Randomized Phase II Study of Durvalumab with or without Tremelimumab in Patients with Metastatic Castration Resistant Prostate Cancer.

PURPOSE: Programmed death-ligand 1 (PD-L1) is overexpressed by dendritic cells in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing on androgen receptor pathway inhibitors. We tested whether checkpoint blockade could enhance antitumor activity in mCRPC. METHODS: In a multicenter open-label non-comparative randomized phase II study, patients with mCRPC treated with £ 1 prior cytotoxic chemotherapy, with measurable disease and progression on abiraterone and/or enzalutamide were randomized to durvalumab (D) 1500mg IV Q4 weeks ± 4 doses of tremelimumab (T) 75mg IV. The primary endpoint was objective response (OR) by iRECIST using a Simon 2-stage design. Correlative testing included PD-L1/CD8 immunohistochemistry on baseline tumour biopsies and deep targeted sequencing of plasma cell-free DNA. RESULTS: 52 patients were enrolled. Median age was 70 years (range, 50-83 years) and 52% had prior taxane therapy for mCRPC. In stage 1, 13 patients were randomized to D with no OR observed. D+T advanced to stage 2 with 39 patients enrolled (receiving a median 3 cycles, range 1-53). D+T related adverse events (AEs) were mainly £ grade 2 but led to discontinuation in 7 patients . There were seven OR (19.4% [95% confidence interval: 8.2-36.0%]; intention to treat (ITT) 17.9% [95% confidence interval: 7.5-33.5%]). Five responding tumours were PD-L1 positive and two exhibited DNA damage repair defects. Responses were observed without high tumour mutational burden or other genomic indices of immunotherapy sensitivity. CONCLUSION: D+T is active in mCRPC but patient selection remains a challenge. Further studies to develop predictive biomarkers are warranted.