Background: Patients (pts) with high-risk localized prostate cancer (HRLPC) have a significant risk of disease recurrence and metastasis after radical prostatectomy (RP). Neoadjuvant therapy remains investigational but there may be a role for the next-generation androgen signaling inhibitors. We sought to evaluate pathologic and imaging response after the intense neoadjuvant approach. Methods: This is a phase II investigator-initiated randomized trial of 3-month neoadjuvant therapy with goserelin (androgen deprivation therapy, ADT) + abiraterone acetate and prednisone (AAP arm) or AAP + apalutamide (A-APA arm) before RP for pts with HRLPC (Gleason ≥ 8 and/or cT3N0-1 and/or PSA ≥ 20 ng/mL). The primary endpoint was the rate of pathologic complete response (pCR) or minimal residual disease (MRD, tumor ≤ 0.5 cm). The secondary endpoints were safety, rate of residual cancer burden ≤0.25 cm³ (RCB = tumor volume x cellularity), Gallium 68 prostate-specific membrane antigen (PSMA) positron emission tomography (PET)/magnetic resonance correlates and rate of biochemical relapse (BR). Results: Sixty-two pts were randomized to A-APA (N = 31) or AAP (N = 31). Median age was 65 (range 47-77) years. NCCN risk groups included high-risk disease in 19%, very high-risk in 76% and regional (N1) disease in 5% (79% cT3, 65% Gleason 8-10, 57% PSA ≥ 20 ng/mL). Outcomes after intense neoadjuvant ADT are described in the Table. There was no statistically significant difference between study arms regarding pCR/MRD or RCB ≤ 0.25 cm³ rates. Patients with complete PSMA-PET response (psmaCR) demonstrated a RCB ≤ 0.25 cm³ rate of 50% compared to 7.5% in pts without a psmaCR (P= 0.001). The rate of BR was 14% for pts with RCB ≤ 0.25 cm³ versus 38% in pts with RCB > 0.25 cm³ (P= 0.118). At current median follow-up of 2.6 years, all patients with both psmaCR and RCB ≤ 0.25cm³ (N = 11, 18%) are free of BR. There were 2 grade (G) 5 adverse events (AEs) in the AAP arm (pulmonary embolism and sudden death, both after surgery). Nine (14.5%) pts (6 in A-APA; 3 in AAP) experienced G3-4 treatment-related AEs. The most common G3-4 AEs were hypertension (11.3%), AST/ALT elevations (3.2%) and skin rash (1.6%). Conclusions: No difference in pCR or MRD was observed between arms. Although pCR or MRD after intense neoadjuvant ADT was infrequent, a significant proportion of pts achieved a favorable pathologic response with RCB ≤ 0.25 cm³. PSMA-PET response is a potential surrogate for pathologic response. Clinical trial information: NCT02789878.