PARP阻害薬と免疫療法の併用による相乗効果を臨床試験で検証 ―基礎研究で期待された相乗効果の再考につながる知見―

Preclinical studies suggest that poly (ADP-ribose) polymerase inhibition enhances tumor immunogenicity through stimulation of IFN genes pathway activation, providing rationale for combination with immune checkpoint inhibitors. However, clinical evidence supporting this synergy remains limited. We conducted a neoadjuvant pilot study evaluating olaparib with or without pembrolizumab in homologous recombination deficiency (HRD)–positive advanced ovarian cancer.

Patients with newly diagnosed, HRD-positive International Federation of Gynecology and Obstetrics stage III to IV high-grade serous or endometrioid ovarian cancer were enrolled. HRD status was determined using the Myriad MyChoice HRD Plus test. Patients received olaparib monotherapy (300 mg twice daily for 6 weeks; cohort 1, n = 10) or olaparib plus pembrolizumab (200 mg every 3 weeks for two cycles; cohort 2, n = 20), followed by surgery and platinum-based chemotherapy. The primary endpoint was the overall response rate (ORR). Exploratory IHC and single-cell RNA sequencing analyses assessed tumor microenvironmental changes.

The ORR was 50% [95% confidence interval (CI), 18.7–81.3] in cohort 1 and 70% (95% CI, 45.7–88.1) in cohort 2 (P = 0.2839). In cohort 1, responses occurred only in BRCA2-mutated tumors (5/5, 100%). In cohort 2, the ORR was 84.6% (11/13) in BRCA1/2-mutated tumors and 42.9% (3/7) in non–BRCA1/2-mutated tumors. Programmed cell death ligand 1 expression, tumor mutational burden, and microsatellite instability were not associated with response. Olaparib monotherapy did not increase tumor immunogenicity, whereas the combination increased CD8⁺ T-cell infiltration and immune-related transcriptional changes. No unexpected toxicities were observed.

Neoadjuvant olaparib showed measurable radiographic activity in HRD-positive advanced ovarian cancer. Pembrolizumab enhanced immune activation, but its impact on early clinical response seemed limited.