This is a Clinical Exploration Award funding a clinical trial for patients with metastatic, castration resistant prostate cancer CRPC. For patients with metastatic CRPC, there are few established therapeutic options and the prognosis remains dire. The overarching goal of this award is to build on concept that under the selective pressure of androgen receptor AR targeted therapies, prostate cancer adapts. One way it adapts is by upregulating another hormone receptor, the glucocorticoid receptor GR, which may compensate for diminished AR activity. The clinical trial within this award is a phase III clinical trial of the GR antagonist mifepristone in combination with the FDA-approved AR antagonist enzalutamide. The first objective is, within the context of a phase I clinical trial, to establish safe and pharmacologically active doses of the two drugs for use in combination for daily dosing. The second objective is to use pharmacodynamic biomarkers to support the hypothesis that GR antagonism in combination with AR antagonism will delay CRPC progression. During this funding period, the phase I was completed and randomized phase II portion initiated. Thus far the combination of mifepristone and enzalutamide has been well tolerated with no dose limiting toxicities. During this period, agreement with contract execution for enzalutamide to be provided free of cost was reached with Astellas this will greatly facilitate accrual. During the next year, the goal is to accrue to the phase II with addition of three other external sites to augment accrual.