Efficacy of PARP inhibitor and immune checkpoint inhibitor combination therapy in PD-L1-negative cancers: a systematic review and meta-analysis.

INTRODUCTION: Poly (ADP-ribose) polymerase inhibitors (PARPis) can enhance antitumor immunity and improve the efficacy of immune checkpoint inhibitors (ICIs) through PD-L1 upregulation and STING pathway activation. However, the benefit of this combination in PD-L1-negative patients remains unclear. METHODS: We conducted a systematic review and meta-analysis of 22 clinical trials including 1,849 patients, of whom 718 were PD-L1-negative. Pooled objective response rate (ORR), disease control rate (DCR) and 12-month progression-free survival (12-m PFS) were estimated using a random-effects model. Subgroup analyses were conducted by BRCA mutation, homologous recombination deficiency (HRD), and cancer type. RESULTS: PD-L1-negative patients had a lower ORR than PD-L1-positive patients (21% vs. 36%; p = 0.046). However, BRCA-mutated tumors demonstrated high ORRs irrespective of PD-L1 status (67% vs. 73%; p = 0.643), with a similar trend in HRD-positive tumors. The impact of PD-L1 varied by tumor type: reduced activity was observed in breast cancer, whereas ovarian cancer maintained meaningful responses regardless of PD-L1 expression. Responses were limited in other tumor types. DCR and 12-m PFS were numerically lower in PD-L1-negative patients without statistical significance. CONCLUSIONS: HRD/BRCA-driven genomic instability appears to play a dominant role in treatment response, suggesting that PD-L1 negativity alone should not preclude use of this combination. PROTOCOL REGISTRATION: www.crd.york.ac.uk/prospero identifier is CRD420251163119.