The safety of PARP inhibitors combined with immune checkpoint inhibitors versus immune checkpoint inhibitor monotherapy: A systematic review, meta-analysis, and trial sequential analysis of randomized controlled trials

Background: The combination of poly(ADP-ribose) polymerase inhibitors (PARPi) and immune checkpoint inhibitors (ICI) represents a promising strategy with potential synergistic effects. Preclinical studies suggest that PARPi-induced DNA damage may enhance tumor immunogenicity and augment the efficacy of ICI. Currently, this approach is being studied across multiple malignancies. However, the risk of additive adverse events remains a major concern. We conducted the first meta-analysis of randomized controlled trials (RCTs) to assess the safety of PARPi plus ICI versus ICI monotherapy. Methods: We conducted a PRISMA-compliant systematic review, searching PubMed, Web of Science, and the Cochrane Library for RCTs comparing PARPi+ICI combination therapy against ICI monotherapy. The safety outcomes were serious adverse events (SAEs), immune-mediated adverse events (imAEs), treatment discontinuation, and specific treatment-related adverse events. Risk ratios (RR) and 95% confidence intervals (CI) were pooled using a random-effects model. Heterogeneity was assessed using the I² statistic. Finally, Trial Sequential Analysis (TSA) was performed to test the reliability of the pooled results and classify findings as conclusive, inconclusive, or suggestive. Results: Six RCTs (DUO-E, KEYLYNK-008, ORION, SWOG 1929, MORPHEUS, and BAYOU) encompassing 1537 patients comparing PARPi+ICI with ICI monotherapy were included. The combination was associated with a significantly suggestive higher risk of SAEs (N=5; RR 1.77; 95% CI: 1.29-2.43; I²=0%) and anemia (N=6; RR 3.27; 95% CI: 2.50-4.29; I²=16%), neutropenia (N=5; RR 4.13; 95% CI: 2.35-7.27; I²=18%), and significantly conclusive leukopenia (N=3; RR 3.93; 95% CI: 2.24-6.91; I²=2%), vomiting (N=6; RR 3.47; 95% CI: 2.20-5.46; I²=0%). Conversely, the combination led to a significantly inconclusive lower incidence of imAEs (N=3; RR 0.77; 95% CI: 0.61-0.98; I²=0%). No significant differences were observed in discontinuation of the ICI component (N=5; RR 1.31; 95% CI: 0.85-2.02; I²=0%, INC), diarrhea (N=6; RR 1.15; 95% CI: 0.81-1.64; I²=5%), hypothyroidism (N=5; RR 0.77; 95% CI: 0.51-1.16; I²=0%,), however they all were inconclusive. Conclusions: The addition of PARPi to ICI therapy conclusively increases the risk of leukopenia and vomiting. Furthermore, our TSA found suggestive evidence for an increased risk of SAEs, anemia, and neutropenia. Conversely, while pooled analysis suggested a reduced risk of imAE, our TSA revealed this finding to be inconclusive and warrants further investigation. Similarly, the current evidence is inconclusive for the risk of ICI discontinuation or diarrhea. Based on these findings, watchful clinical monitoring and risk-benefit assessment are essential when considering this combination.