Perioperative (neoadjuvant and adjuvant) apalutamide (APA) + androgen deprivation therapy (ADT) vs placebo (PBO) + ADT with radical prostatectomy (RP) in high-risk localized or locally advanced prostate cancer (HR LPC/LAPC): Final analysis of the PROTEUS phase 3 study.

LBA1 Background: RP is potentially curative for patients (pts) with HR LPC/LAPC, yet ≈50% of pts relapse. PROTEUS evaluated whether APA + ADT vs PBO + ADT before and after RP with pelvic lymph node dissection (henceforth, RP) improves pathologic complete response/minimal residual disease (pCR/MRD) and metastasis-free survival (MFS) in HR LPC/LAPC. Methods: Pts with newly diagnosed HR LPC/LAPC (histology, prostate-specific antigen [PSA], and cN0/cN1 on conventional imaging) were randomized 1:1 to blinded APA (240 mg/d) or PBO as neoadjuvant treatment (tx) for 6 mo + ADT, with a 2-wk break prior to and a 4-wk break post RP, followed by 6 mo of assigned tx. Dual primary end points, pCR/MRD (≤ypT2, ≤5 mm tumor diameter) and MFS based on conventional or prostate-specific membrane antigen positron emission tomography (PSMA PET) imaging, were assessed by blinded independent central review (BICR). Secondary end points included event-free survival (EFS), time to first subsequent tx (TTST1), time to distant metastasis (TTDM), and safety. Exploratory end points included residual cancer burden (RCB/MRD; ≤ypT2, ≤0.25 cm 3 ) and investigator-assessed MFS. Results: Of 2109 pts randomized (APA + ADT [1057] or PBO + ADT [1052]), median (range) age was 66.0 (41-89) years (y); PSA, 14.8 (0.0-2798.0) ng/mL; GS ≥8, 95.8%. Median follow-up was 61.7 mo. Both primary end points were met with APA + ADT vs PBO + ADT: pCR/MRD rate was significantly higher, 8.9% vs 1.0% (odds ratio [OR] 10.17; 95% CI 5.27-19.64; p