Background: Adjuvant ADT with an LHRH analog (LHRHA) given before during and after radiotherapy (RT) is standard of care for high risk localised prostate cancer (PC). Enzalutamide is more effective in metastatic disease than conventional non-steroidal anti-androgens (NSAA). We hypothesize that addition of enzalutamide to adjuvant ADT and RT will improve outcomes. Aim: To determine the efficacy of enzalutamide as part of adjuvant ADT with LHRHA in men planned for RT for localized high risk or node-positive PC. Methods: Open label, randomised, stratified, 2-arm multicentre, phase 3 clinical trial. Primary endpoint: OS. Secondary endpoints: cause-specific survival, PSA PFS, clinical PFS, time to subsequent hormonal therapy, time to castration-resistant disease (PCWG2 criteria), metastasis free survival, adverse events and HRQOL. Tertiary objectives: identification of prognostic/predictive biomarkers from archival tumour tissue and serial fasting blood. Treatment is LHRHA for 24 months and radiotherapy starting after week 16. Radiotherapy delivered as 78Gy in 39 Fx or 46Gy in 23Fx plus brachytherapy (nodal RT optional for N0, mandatory for N1). Participants are randomised 1:1 to enzalutamide 160mg daily for 24 months versus conventional NSAA for 6 months. Assessments at baseline, then every 8 weeks until year 2, then 3-4 monthly until year 5, 6-monthly until year 7, then annually. CT/MRI and bone scan at baseline, PSA progression, 6 monthly until re-initiation of ADT and 3 monthly until evidence of metastases. Target accrual is 800 with 2 yrs accrual + 5.5 yrs minimum followup. 80% power to detect 33% reduction in the hazard of death assuming 5-year survival rate of 76% amongst controls. As of Jan 2016, 43 sites open in Australia, New Zealand, Ireland, UK and USA with 164 patients recruited. EORTC sites will enter in 2016. ENZARAD is an international investigator-initiated cooperative group trial led by ANZUP Cancer Trials Group with funding from Astellas. ANZUP is supported by Cancer Australia and CI NSW ClinicalTrials.gov: NCT02446444, ANZCTR: ACTRN12614000126617 Clinical trial information: NCT02446444