Background: The androgen receptor (AR) splice variant-7 (AR-V7) is a truncated, constitutively active splice variant of the AR that lacks the C-terminal ligand binding domain (LBD). Mechanistically, enzalutamide and abiraterone both require a functional AR-LBD for their activity. Preliminary data suggest that the presence of AR-V7 may predict drug resistance to both enzalutamide and abiraterone in patients with mCRPC. Galeterone is an oral small molecule that disrupts AR signaling via multiple pathways: AR degradation, CYP17 lyase inhibition, and AR antagonism. In preclinical models, galeterone has demonstrated activity against the full-length AR and AR alterations including AR-V7 and AR^v567es splice variants, and against activating AR mutations. These data, combined with activity seen in mCRPC patients with loss of LBD in the phase 2 ARMOR2 study, supported the design of the ongoing pivotal phase 3 study ARMOR3-SV. Methods: ARMOR3-SV is a randomized, open-label, multicenter study that compares galeterone vs enzalutamide in men with mCRPC. Eligible patients are prescreened and subsequently enrolled only if they have circulating tumor cells that express AR-V7 mRNA. Patients must maintain castrate testosterone levels, and must not have received prior chemotherapy, abiraterone, or enzalutamide for CRPC. ARMOR3-SV is the first precision medicine-based registration study in prostate cancer. 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. Key secondary endpoints include time to next anticancer therapy and overall survival. Other endpoints include time to first symptomatic skeletal event, PSA response rate, time to PSA progression, and objective response rate (in men with measureable disease [RECIST1.1]). The safety and pharmacokinetics of galeterone will be assessed. CTCs will be enumerated and characterized molecularly, and changes in the levels of AR-V7 transcript will be assessed serially over time. Clinical trial information: NCT02438007