Prostate cancer is the second leading cause of cancer-related death in men. Androgen deprivation is commonly used to treat hormone-sensitive prostate cancer, while second-generation antiandrogens, including enzalutamide and abiraterone, benefit patients with castration-resistant prostate cancer (CRPC). New therapeutic strategies are needed for patients who relapse with metastatic CRPC. The glucocorticoid receptor (GR) has been implicated as a major bypass mechanism to escape androgen blockade in patients with CRPC, indicating that GR-targeted therapies may provide an avenue to overcome therapeutic resistance in this clinical setting. We discovered a novel, selective, oral GR antagonist, ORIC-101, which fully reverses GR-driven resistance to enzalutamide in a dose-dependent manner in preclinical models. Specifically, we show that GR is widely expressed in prostate cancer cell lines, organoids, and tumor tissue, and that GR levels are upregulated upon enzalutamide treatment. We demonstrate in preclinical studies that physiological levels of glucocorticoids promote tumor cell growth, stimulate androgen-regulated gene expression, and drive resistance to enzalutamide. Importantly, these effects were completely reversed by ORIC-101, suggesting ORIC-101 overcomes GR-driven resistance to enzalutamide. To inform the clinical development of ORIC-101 in combination with enzalutamide, we identified FKBP5 and KLK3 as direct transcriptional targets of both androgen receptor and GR. We subsequently validated that secreted PSA, a product of the KLK3 gene, can be induced by glucocorticoids and this induction is fully inhibited by ORIC-101. These findings confirm that targeting GR may help overcome resistance to enzalutamide in CRPC, and that FKBP5 and KLK3 are rational PD biomarkers that may be used in clinical trials of ORIC-101, along with PSA.

Citation Format: Haiying Zhou, Shravani Barkund, Aleksandr Pankov, Sharvani Sinha, Dena Sutimantanapi, Lori S. Friedman, Omar Kabbarah. ORIC-101 overcomes glucocorticoid-driven resistance to enzalutamide in castration-resistant prostate cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr LB-A10. doi:10.1158/1535-7163.TARG-19-LB-A10