Background: mCRPC patients with tumors expressing the androgen receptor (AR) splice variant-7 (AR-V7), a constitutively-active truncated form of the AR lacking the ligand-binding domain, have been shown to have worse clinical outcomes after AR-targeting drugs than those without detectable AR-V7. Galeterone, a small molecule drug, disrupts AR signaling via selective inhibition of CYP17 lyase, AR blockade, and enhanced degradation of the AR protein. In preclinical models, galeterone showed activity against the full-length AR and AR alterations including AR-V7 and AR^v567es splice variants, and against activating AR mutations (eg, AR-T878A, AR-F876L). Given the encouraging results in patients with AR C-terminal loss in the galeterone Phase 2 ARMOR2 trial, further research is warranted in this patient subset. Methods: ARMOR3-SV is a Phase 3, randomized, open-label, multicenter study of galeterone vs enzalutamide in men with mCRPC expressing AR-V7 mRNA in circulating tumor cells (CTCs). Among other inclusion criteria, eligible patients must continue medical castration or have had surgical castration, and must not have received prior chemotherapy, abiraterone, or enzalutamide. Eligible patients will be prescreened and subsequently enrolled only if AR-V7 is detected in CTCs using a CLIA-certified, analytically-validated assay. A total of 148 patients will be randomized (1:1) to receive once-daily oral galeterone 2550 mg or enzalutamide 160 mg. The primary endpoint is radiographic progression-free survival determined by independent blinded, central radiologic review. Secondary endpoints include time to cytotoxic therapy or next anticancer intervention and overall survival. Other endpoints include time to first skeletal related event, decline in PSA, time to PSA progression, and best objective response rate (in men with measureable soft tissue disease [RECIST1.1]). Safety and pharmacokinetics of galeterone will also be assessed. CTCs will be enumerated and characterized molecularly in an exploratory fashion.