Background: Prostate specific membrane antigen (PSMA) has been explored as a target in imaging studies using positron emission tomography (PSMA-PET) to unveil occult prostate cancer metastasis, and as a target for radioligand therapy. Preclinical and retrospective clinical studies suggest that PSMA expression can be rapidly increased by androgen suppression, which might impact the accuracy of disease detection using PSMA-PET scans and radioligand treatment efficacy. Methods: Daro-PET (NCT05900973) is a single-arm phase 2 study to evaluate the efficacy of a limited course of darolutamide as a PSMA expression enhancer in men planned for radical prostatectomy due to high-risk localized prostate cancer as per conventional imaging. PSMA PET/CT scans will be acquired before (PSMA-PET 1) and after (PSMA-PET 2) a 7-day treatment with darolutamide 600 mg PO q12 h. The primary endpoint is the proportion of patients achieving an increase in SUVmax of 20% or greater from PSMA-PET 1 to PSMA-PET 2. Key secondary endpoints include other PSMA PET parameters (e.g. SUVmean, Total lesion PSMA), proportion of planned management changes, detection of pelvic or extrapelvic metastatic disease, and safety. Correlative exploratory studies will include PSMA expression by immunohistochemistry, gene expression, and methylation patterns between tissue samples from prostate biopsy and prostatectomy. The trial will enroll up to 16 patients using a Simon’s two-stage design, with a power of 0.80 and a one-sided alpha error of 0.05. As of September 20^th, 1 patient was included in the study. Clinical trial information: NCT05900973.