Abstract 2730: Exceptional activity of ARN-509 (apalutamide) in prostate cancer prevention in rats

Abstract

ARN-509 (apalutamide) is a “next-generation” non-steroidal androgen receptor (AR) antagonist that is approved by the FDA for treatment of non-metastatic castration-resistant prostate cancer. Studies were performed in a well-studied rat model to evaluate the efficacy of ARN-509 as an inhibitor of androgen-dependent prostate carcinogenesis. To support dose selection for the prostate cancer chemoprevention bioassay, a six-week pilot study was performed to evaluate the safety of ARN-509 in Wistar rats, and to characterize its PK parameters and dose-response relationships for pharmacodynamic activity (modulation of AR-dependent signaling pathways in the prostate). Several androgen-dependent signaling pathways were modulated by ARN-509; the most reliable biomarker of ARN-509 action in the prostate was down-regulation of kallikrein 1-related peptidase c9 (Klk1c9). Efficacy in prostate cancer prevention was evaluated using a rat model in which invasive prostate cancers are induced by sequential administration of anti-androgen, androgen, and chemical carcinogen (N-methyl-N-nitrosourea; MNU), followed by chronic androgen stimulation. Beginning one week after a single dose of MNU (30 mg/kg), male Wistar rats received daily oral (gavage) administration of ARN-509 at doses of 0 (vehicle control), 15, or 30 mg/kg body weight/day for 60 weeks; a fourth group received daily gavage administration of ARN-509 at 30 mg/kg/day for 60 weeks using an intermittent (one week on; one week off) schedule. Chronic oral administration of ARN-509 was well-tolerated by male Wistar rats; the compound is an extraordinarily potent inhibitor of prostate carcinogenesis. In comparison to a 53% incidence of accessory sex gland cancers (20/38 rats) and a 47% incidence of cancers that were clearly confined to the dorsolateral/anterior prostate (18/38 rats), cancer incidence in the accessory sex glands in both groups of rats receiving continuous daily administration of ARN-509 was 0% (30 mg/kg/day: 0/39 rats; 15 mg/kg/day: 0/37 rats). Intermittent (one week on; one week off) administration of the high dose of ARN-509 (30 mg/kg/day) was also highly effective in cancer prevention, but did not confer the complete protection seen with continuous daily administration: the group receiving intermittent exposure to ARN-509 demonstrated a 10% incidence of accessory sex gland cancer (4/39 rats), with 3% of animals (1/39 rats) demonstrating cancers that were clearly confined to the dorsolateral/anterior prostate. ARN-509 is the most potent inhibitor of prostate carcinogenesis identified in more than two dozen in vivo prostate cancer prevention bioassays performed in our laboratory, and is substantially more active in prostate cancer prevention in this model than is flutamide. These data suggest that ARN-509 merits consideration for evaluation in clinical trials for prostate cancer prevention. [Supported by HHSN261201500042I from NCI] Citation Format: Genoveva Murillo, Xinjian Peng, Miguel Muzzio, Maarten C. Bosland, Elizabeth R. Glaze, Chen Suen, David L. McCormick. Exceptional activity of ARN-509 (apalutamide) in prostate cancer prevention in rats [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2730.