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• Overexpression of the androgen receptor (AR) is frequent and believed to contribute to the progression of castration-resistant prostate cancer (CRPC).1,2 • MDV3100 is a novel small molecule AR antagonist selected for activity against prostate cancer model systems with AR overexpression. Unlike bicalutamide, MDV3100 also inhibits AR function by blocking nuclear translocation of AR and DNA binding, and has no known agonist activity in the setting of AR overexpression. • MDV3100 is active in bicalutamide-resistant prostate cancer models in a dose-dependent manner. • A Phase 1-2 trial was initiated to determine safety, pharmacokinetics, and antitumor activity including post-therapy changes on prostate-specific antigen (PSA), circulating tumor cells (CTC), soft tissue disease, and bone metastases. In selected patients, uptake of [18F]-fluorodihydrotestos-terone (FDHT) and [18F]-2-fluorodeoxyglucose (FDG) was assessed by positron emission tomography (PET). Except where noted, values are median (minimum-maximum) *FDHT and FDG PETs in selected patients Age (years) 68 (44–93