Background: Radiotherapy (RT) associated sexual dysfunction occurs in half of men following treatment for localized prostate cancer. Proposed mechanisms include vascular injury of adjacent internal pudendal arteries (IPA), penile bulb (PB), corpora cavernosa (CC) or neurovascular bundles (NVB). Ability to spare these structures has been limited by a presumed need to treat the entire prostate gland, while also preventing rectal injury. Recent innovations have challenged this issue: a) precise dose delivery with stereotactic ablative RT (SAbR), b) improved spatial mapping of clinically significant disease with mpMRI, c) rectal avoidance with rectal spacer use. Methods: POTEN-C is a multi-center phase II randomized control trial, which includes men with a) low-intermediate risk prostate cancer eligible for SAbR without ADT, b) potent by sexual composite score ≥60 on EPIC patient-reported quality of life instrument, c) mpMRI delineated disease (PIRADS v2 score 3-5) ≥5mm to at least one ‘spared’ NVB. After placement of rectal spacer gel and CT/MRI simulation, men are randomized to standard SAbR to 40-45Gy/5fx or neurovascular-sparing SAbR. In the sparing experimental arm, the prostate PTV is given 30Gy/5fx excluding unilateral ‘spared’ NVB, while a 40-45Gy PTV further excludes a 5mm protective shell on the unilateral ‘spared’ NVB+IPA+PB+CC. Centralized rapid review of initial contours/plans and online training materials are integrated. The primary endpoint is 2-year patient-reported potency, measured by EPIC sexual composite score. We hypothesize that neurovascular sparing SAbR will reduce 2-year EPIC score decline from a control of 20 to 10 (corresponding to a MCID). Assuming standard deviation 20, two-sided significance level 0.10 with two-sample t-testing, and 15% attrition, we intend to enroll 120 patients to provide 80% power to detect this difference. Secondary endpoints include sexual medication/aid use, relapse rates, GU/GI toxicity. Enrollment is ongoing. Details: http://www.poten-c.org. Clinical trial information: 03525262.