Background: Androgen deprivation therapy (ADT) is the cornerstone of treatment for prostate cancer (CaP). However, the relationship between ADT and the development of cognitive dysfunction in men with CaP is controversial. Past studies had various methodological limitations, including the inconsistency and insensitivity of measures used for cognitive testing. Methods: COGCaP is a multi-site, prospective observational study of cognitive function and patient reported outcomes in men with CaP treated with ADT and androgen receptor (AR) directed therapies such as enzalutamide or abiraterone acetate (AA) conducted across four U.S. sites. Patients with metastatic castration-resistant or hormone sensitive CaP starting abiraterone (N=50), or non-metastatic or metastatic castration-resistant CaP starting enzalutamide (N=50) undergo cognitive and patient reported outcome assessments at baseline, 3, 6, and 12 months. The primary endpoint compares mean change in cognitive function between groups at 3 months using CANTAB, a computer-based measure of cognitive function. This design achieves a power of 80% to detect a between-group difference in mean cognitive composite score of < 1 standard deviation and a two-sided type I error rate of 0.05. Functional MRI (fMRI) images will be assessed between baseline and 3 months to assess structural and functional changes in the brain as secondary endpoints. Study patients will be incorporated into a model of genetic risk of cognitive dysfunction in order to identify populations that are especially vulnerable to cognitive change when undergoing androgen deprivation. This ongoing study will define a reproducible methodology for cognitive assessments via computer based tests that can be standardized and disseminated within multi-site trials of men with CaP. Clinical trial information: NCT03016741