 1.16-4.93; high certainty). Observed treatment efficacy and toxic effects varied across PARP inhibitor regimens; for example, the risk ratio for any recurrence or death in the overall study group ranged from 0.53 (95% CI, 0.40-0.70) for senaparib to 0.83 (95% CI, 0.68-1.00) for olaparib, while the risk ratio for high-grade adverse events ranged from 1.15 (95% CI, 0.64-2.06) for veliparib to 4.73 (95% CI, 2.77-8.07) for niraparib.Conclusions and RelevanceIn this study, no subgroup showed an association between first-line PARP inhibitor maintenance therapy in advanced-stage EOC and improved OS, and findings suggest that the consistency of associated PFS benefits may vary, particularly in homologous recombination proficient and BRCA wild type tumors. Variability in efficacy and toxic effects across subgroups and PARP inhibitor regimens underscores the importance of individualized treatment decisions.