Background: Enzalutamide (ENZA) is an oral androgen receptor inhibitor that has been approved in the US and shown to increase overall survival by 4.8 months over a placebo (HR, 0.63) in patients with metastatic castration resistant prostate cancer (CRPC) previously treated with docetaxel (Scher et al, N Engl J Med 2012;367:1187). Compared with bicalutamide in nonclinical studies, enzalutamide had higher androgen receptor–binding affinity, prevented nuclear translocation, showed no DNA binding, and induced apoptosis (Tran et al, Science 2009;324:787). In contrast to previous phase II and III studies that exclusively enrolled patients with CRPC receiving androgen deprivation therapy (ie, testosterone (T) levels ≤50 ng/dL), this phase II study assessed the efficacy and safety of ENZA monotherapy in patients who had never received hormone therapy; presenting with non-castrate T levels (≥230 ng/dL). Methods: This was a 25-wk, open-label, single-arm study of patients with hormone-naïve, histologically confirmed prostate cancer (all stages) requiring hormonal treatment, an ECOG PS score of 0, and a life expectancy >1 y. All patients received ENZA 160 mg/d without concomitment castration. Primary endpoint was PSA response (>80% decrease at wk 25). Secondary endpoints included changes in endocrine levels and safety/tolerability. Results: Among 67 men enrolled, the median (range) age was 73 (48, 86) y; 39% had metastases; 36% and 24% had undergone prostatectomy or radiotherapy before study entry. The PSA response rate (>80% PSA decline at wk 25) was 93%, with a median (range) decrease of −99% (−100, −57) at wk 25. Serum T and estrogen levels increased by a median (range) of 113% (−32, 300) and 58% (−49, 321) at wk 25, respectively, compared with baseline. 82% of men reported drug-related AEs (mostly Grade 1 or 2). Most frequent treatment-emergent AEs included gynaecomastia (36%), fatigue (34%), and hot flush (18%). 7% of men experienced SAEs; none were drug-related. Conclusions: ENZA monotherapy (160 mg) was associated with significant PSA response in nearly all men with hormone-naïve prostate cancer. Endocrine level changes and most common AEs (gynecomastica, fatigue and hot flush) were consistent with potent AR inhibition. Clinical trial information: NCT01302041.