Background: Prostate cancer (PC) patients (pts) who select active surveillance (AS) are a heterogeneous population with varying risks for disease progression. Studies have estimated that approximately 31–42% of pts electing AS have experienced disease progression (pathological or therapeutic) over 1.8 and 2.3 years. There is no evidence-based pharmacological intervention which has effectively lessened this progression event. Pharmacological intervention with enzalutamide (ENZ), an androgen receptor inhibitor approved for treatment of metastatic castration-resistant PC, may lessen this progression. The aims of this study are to evaluate the efficacy of ENZ versus AS alone for delaying time to progression in pts with clinically localized PC undergoing AS. This study examines the effects of ENZ on progression in a subset of pts with low- or intermediate-risk PC who would otherwise elect an AS protocol. Methods: This is a multicenter, randomized, open-label study (NCT02799745). Eligibility criteria include histologically confirmed prostate adenocarcinoma within 6 months of screening, low or intermediate risk PC (T1c−T2c, prostate-specific antigen [PSA] < 20, N0, M0, Gleason score ≤7 [3+4 pattern only]), Eastern Cooperative Oncology Group status ≤2 and estimated life expectancy > 5 years. Exclusion criteria include any prior PC intervention. Pts will be randomized to receive open-label oral ENZ 160 mg/day once daily or to AS during the 1-year study treatment period. After the first year, all pts will be followed for one additional year with no other intervention. All pts will undergo prostate biopsy at 1 and 2 years. The primary end point is time to PC progression (pathological or therapeutic). Secondary end points include safety, incidence of negative biopsies for cancer at 1 and 2 years, percentage of cancer positive cores at 1 and 2 years, time to PSA progression, incidence of secondary rise in serum PSA, and quality-of-life questionnaires. Exploratory end points include biomarker assessment and genomic analysis. Study enrolment commenced in June 2016, with study completion expected in March 2019. Planned total enrolment is 222 pts from ~60 United States/Canadian sites. Clinical trial information: NCT02799745