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<0.0001); MFS by BICR was significantly improved with HR 0.80; 95% CI 0.67-0.96; p=0.0169 and 5-y MFS rate of 78.2% vs 73.5%; median not reached NR. Investigator-assessed MFS favored APA + ADT, with HR 0.74; 95% CI 0.62-0.87; nominal p=0.0004. EFS, TTST1, TTDM were all significantly improved with APA + ADT (Table), as was RCB/MRD: MRD 30.6% vs 11.7%; OR 3.36; 95% CI 2.67-4.23; nominal p<0.0001. Grade 3/4 tx-emergent adverse events (TEAEs) for APA + ADT vs PBO + ADT were 39.6% vs 31.0%, with discontinuation due to TEAEs 7.4% vs 2.7%, respectively. Conclusions: APA + ADT significantly increased the curative success of RP in pts with HR LPC/LAPC, with a 10-fold higher odds of pCR/MRD and a clinically meaningful 20% reduction in risk of distant metastasis or death. Secondary end points all favored APA + ADT. These results support combined APA + ADT and RP as a new standard of care for pts with HR LPC/LAPC. Clinical trial information: NCT03767244 . HR(95% CI) p Value a APA + ADTn=1057Median (mo) PBO + ADTn=1052Median (mo) EFS 0.71(0.63-0.80) <0.0001 57.1 38.4 TTST1 (local, regional, or systemic, including ADT reinitiation) 0.65(0.57-0.73) <0.0001 74.2 41.5 TTDM (conventional or PSMA PET imaging) 0.68(0.55-0.83) 0.0002 NR NR a Stratified by GS (7, ≥8), nodal status, and geographic region (North America, European Union, rest of world).