Metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease with significant morbidity, despite the availability of multiple classes of therapies. Combining the selective glucocorticoid receptor (GR) modulator exicorilant (EXI) with the androgen receptor (AR) antagonist enzalutamide (ENZA) may block an important tumor escape pathway via dual antagonism of GR and AR. We report safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) results from the first study evaluating EXI + ENZA in patients with CRPC. Segment 1 of this phase 1/2a dose-finding study (NCT03437941) evaluated open-label, twice-daily dosing of EXI. Patients (irrespective of prior ENZA exposure) received either EXI 180 mg BID + ENZA 160 mg QD, EXI 140 mg BID + ENZA 160 mg QD with a 28-day ENZA lead-in, or EXI 140 mg BID + ENZA 160 mg QD without an ENZA lead-in. Segment 2 evaluated QD dosing of EXI in a double-blind design in patients on a stable ENZA dose with rising PSA (25% increase over nadir and absolute value >1 ng/mL). All patients received EXI 240 mg QD + ENZA and were randomized 3:1 to EXI titration (to 280 mg followed by 320 mg) or to stay on EXI 240 mg. PK (EXI, ENZA) and PD (including cortisol and ACTH) were measured throughout the study. 14 and 25 patients were enrolled in segments 1 and 2, respectively. 37 patients received at least one dose of EXI. Most frequent EXI-related adverse events (AEs) included fatigue (57%), back pain (35%), decreased appetite (27%), and neuropathic pain (22%). Dose-limiting toxicities were fatigue, musculoskeletal pain, and pancreatitis in segment 1, and fatigue, lipase increase, hypophosphatemia, AST/ALT/GGT increase, back pain, and vomiting in segment 2. EXI exposures were largely overlapping across dose levels in segment 2. No clinically relevant changes in the exposures of ENZA or its active metabolite, N-desmethyl ENZA, were observed when combined with EXI. ENZA exposures were consistent with historical data for ENZA 160 mg alone. A maximum-tolerated dose of EXI in combination with ENZA was identified with fatigue and pain as the most common AEs. No clinically relevant changes were observed in ENZA exposure when given with EXI relative to ENZA alone.