Incremental risk of high-grade adverse events with immune checkpoint inhibitors with or without poly(adenosine diphosphate-ribose) polymerase inhibitors in first-line treatment of advanced endometrial cancer: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the incremental risk of adverse events associated with immune checkpoint inhibitors, with or without poly(adenosine diphosphate-ribose) polymerase inhibitors, when added to first-line platinum-based chemotherapy for advanced or recurrent endometrial cancer. METHODS: We conducted a systematic review and meta-analysis of randomized phase II or III trials evaluating first-line chemo-immunotherapy with or without poly(adenosine diphosphate-ribose) polymerase inhibitors in advanced or recurrent endometrial cancer. PubMed, Embase, and Cochrane databases were searched through October 12, 2025. The primary end point was safety. Pooled risk ratios and 95% confidence intervals were calculated using random-effects models. Sub-group analyses compared doublet therapy (chemotherapy plus an immune checkpoint inhibitor) and triplet therapy (chemotherapy plus an immune checkpoint inhibitor and a poly(adenosine diphosphate-ribose) polymerase inhibitor) with chemotherapy alone. RESULTS: Six randomized trials involving 2995 patients were included. Neither doublet nor triplet therapy increased the risk of any-grade adverse events compared with chemotherapy alone. Doublet therapy significantly increased grade ≥3 adverse events (risk ratio 1.12, 95% confidence interval 1.02 to 1.24), whereas triplet therapy showed a nonsignificant trend toward increased grade ≥3 toxicity (risk ratio 1.41, 95% confidence interval 0.99 to 2.01). Triplet therapy significantly increased serious adverse events (risk ratio 2.20, 95% confidence interval 1.74 to 2.78), whereas doublet therapy did not. No significant increase in fatal adverse events or treatment discontinuations was observed with either strategy. Both doublet and triplet regimens increased immune-related adverse events, including hypothyroidism. Triplet therapy was associated with a significantly higher risk of grade ≥3 anemia (risk ratio 1.66, 95% confidence interval 1.14 to 2.42), whereas doublet therapy was not. Most immune-related toxicities were low grade, with no clear increase in grade ≥3 immune-related adverse events. CONCLUSIONS: Chemo-immunotherapy demonstrates a manageable safety profile and remains the standard first-line treatment backbone for advanced endometrial cancer. The addition of poly(adenosine diphosphate-ribose) polymerase inhibitors appear to increase serious adverse events and hematologic toxicity, particularly grade ≥3 anemia, without increasing treatment-related mortality. In the absence of validated predictive biomarkers or a demonstrated overall survival benefit, poly(adenosine diphosphate-ribose) polymerase inhibitor-based treatment intensification should be individualized and carefully weighed against its additional toxicity burden.