Background: In recent years, the treatment of mCRPC has evolved and next-generation androgen receptor (AR)-axis targeting drugs (enzalutamide (ENZ), and abiraterone) have been approved and are routinely used. Darolutamide (DARO) is a new next-generation AR inhibitor which has shown strong activity and minimal toxicity in two phase I-II trials ARADES (Fizazi, Lancet Oncol 2014) and ARAFOR (Massard, Eur Urol 2016) and is currently evaluated in a study in men with non-metastatic CRPC (ARAMIS trial). In contrast to ENZ, DARO does not significantly penetrate the blood-brain barrier in vivo, and this may reduce the risk of fatigue, cognitive impairment, and seizure. Assessing patient preference between DARO and ENZ may contribute further differentiating between these two agents. Methods: ODENZA is a prospective, randomized, open-label, multicenter, cross-over phase II trial assessing patient preference between DARO and ENZ. It was initiated in November 2017. Eligibility criteria include: men with asymptomatic or mildly symptomatic mCRPC, performance status 0-1, no prior next generation AR axis-targeted agent. The randomization is stratified on performance status and prior treatment with a taxane for CSPC. 250 patients will be randomized 1:1 to: 12-week ENZ followed by 12-week DARO or 12-week DARO followed by 12-week ENZ. The primary endpoint is patient preference between DARO and ENZ, assessed after the second treatment period. A two-sided binomial test with a power of 80% and a bilateral α of 0.05 will be used. Secondary endpoints include: reasons for patient preference, dose modifications and time to dose modification, safety, fatigue (BFI), cognitive function as assessed by Cogstate computerized cognitive tests, depression screening (CES-D) test, frequency of falls, PSA declines using Waterfall plots after each treatment period, Progression-Free Survival (PFS), association between 4-weeks PSA value and PFS, incidence of cancer progression or death, and tumor response. The study is recruiting. By October 23, 2018, 75 patients have been screened and 66 have been randomized. Clinical trial information: NCT03314324