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

Abstract Purpose: 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. Patients and Methods: In a multicenter open-label noncomparative 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 1,500 mg intravenously every 4 weeks ±4 doses of tremelimumab 75 mg intravenously. The primary endpoint was objective response (OR) by iRECIST using a Simon two-stage design. Correlative testing included PD-L1/cluster designation 8 IHC on baseline tumor biopsies and deep targeted sequencing of plasma cell–free DNA. Results: Fifty-two patients were enrolled. Median age was 70 years (range, 50–83 years), and 52% had prior taxane therapy for mCRPC. In stage I, 13 patients were randomized to durvalumab with no OR observed. Durvalumab + tremelimumab advanced to stage II with 39 patients enrolled (receiving a median three cycles, range 1–53). Durvalumab + tremelimumab–related adverse events were mainly ≤ grade 2 but led to discontinuation in seven patients. There were seven ORs [19.4% (95% confidence interval: 8.2%–36.0%); intention to treat 17.9% (95% confidence interval: 7.5%–33.5%)]. Five responding tumors were PD-L1–positive and two exhibited DNA damage repair defects. Responses were observed without high tumor mutational burden or other genomic indices of immunotherapy sensitivity. Conclusions: Durvalumab + tremelimumab is active in mCRPC, but patient selection remains a challenge. Further studies to develop predictive biomarkers are warranted.