Background: Castrating androgen deprivation therapy (ADT) is standardly prescribed in combination with radiation therapy (RT) for intermediate or high-risk prostate cancer (PCa). ADT is associated with multiple side effects including weight gain, loss of libido, hot flashes and muscle atrophy. In contrast, enzalutamide monotherapy is associated with much fewer side effects. Methods: At Dana-Farber/ Harvard Cancer Center we performed an open label phase II study of enzalutamide for 6 months as neo- and adjuvant treatment for intermediate risk PCa patients (NCCN criteria) receiving RT. The primary endpoint was the proportion of patients achieving a PSA response of ≤0.2 . This endpoint is predictive of long term PSA response in a similar risk-group of patients treated with RT and ADT. PSA values were obtained at baseline and monthly on 6 cycles of enzalutamide (160mg/day). 79.2 Gy in 44 fractions of IMRT was started between 6 and 10 weeks after the initiation of enzalutamide. Quality of life questionnaires, hormone levels and anthropomorphic measurements were obtained. Results: 45 of 60 evaluable patients had a PSA ≤0.2 at the end of 6 months of enzalutamide. With a sample size of 64 evaluable patients, if the number achieving a PSA level is ≤0.2 is 44 or more, the null hypothesis is rejected with a target error rate of alpha = 0.10. Also 54 of 60 evaluable patients had a PSA of ≤0.5ng/ml. Importantly, less than half of the participants experienced erectile dysfunction or decreased libido and these were predominantly grade I. Less than a quarter of patients reported hot flashes (all grade I). Waist circumference did not change with therapy. The most frequent grade 2 or greater events were hypertension and gynecomastia. Testosterone and free testosterone levels rose significantly on enzalutamide therapy. Conclusions: Enzalutamide monotherapy with RT may be as effective as castrating ADT, and associated with fewer side effects. Larger, randomized trials are needed to further evaluate enzalutamide monotherapy, instead of ADT, to be used in combination with RT. Clinical trial information: NCT0208988