Neoadjuvant apalutamide (APA) plus leuprolide (LHRHa) with or without abiraterone (AA) in localized high-risk prostate cancer (LHRPC)

5504 Background: Novel androgen signaling inhibitors (ASI) with medical castration may improve outcomes in LHRPC. We previously reported relapse free survival association with pathologic measures of tumor regression. However a wide range of persistent cancers was recorded. To build on our findings and test candidate predictors of outcome, we conducted a study examining APA effect in LHRPC. Methods: This is a phase II neoadjuvant study of 6 months APA+LHRHa +/- AA (randomized 1:1) in LHRPC (≥ cT2 + Gleason Score ≥ 8 or ≥ cT2b + Gleason ≥ 7 + PSA > 10 ng/mL) followed by radical prostatectomy (RP). We studied treatment effect by pathology measures [path. stage, tumor volume (TV), tumor cellularity % (TC), tumor epithelial volume (TEV: TC x TV)]. Tumor expression of candidate markers of outcome was assessed in the diagnostic biopsy by IHC [AR signaling (AR-N, ARC19, ARV7, PSA), PTEN, glucocorticoid receptor (GR), Ki67, p53, RB] and DNA/RNA seq. A previously identified candidate predictive molecular signature (AR-N overexpression, nARV7 absence, no GR overexpression, Ki67 ≤10%) was tested. Univariate (Fisher’s exact, Wilcoxon) and multivariate (logistic, linear models) analyses employed. Results: Sixty three -of 65 pts enrolled- had RP. PS-ECOG 0, median age 65 (43-77). Treatment was well tolerated with Grade 3 hypertension in 7 (2 APA + LHRHa). Presurgical PSA was ≤0.1 in 62/63 (98%). Organ confined disease (≤ypT2N0) found in 13/32(41%) APA+LHRHa vs. 12/31 (39%) APA+AA+LHRHa treated. 2 (3%) had pathologic complete remission (APA+AA+LHRHa), 6 (10%) minimal residual disease (5 on APA +LHRHa). Despite uniformity in PSA response, we recorded heterogeneity in measures of tumor viability: TV (0-11.5cc), TC (1-80%), TEV (0-6.1cc). ≤ypT2N0 associates with diagnostic biopsy positivity for the prespecified molecular signature (p