PARP inhibitor and immune checkpoint inhibitor combination therapy in PD-L1-negative tumors: A meta-analysis.

Abstract

e14568 Background: Poly(ADP-ribose) polymerase inhibitors (PARPis) can enhance antitumor immunity and potentially improve the efficacy of immune checkpoint inhibitors (ICIs) through mechanisms such as PD-L1 upregulation and STING pathway activation, providing a rationale for combining ICIs with PARPis. However, whether PD-L1-negative patients benefit from this combination therapy remains unclear. Methods: We performed a systematic search of PubMed, Embase, Web of Science, Cochrane library, and relevant conference proceedings for clinical trials evaluating PARPi-ICI combination therapy in patients with PD-L1-negative tumors. The pooled objective response rate (ORR), disease control rate (DCR) and 12-month progression-free survival (12-m PFS) were estimated using a random-effect model and were compared with those in PD-L1-positive patients within the same trials. Subgroup analyses were conducted based on BRCA mutation and HRD status, as well as cancer type. Results: Twenty-two clinical trials comprising 1849 patients (718 PD-L1-negative) were included. Among unselected all-comers, the pooled ORR was significantly lower in the PD-L1-negative patients (21% [95% CI: 12-30%]) than in PD-L1-positive patients (36% [95% CI: 26-47%], p = 0.046). BRCA-mutant patients showed high ORR irrespective of PD-L1 status (67% vs. 73%, p = 0.643), and HRD-positive patients showed no significant difference (31% vs. 57%, p = 0.139). By cancer type, breast cancer showed significantly lower ORR in PD-L1-negative patients (24% vs. 46%, p = 0.090), whereas ovarian cancer showed no significant difference (36% vs. 43%, p = 0.578). Non–breast/ovarian cancers had low ORRs overall, although significant difference was observed between PD-L1-negative and PD-L1-positive subpopulations (9% vs. 19%, p = 0.001). The pooled DCR and 12-m PFS rates were numerically but not significantly lower in PD-L1-negative patients compared with PD-L1-positive patients (40% vs. 55%, p = 0.217; and 40% vs. 56%, p = 0.350, respectively). Conclusions: Despite generally lower responses in PD-L1-negative patients, HRD—particularly BRCA-mutant—tumors and PARPi–sensitive cancers like ovarian cancer derived clinically relevant benefit regardless of PD-L1 status, underscoring the dominant role of HRD/BRCA-driven genomic instability and other intrinsic tumor features in determining treatment sensitivity. These results indicate that PD-L1 negativity alone should not preclude patients from receiving this regimen. N PD-L1-negative PD-L1-positive p ORR All-comer 30 21% [12-30%] 36% [26-47%] 0.046 BRCA-mutantHRD-positive 511 67% [45-86%]31% [10-57%] 73% [43-97%]57% [33-80%] 0.6430.139 BreastOvarianNon–breast/ovarian 81411 24% [10-40%]36% [18-56%]9% [5-13%] 46% [29-65%]43% [25-62%]19% [11-27%] 0.090 0.578 0.001 DCR All-comer 12 40% [30-51%] 55% [38-72%] 0.217 12m PFS All-comer 5 40% [22-59%] 56% [33-78%] 0.350