Background: Recent data showed that mCRPC patients (pts) with the androgen receptor (AR) SV AR-V7, a truncated form of the AR that lacks the ligand-binding domain and remains a constitutively active transcription factor, had worse clinical outcomes than patients without AR-V7 (Antonarakis et al, NEJM 2014; Efstathiou et al, ASCO 2014; Bambury et al, ESMO 2014). Galeterone, a small molecule, disrupts AR signaling via selective inhibition of CYP17 lyase, competitively inhibits androgen binding to AR, and degrades AR protein. In preclinical models, it demonstrated activity against many AR aberrations, including AR-V7, AR^v567es, AR-T878A, and AR-F876L. Given the encouraging results in pts with AR C-terminal loss in the phase 2 ARMOR2 trial (Taplin et al, ESMO 2014),further research is warranted. Methods: ARMOR3-SV is a global, phase 3, randomized, open-label, multicenter, controlled study of galeterone vs enz in men expressing AR-V7 SV–mCRPC. Among other enrollment criteria, eligible pts must have the AR-V7 splice variant, be on GnRH therapy or have had a bilateral orchiectomy with testosterone <50 ng/dL. Approximately <170 pts will be randomized to receive once-daily oral therapy with galeterone 2550 mg or enz 160 mg. The primary endpoint is radiographic progression-free survival. Secondary endpoints include overall survival, time to cytotoxic therapy, and skeletal related events. Pts will be followed until radiographic disease progression as assessed by an independent, blinded radiologic review. Post-progression anticancer interventions will be collected and pts will be followed until death or study termination. Results: Because AR-V7 status must be determined for enrollment, the availability of a validated, accurate, rapid, quantitative, and universally applicable assay performed in a central CLIA-certified laboratory is critical to the trial. Conclusions: Choice of assay to identify and select mCRPC pts harboring AR-V7 is key to enrollment strategy for ARMOR3-SV. The study is expected begin in the first half of 2015.