A systematic review and meta-analysis published in JAMA Network Open found first-line PARP inhibitor maintenance after platinum-based chemotherapy was linked to improved progression-free survival across multiple patient populations with advanced-stage epithelial ovarian cancer. However, according to Petousis et al, the lack of overall survival benefit, increased toxic effects, and variability across subgroups and regimens indicate that treatment should be individualized.
“These findings advocate for a paradigm shift from a one-PARP-inhibitor-fits-all approach to a right-PARP-inhibitor-for-the-right-patient strategy,” the investigators remarked.
Study Details
The investigators searched MEDLINE, Embase, Web of Science, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for randomized clinical trials and prospective two-arm studies evaluating PARP inhibitor maintenance therapy in patients with advanced-stage epithelial ovarian cancer who responded to first-line platinum-based chemotherapy, from database inception through August 2024. Seven randomized clinical trials comprising 4,013 patients were included.
Data were independently extracted by two reviewers. Meta-analyses were performed using random-effects models. Risk of bias was assessed with the Cochrane Risk of Bias tool, and the certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework.
Progression-free and overall survival were evaluated as primary outcomes; secondary outcomes included high-grade adverse events.
Key Findings
First-line PARP inhibitor maintenance therapy was found to be associated with improved progression-free survival in the overall population (hazard ratio [HR] = 0.57, 95% confidence interval [CI] = 0.46–0.70; high certainty), as well as 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). Progression-free survival benefits seemed to remain consistent across different surgical timings, chemotherapy responses, and levels of residual disease; for example, hazard ratios for surgical timing were 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). None of the molecular subgroups demonstrated a statistically significant overall survival benefit (high to low certainty).
High-grade adverse events were most frequently reported in patients treated with PARP inhibitors vs without (HR = 2.40, 95% CI = 1.16–4.93; high certainty). Variability in treatment efficacy and toxic effects was observed across PARP inhibitor regimens; for instance, risk ratios for any recurrence or death in the overall population ranged from 0.53 (95% CI = 0.40–0.70) for senaparib to 0.83 (95% CI = 0.68–1.00) for olaparib, and risk ratios 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.
The investigators concluded, “In this meta-analysis of seven randomized clinical trials, no molecular subgroup demonstrated a statistically significant overall survival benefit with first-line PARP inhibitor maintenance therapy in epithelial ovarian cancer, and findings suggest that the consistency of progression-free survival benefit may vary, particularly among patients with BRCA wild-type or homologous recombination–proficient tumors. The observed variability in efficacy, toxic effects, and long-term outcomes across subgroups and PARP inhibitor regimens suggests that treatment decisions should be individualized. The identification of predictive biomarkers and inclusion of patient-centered outcomes, such as quality-adjusted survival, should be prioritized to guide optimal maintenance strategies.”
Tibor A. Zwimpfer, MD, of University Hospital Basel, Switzerland, and Stamatios Petousis, PhD, MD, of Aristotle University of Thessaloniki, Greece, are the corresponding authors of the JAMA Network Open article.
Disclosure: The study was funded by grants from the Swiss National Foundation and Bangerter-Rhyner Stiftung, as well as by Margarete and Walter Lichtenstein-Stiftung and Freie Gesellschaft Basel. Additional support was provided by the Swiss National Foundation Return CH Postdoctoral Mobility, the Victorian Cancer Agency/Ovarian Cancer Australia Low-Survival Cancer Philanthropic Mid-Career Research Fellowship, the National Health and Medical Research Council of Australia, and the U.S. Army Medical Research and Material Command Ovarian Cancer Research Program. For full disclosures of the study authors, visit jamanetwork.com.
