Phase II study of olaparib and durvalumab in patients with metastatic castration-resistant prostate cancer.

Poly(ADP-ribose) polymerase (PARP) inhibition (PARPi) is a precision medicine strategy in advanced prostate cancer, with the greatest benefit seen in a subset of patients with homologous recombination repair (HRR) gene alterations. Combination approaches may expand activity beyond HRR-altered disease. We conducted a phase 2 study of the PARP inhibitor olaparib in combination with the anti-PD-L1 antibody durvalumab in an HRR-unselected population of men with metastatic castration-resistant prostate cancer (mCRPC). This is a single-arm, open-label phase 2 trial of olaparib plus durvalumab in men with mCRPC previously treated with abiraterone and/or enzalutamide. Pretreatment biopsies of metastatic lesions were attempted for tumor sequencing. Peripheral blood was collected longitudinally for immune profiling of cell subsets and soluble factors, circulating tumor DNA (ctDNA) analyses, and peripheral blood mononuclear cell (PBMC) gene expression profiling. 61 patients were enrolled; 60 were evaluable. Median age was 65 years (45-88). Median radiographic progression-free survival (rPFS) was 5.0 months (95% CI 4.6 to 7.6) and median overall survival (OS) was 19.1 months (95% CI 15.0 to 29.3 months). 10 patients achieved partial responses, and 17 (28%) had ≥50% prostate-specific antigen declines. Patients with BRCA2 variants experienced longer rPFS (13.2 months; 95% CI 7.7 to 20.2 months) than patients without BRCA2 variants (4.8 months; 95% CI 4.5 to 6.4 months, p=0.0026). Baseline ctDNA fraction was higher in patients with radiographic progression than in those with partial response (p=0.022) and inversely correlated with time-to-progression (ρ=-0.51). Treatment- induced early peripheral immune perturbations included transient inflammatory cytokine increases and expansion of activated/proliferating T cells with concurrent regulatory features. Exploratory PBMC profiling identified IL1R2 as a response-associated transcript, and lower IL1R2 expression was associated with longer OS. Olaparib plus durvalumab demonstrated modest activity in HRR-unselected mCRPC, with clinical benefit enriched in BRCA2-variant disease. Integrated ctDNA and peripheral immune analyses support ongoing efforts to refine molecular and immune selection strategies and to better define mechanisms of benefit and resistance for combination approaches in mCRPC. NCT02484404.