Background:α-emitting radiopharmaceutical Ra-223 reduces the risk of death by 30% vs placebo in phase 3 ALSYMPCA (Parker et al. NEJM 2013). Ra-223’s favourable safety profile and lack of significant toxicity support combining it with other agents. The ALSYMPCA trial was developed to add Ra-223 on the contemporary standard of care that did not include last generation AR pathway inhibitors enzalutamide, one of the modern reference treatments for asymptomatic or moderately symptomatic metastatic CRPC (Gillessen et al. Eur Urol. 2017). In addition Ra-223 is registered in symptomatic prostate cancer (PCa), a very late stage of modern patient disease. There is thus a good rationale to combine Ra-223 to modern AR pathway inhibitors and to initiate the treatment in asymptomatic or moderately symptomatic patients. Methods: The EORTC 1333-GUCG study will run in 51 sites (21 activated) across 7 European countries, 4 sites in US and 12 sites in Canada. The study is an intergroup initiative between EORTC (Coordinating Group), UNICANCER; Cancer Trials Ireland (Ireland), ACCRU (The United States), and CUOG (Canada). A total of 560 patients will be randomized in a 1:1 ratio to receive enzalutamide 160 mg q.d. p.o. or enzalutamide at the same dose and Ra223 at 55 kBq/kg i.v. monthly for 6 months. Patients will be stratified by country, pain (BPI 0-1 vs BPI 2-3), prior docetaxel use (no vs yes) and use of bone targeting agents (no vs yes). The main inclusion criteria require asymptomatic or mildly symptomatic (defined as no opioids and BPI-SF question 3 < 4), metastatic to bone with ≥ 2 bone metastases with or without additional lymph node metastases. Visceral metastases are not allowed. The primary endpoint is radiological progression-free survival (rPFS1), according to PCWG3. Secondary endpoints include: overall survival, PCa specific survival, 1^st symptomatic skeletal event (SSE), time to initiation of next systemic anti-neoplastic therapy, time to pain progression, health-related quality of life (EQ-5D-5L and BPI). Clinical trial information: NCT02194842