Background: Patients with high-risk PC have an increased risk of recurrence and mortality despite therapy. Abiraterone, a CYP17 inhibitor, and enzalutamide, a next generation anti-androgen, have demonstrated improved overall survival in metastatic PC. In this multicenter randomized phase II trial, we evaluate the impact of second generation hormone therapy on RP pathologic outcomes. Methods: Eligible patients had biopsy Gleason score ≥4+3=7, PSA >20 ng/mL or cT3 disease (by prostate MRI). Lymph node were require to be <20 mm. Patients were randomized 2:1 to APE:EL for 6 cycles (24 weeks) followed by RP. All RPs underwent central pathology review. The primary endpoint was the rate of pathologic complete response (pCR) or minimum residual disease (MRD, tumor ≤5 mm). Secondary endpoints include PSA response, surgical staging at RP, positive margin rate, and safety. Results: 75 patients were enrolled at four sites: DFCI/BWH (n=55), BIDMC (n=11), UW (n=5), JHU (n=4). Median age was 62 years. Most patients had NCCN high-risk disease [n=66, 88%; cT3 n=21 (28%), Gleason 8-10 n=59 (79%), PSA >20 ng/mL n=17 (23%)]. All patients completed 6 cycles followed by RP. Median PSA nadir was 0.03 and 0.02 ng/mL and time to nadir was 3.7 and 4.6 months in the APEL and EL arms, respectively. The combined pCR or MRD rate was 30% (n=15/50) in the APEL arm and 16% (n=4/25) in the EL arm. The response difference was 14% (80% CI -3%-30%, p=0.263). 15 patients (14 in APEL; 1 in EL) had grade 3 adverse events (AEs). The most common grade 3 AEs were hypertension (n=7) and ALT increase (n=5). No grade 4-5 AEs occurred. Conclusions: Neoadjuvant hormone therapy plus RP in men with high-risk PC resulted in favorable pathologic responses (≤5 mm residual tumor) in 16-30% with a trend towards improved pathologic outcomes with APEL and acceptable safety profile. Follow-up is necessary to evaluate the impact of therapy on recurrence rates. Clinical trial information: NCT02268175