Background: In pts with localized high-risk PC, disease recurrence rate following RP is ̃50% (Kane et al. J Urol. 2007). Treatment (tx) with androgen blockade before RP can reduce tumor burden post RP (Taplin et al. J Clin Oncol. 2014; McKay et al. Prostate Cancer Prostatic Dis. 2018; Efstathiou et al. Eur Urol. 2019). This study examines if 12 months of perioperative APA + ADT tx before and after RP with pelvic lymph node dissection (pLND) in localized/locally advanced high-risk PC improves pathologic complete response (pCR) rate and metastasis-free survival (MFS) vs PBO + ADT. Methods: PROTEUS, an international multicenter study, is enrolling ̃2000 pts with localized/locally advanced high-risk/very high-risk PC who are candidates for RP with pLND over 3 years at > 203 sites in 18 countries. Stratification variables: Gleason score (7 vs ≥ 8), pelvic node status (N0 vs N1), international region. Randomization: 1:1 to APA (240 mg/d) + ADT or PBO + ADT. Pts receive 6-month neoadjuvant tx followed by RP and then 6 months’ adjuvant tx. Primary end points: pCR rate and MFS. In addition to MFS based on conventional imaging, MFS based on PSMA PET or conventional imaging will be assessed as a separate end point. Both pCR and MFS are assessed by blinded independent central review. Conventional imaging by CT or MRI and bone scan are done at screening, within 4 weeks after RP, at biochemical failure (BCF), and then every 6 months after BCF until distant metastasis or death. During the direct perioperative period, APA/PBO is stopped 2 weeks prior to planned RP and then resumed 4 weeks after RP if post-RP imaging has been conducted to assess for lymphocele and disease progression and resolution to grade ≤ 1 of any clinically significant adverse events considered related to RP. To reflect evolving standard of care, the following protocol amendments were added: PSMA-PET imaging at 3 months post adjuvant tx, at BCF, and every 6 months until distant metastasis or death; cardiovascular and thrombotic risk assessment at screening, prior to, and after RP; and guidance for standard thrombotic prophylaxis in the perioperative setting. An independent data monitoring committee will review trial data. Clinical trial information: NCT03767244.