Background: Currently, the challenge is to reach a consensus on the best way to sequence different therapies for mCRPC patients (pts) in terms of efficacy and tolerability. Radium223 is a novel survival-prolonging targeted-α-therapy, but timing of its use in the treatment sequence of mCRPC remains an unanswered question, given the wide availability of therapeutic options Methods: This is a prospective, multicenter, randomized phase II study in symptomatic bone-only mCRPC pts who progressed after any androgen deprivation therapy, abiraterone and/or enzalutamide. Pts will be randomized 1:1 to receive radium223 initially followed by docetaxel+prednisone at the time of progression, or docetaxel+prednisone initially followed by radium223 at progression. In both treatment arms, the second step will be optional according to clinical evolution of disease (clinical deterioration and/or development of visceral metastases); however, each patient that will not enter in the second step will be still evaluable for the objectives of the study. No stratification factor will be used for randomization. Primary endpoint is to determine the better tolerated sequencing between radium223 and docetaxel in terms of health-related quality of life after completing the sequence and separately after each treatment. Based on primary endpoint, considering a type I error 0.1, type II error 0.2, proportion of responder pts in the standard arm 0.1 and in the experimental arm of 0.4, and assuming 10% loss to follow-up, a total of 70pts (35 for each arm) will be enrolled in the study. The study duration will be 36months; 15months of accrual, and 1 year of follow-up on the last participant enrolled. Secondary endpoints are to compare overall/progression-free/total progression free survival in pts treated with sequential therapy between radium223 and docetaxel. Additional secondary objective is to identify predictive factors for radium223 therapy, including potential circulating biomarkers through the plasma collection from all enrolled pts at different timepoints and the early prognostic role of functional imaging, such as PET with choline and/or PSMA. Clinical trial information: NCT03230734