This study evaluates the antitumor activity and safety of MDV3100, a novel androgen receptor (AR) antagonist, in patients with castration-resistant prostate cancer (CRPC). MDV3100 was administered at doses ranging from 30 to 600 mg daily, and the primary objectives were to assess pharmacokinetics, safety, and tolerability, as well as to define the maximal tolerated dose. Secondary objectives included evaluating antitumor effects based on changes in prostate-specific antigen (PSA), imaging of soft-tissue and osseous disease, circulating tumor cell (CTC) number, and time to disease progression. 140 patients were enrolled, with a mean age of 68 years. The majority had bone metastases (78%), and 54% had lymph node metastases. The most common adverse event was fatigue, which generally resolved with dose reduction. MDV3100 demonstrated significant antitumor activity, with substantial and sustained PSA declines, tumor regressions, and stable disease in both chemotherapy-naïve and post-chemotherapy patients. The median time to PSA progression was 47 weeks, and the median time to radiographic progression was 47 weeks. The maximal tolerated dose was determined to be 240 mg/day due to increasing fatigue and seizure events at higher doses. The study concludes that MDV3100 shows encouraging antitumor activity in CRPC, validating preclinical models and establishing that a substantial fraction of tumors remain dependent on AR signaling for growth. A phase 3 trial is underway to further evaluate MDV3100 in patients with progressive CRPC.This study evaluates the antitumor activity and safety of MDV3100, a novel androgen receptor (AR) antagonist, in patients with castration-resistant prostate cancer (CRPC). MDV3100 was administered at doses ranging from 30 to 600 mg daily, and the primary objectives were to assess pharmacokinetics, safety, and tolerability, as well as to define the maximal tolerated dose. Secondary objectives included evaluating antitumor effects based on changes in prostate-specific antigen (PSA), imaging of soft-tissue and osseous disease, circulating tumor cell (CTC) number, and time to disease progression. 140 patients were enrolled, with a mean age of 68 years. The majority had bone metastases (78%), and 54% had lymph node metastases. The most common adverse event was fatigue, which generally resolved with dose reduction. MDV3100 demonstrated significant antitumor activity, with substantial and sustained PSA declines, tumor regressions, and stable disease in both chemotherapy-naïve and post-chemotherapy patients. The median time to PSA progression was 47 weeks, and the median time to radiographic progression was 47 weeks. The maximal tolerated dose was determined to be 240 mg/day due to increasing fatigue and seizure events at higher doses. The study concludes that MDV3100 shows encouraging antitumor activity in CRPC, validating preclinical models and establishing that a substantial fraction of tumors remain dependent on AR signaling for growth. A phase 3 trial is underway to further evaluate MDV3100 in patients with progressive CRPC.