Background: Metastatic castration-resistant prostate cancer (mCRPC) remains an incurable disease with significant morbidity. Androgen receptor (AR) signaling is a key driver of tumor growth in mCRPC, and AR-targeted therapies are the mainstay for patients (pts) with locally advanced or metastatic disease. Enzalutamide (ENZA) is commonly used, but resistance typically develops within 1–2 years. The glucocorticoid receptor (GR) can substitute for the AR, providing a tumor escape pathway (Arora et al. Cell 2013). In the 22Rv1 CRPC xenograft model, the selective GR modulator exicorilant (EXI) combined with ENZA reduced tumor growth, supporting the hypothesis that dual antagonism of GR + AR may block this escape pathway. Safety and pharmacokinetics from the first study of EXI + ENZA in pts with mCRPC (NCT03437941) were previously presented (Linch et al. ESMO 2022). Here, we report efficacy and pharmacodynamic (PD) results from the same study. Methods: Segment 1 (Seg 1) of this phase 1 study evaluated open-label, fasting, BID dosing of EXI (140 or 180 mg) + ENZA 160 mg QD. Segment 2 (Seg 2) tested QD dosing of EXI with food in a double-blind design: All pts received EXI 240 mg + ENZA and were randomized 3:1 to EXI titration (to 280 mg followed by 320 mg) or to remain on EXI 240 mg + placebo. Efficacy assessments included radiographic response and changes in prostate-specific antigen (PSA) levels. PSA was collected prior to study entry and PSA doubling times were calculated before and during treatment. PD analyses included baseline (BL) tumor GR expression and modulation of GR target genes in whole blood. As not all pts enrolled in Seg 1 were ENZA naïve, efficacy data are reported for Seg 2 only. Data cutoff date: July 7, 2022. Results: 39 pts were enrolled (Seg 1: 14, irrespective of prior ENZA exposure; Seg 2: 25, on a stable ENZA dose with rising PSA, defined as a 25% increase over nadir and absolute value >1 ng/mL). In Seg 2, there were no radiographic responses, 18 pts had a best overall response of stable disease per PCWG3, and 1 pt achieved a PSA response (≥50% PSA reduction from BL). BL tumor GR expression was detectable in all assessed tumors. PD analyses demonstrated EXI modulation of GR target genes, such as CDKN1C. Comparable PD effects were observed across EXI doses (240–320 mg QD). While BL 24-h urinary free cortisol (UFC) for most pts was within the normal range, improvements in PSA doubling times after treatment with EXI + ENZA were predominantly observed in pts with higher BL UFC (P<0.05). Conclusions: This study did not include an ENZA-alone arm and was thus not designed to assess the contribution of EXI to the efficacy of the EXI + ENZA combination. In heavily pretreated pts with prior ENZA exposure, 1 PSA response and no radiographic responses were observed. PD analysis confirmed systemic GR modulation. Instances of PSA doubling time improvements were observed in pts with relatively higher UFC. Clinical trial information: NCT03437941.