Background: Metastatic castration-resistant prostate cancer (mCRPC) is a lethal disease with limited therapeutic options. AR targeting therapies such as enzalutamide (Enz) are often effective for the treatment of mCRPC; however, resistance is common. The central hypothesis of this trial is that another nuclear hormone receptor, the glucocorticoid receptor (GR), can compensate for AR that is therapeutically inhibited and lead to disease progression. Studies of patient-derived prostate cancer tissues have shown that expression of the GR increases with AR inhibition (Szmulewitz et al, The Prostate, 2012; Arora et al, Cell 2013). Furthermore, therapeutic blockade of GR signaling with mifepristone (Mif), a steroidal GR antagonist, inhibited CRPC growth and delayed CRPC progression in preclinical models (Isikbay, Hormones and Cancer, 2014). Methods: This is a phase I/II, open label study of Enz in combination with Mif for patients with mCRPC. Major inclusion criteria include metastatic CRPC according to standard Prostate Cancer Working Group (PCWG) criteria, ECOG performance status 0-2, adequate hepatic function, and lack of seizure history. The phase I portion will assess the safety of the two-drug combination along with pharmacokinetic (PK) impact of Mif on Enz exposure. Dose titration will be made based on PK and safety to arrive at the randomized phase II dose (RP2D). For the phase II portion, patients will be randomized after 12 weeks of Enz to stay on Enz alone or to change to Enz plus Mif at the RP2D. The primary endpoint of the phase II study is to determine if Mif when added to Enz delays time to PSA progression, as a pharmacodynamic biomarker of AR and GR antagonism. Secondary objectives include to evaluate the effect of Mif/Enz on serum cortisol and TSH, to determine the effect of Mif addition on PCWG-defined progression, and to explore the role of circulating tumor cells, as a pharmacodynamic biomarker for Mif and Enz in CRPC using the Epic Sciences platform and by RNA sequencing. The study has completed accrual to the third dosing cohort (120mg Enz/300mg Mif daily) and there have been no dose limiting toxicities to date in any cohort. Clinical trial information: NCT02012296