Background: The investigational agent TAK-700 is a selective inhibitor of 17,20-lyase, a key intermediary in adrenal androgen and testosterone synthesis. In a phase II study in patients with mCRPC, TAK-700 inhibited testosterone and dehydroepiandrosterone sulfate (DHEA-S) levels consistent with 17,20-lyase inhibition, and reduced prostate-specific antigen (PSA) levels (Dreicer R, et al. J Clin Oncol 2010;28:15s abst 3084). Methods: This randomized, double-blind, placebo-controlled multicenter study is investigating efficacy and safety of TAK-700 plus prednisone vs placebo plus prednisone in patients with mCRPC who have not received prior chemotherapy. This will enable evaluation of TAK-700 at an early stage of mCRPC, where it may be more effective and delay the need for chemotherapy. Planned enrollment is 1,454 patients. Main inclusion criteria are: radiographically documented mCRPC; surgical castration or use of an agent for medical castration; with baseline testosterone <50 ng/dL; and evidence of disease progression (radiographic or with a rising PSA). Patients must not have received prior adrenal-targeted therapy or chemotherapy in the past 2 years, and must have no or mild cancer pain not requiring opioids. Treatment will be TAK-700 400 mg twice daily (BID) or placebo, with prednisone 5 mg BID. The primary outcomes are overall survival (OS) and radiographic progression-free survival (rPFS). Secondary outcomes include the PSA response rate (decrease by ≥50%) at 12 weeks, change in circulating tumor cell numbers, and time to pain progression. Two interim analyses are planned: after ~412 disease progression events for rPFS; and after ~600 deaths for OS. Patients may remain on TAK-700 after disease progression until they receive further antitumor therapy. Tumor specimens will be analyzed for candidate biomarkers of TAK-700 antitumor activity, including the TMPRSS2:ERG fusion gene. This study is registered on ClinicalTrials.gov: NCT01193244. A companion phase III study is assessing the same regimens in patients who have received docetaxel-based therapy for mCRPC (ClinicalTrials.gov: NCT01193257).