For a study, researchers investigated the safety, pharmacokinetic impact, and efficacy of the glucocorticoid receptor (GR) antagonist mifepristone combined with enzalutamide in a castration-resistant prostate cancer (CRPC) phase I/II trial. A total of 106 CRPC patients were enrolled. To allow for steady-state accumulation, Phase I subjects were given enzalutamide monotherapy at a dose of 160 mg daily for 28 days. Patients were then enrolled in the dose-escalation combination phase of the study. Patients in phase II were randomly assigned to receive either enzalutamide alone or enzalutamide plus mifepristone. PSA progression-free survival (PFS) was the primary endpoint, with radiographic PFS and PSA response rate (RR) as important secondary endpoints. Before randomization, circulating tumor cells were collected for exploratory translational biomarker studies. When combined with mifepristone, a 25% dose reduction in enzalutamide produced equivalent drug levels as full-dose enzalutamide and was well tolerated. The addition of mifepristone to enzalutamide after a 12-week enzalutamide lead-in, on the other hand, did not delay time to PSA, radiographic or clinical PFS. The trial was called off early due to futility. It is the first study of dual AR–GR antagonism in CRPC. Enzalutamide was safe and well-tolerated in combination with mifepristone, but it did not achieve its primary goal. More specific GR antagonists combined with AR antagonists, potentially studied in an earlier disease state, should be investigated.