A phase 1-2 trial evaluated MDV3100, a novel androgen receptor (AR) antagonist, in patients with castration-resistant prostate cancer (CRPC). The study enrolled 140 patients with progressive metastatic CRPC, receiving doses ranging from 30 to 600 mg/day. MDV3100 demonstrated significant antitumor activity, including reductions in serum PSA levels, responses in soft tissue, stabilization of bone disease, and conversion of unfavorable to favorable circulating tumor cell (CTC) counts. The median time to progression was 47 weeks, with the maximal tolerated dose for sustained treatment (>28 days) being 240 mg/day. The most common adverse event was dose-dependent fatigue, which generally resolved with dose reduction. MDV3100 effectively blocked AR binding, induced apoptosis, and had no agonist activity, even when AR was overexpressed. PET imaging showed reduced FDHT binding at dosages of 60 mg/day and above, confirming AR blockade. Antitumor effects were observed at all dosages, with 56% of patients experiencing a 50% or greater decline in PSA. Chemotherapy-naïve and post-chemotherapy patients showed similar responses, indicating that not all CRPC tumors are uniformly hormone-refractory. Pharmacokinetic studies showed that MDV3100 reached steady-state concentrations within one month, with steady-state levels comparable to those in xenograft models. Pharmacodynamic assessments confirmed AR inhibition, with significant reductions in FDHT uptake across all dosages. The drug also induced regression of established LNCaP/AR xenograft tumors in castrate mice. The study demonstrated that MDV3100 has significant antitumor activity in both chemotherapy-naïve and post-chemotherapy CRPC patients. The results support the development of a phase 3 trial to evaluate MDV3100 in patients with progressive disease after docetaxel treatment. The findings suggest that MDV3100 may significantly alter treatment options for metastatic disease, even in the post-chemotherapy setting. The drug's safety profile, with fatigue as the primary adverse event, and its ability to induce durable responses, make it a promising candidate for further clinical evaluation.A phase 1-2 trial evaluated MDV3100, a novel androgen receptor (AR) antagonist, in patients with castration-resistant prostate cancer (CRPC). The study enrolled 140 patients with progressive metastatic CRPC, receiving doses ranging from 30 to 600 mg/day. MDV3100 demonstrated significant antitumor activity, including reductions in serum PSA levels, responses in soft tissue, stabilization of bone disease, and conversion of unfavorable to favorable circulating tumor cell (CTC) counts. The median time to progression was 47 weeks, with the maximal tolerated dose for sustained treatment (>28 days) being 240 mg/day. The most common adverse event was dose-dependent fatigue, which generally resolved with dose reduction. MDV3100 effectively blocked AR binding, induced apoptosis, and had no agonist activity, even when AR was overexpressed. PET imaging showed reduced FDHT binding at dosages of 60 mg/day and above, confirming AR blockade. Antitumor effects were observed at all dosages, with 56% of patients experiencing a 50% or greater decline in PSA. Chemotherapy-naïve and post-chemotherapy patients showed similar responses, indicating that not all CRPC tumors are uniformly hormone-refractory. Pharmacokinetic studies showed that MDV3100 reached steady-state concentrations within one month, with steady-state levels comparable to those in xenograft models. Pharmacodynamic assessments confirmed AR inhibition, with significant reductions in FDHT uptake across all dosages. The drug also induced regression of established LNCaP/AR xenograft tumors in castrate mice. The study demonstrated that MDV3100 has significant antitumor activity in both chemotherapy-naïve and post-chemotherapy CRPC patients. The results support the development of a phase 3 trial to evaluate MDV3100 in patients with progressive disease after docetaxel treatment. The findings suggest that MDV3100 may significantly alter treatment options for metastatic disease, even in the post-chemotherapy setting. The drug's safety profile, with fatigue as the primary adverse event, and its ability to induce durable responses, make it a promising candidate for further clinical evaluation.