Randomized Phase II Study of Durvalumab with or without Tremelimumab in Patients with Metastatic Castration-Resistant Prostate Cancer
Eric Winquist, Sebastién J. Hotte, Kim N., Srikala S. Sridhar, Susan Ellard, Michael Ong, Nayyer Iqbal, Muhammad Nur Salim, Urban Emmenegger, Joel Roger Gingerich, Aly‐Khan A. Lalani, Pierre Major, Christian Kollmannsberger, Steven Yip, Aaron R. Hansen, Daygen L. Finch, Christina Canil, James Hutchenreuther, Francisco Vera-Badillo, Martin Smoragiewicz, Michael Cabanero, Ming‐Sound Tsao, Elie Ritch, Alexander W. Wyatt, Lesley Seymour
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.