Abstract 3737: Apalutamide (ARN-509) demonstrates therapeutic efficacy in genetically engineered mouse models of Pten-deficient prostate cancer
Authors: Velasco Marco A. De , Nozawa Masahiro , Kura Yurie , Ando Naomi , Sato Noriko , Yoshimura Kazuhiro , Sakai Kazuko , Yoshikawa Kazuhiro , Nishio Kazuto , Uemura Hirotsugu 
Published: August 2018

Abstract
Apalutamide (ARN-509) is an oral nonsteroidal androgen receptor (AR) antagonist that is currently undergoing late-stage clinical development for the management of castration-resistant prostate cancer (CRPC). In this study, we use genetically engineered mouse prostate cancer (GEM-PCa) models to examine the preclinical activity of apalutamide in the setting of castration-naïve and castration-resistant disease and delve into the molecular mechanisms underlying CRPC progression. In an early-stage efficacy model of Pten-deficient prostate cancer, four weeks of treatment with apalutamide (30 mg/kg/d) significantly reduced tumor burden by 33.5% (P=0.002) in castration-naive mice but did not alter tumor burden in orchidectomized mice bearing castration-resistant tumors. Interim analyses from long-term survival studies, using models of advanced prostate cancer driven by the conditional inactivation of Pten and Trp53, have indicated improved median overall survival (OS) times in both castration-naïve (17 days, 95% CI 11.6-38.9 in control mice vs. 36 days, 95% CI 21.8-56.9 in apalutamide treated-mice, P=0.280) and CRPC settings (21 days, 95% CI 15.1-25.8 in control mice vs. 40 days, 95% CI 31.2-50.1 in apalutamide treated-mice, P=0.001). In the CRPC model, time to tumor progression was significantly longer for mice treated with apalutamide, median time 20 days 95% CI 9.8-20.6, in apalutamide treated-mice vs. 7 days, 95% CI 5.1-10.8, in control mice, P=0.029. Molecular characterization indicated increased PI3K-AKT signaling in response to treatment with apalutamide in castration-naïve prostate tumors. In vitro studies using four mouse prostate cancer cell lines revealed synergistic responses with apalutamide and AKT inhibition (GSK-690693), the mean combination index at 50% effective dose ranged from 0.585-0.791. In vivo efficacy studies of combination therapy in Pten-KO mice showed tumor burden reductions of 33.4%, 17.7% and 40.9% in apalutamide, GSK-690693 and combination treatments, respectively, P=0.002 in the castration-naïve setting, and reductions of 1.0%, 12.7% and 15.5% in apalutamide, GSK-690693 and combination treatments, respectively, P=0.101 in the CRPC setting. Studies to further evaluate the therapeutic benefit of apalutamide plus PI3K/AKT signal blockade in models of advanced prostate cancer are underway. In conclusion, our findings show that apalutamide is active in GEM-PCa models and support further investigation for developing rational treatment combinations for the management of advanced prostate cancer.
Citation Format: Marco A. De Velasco, Masahiro Nozawa, Yurie Kura, Naomi Ando, Noriko Sato, Kazuhiro Yoshimura, Kazuko Sakai, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura. Apalutamide (ARN-509) demonstrates therapeutic efficacy in genetically engineered mouse models of Pten-deficient prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3737.