Neoadjuvant Enzalutamide (ENZA) and Abiraterone Acetate (AA) plus Leuprolide Acetate (LHRHa) versus AA+ LHRHa in Localized High-risk Prostate Cancer (LHRPC)

Background: AA added to medical castration augments cytoreduction in LHRPC though wide range of persistent cancer is observed. To build on these findings we conducted a study examining AA+ LHRHa with or without ENZA.

Methods: We performed a neoadjuvant study of 24 wks of AA+ENZA +LHRHa vs AA+LHRHa (randomized 2:1) in pts with LHRPC (clinical stage T1c/T2 with biopsy Gleason ≥ 8, or ≥ T2b with Gleason ≥ 7 and PSA > 10 ng/mL). We primarily studied treatment effect on pathologic stage.

Secondary endpoints include: residual tumor measures; tumor volume, cellularity, tumor epithelial volume (TEV: epithelial component [cellularity %] tumor volume), steroid metabolites (LCMS) and key protein/RNA markers(AR signaling [AR-N ARC19, ARV7, CYP17, PSA], glucocorticoid receptor [GR], neuroendocrine [CD56, CgA], Ki67,p53, RB). Sample size provided 80% power for difference in ≤ pT2N0 per chi-square test at significance of 0.1.

Results: Sixty-five treated pts underwent prostatectomy No Grade ≥ 4 adverse event (AE) reported. Main Grade 3 AEs: LFT increase 19 pts (13 AA+ENZA), hypertension 13 AA+ENZA. PSA nadir ≤ 0.1 ng/mL: 40/44 (91%) in ENZA+ AA+LHRHa vs 17/21 (81%). Pathologic downstaging ( ≤ pT2N0) occurred in 13/44 (30%) AA+ENZA+ LHRHa pts vs 11/21 (52 %) AA+LHRHa (p = 0.07) including 2 pCR. TEV and stage were aligned. Despite high rates of PSA ≤ 0.1, wide range of viable tumor was observed: volume (0-8.64cc), cellularity (0-90%), TEV (0-5.58cc) Metabolomic data in line with previous report. Stage ≤ pT2N0 was associated with lower Ki67 (p 0.005) and increased expression of canonical AR signaling components AR-N, ARC19, CYP17 (p 0.005) but not PSA (p 0.17). ARV7 presence was more frequent in ENZA+AA+LHRH treated tumors (p 0.05). Four CD56/CgA, 1 Rb- and 1 p53 altered, tumors identified.

Conclusions: Findings do not favor adding ENZA to augment AA+LHRHa efficacy in LHRPC. Expression of neuroendocrine markers, p53, loss of RB, are infrequent in persistent cancers. Canonical AR signaling and low Ki67 correlate with lower stage. ARV7 was detected more frequently in the combination arm. Study results emphasize need to consider biologic heterogeneity when applying AR targeting therapies.

Clinical trial information: NCT01946165.

Journal of Clinical Oncology. 2017, May 11 [Epub]

Eleni Efstathiou1, John W. Davis2, Mark Anton Titus2, Brian Francis Chapin2, Amado J. Zurita2, Sijin Wen3, Elsa M. Li Ning Tapia2, Anh Hoang2, Paul Gettys Corn2, Xuemei Wang2, Francine Whittington2, Patricia Troncoso2, Christopher Logothetis2

1. Alexandra General Hospital of Athens, University of Athens, Athens, Greece
2. The University of Texas MD Anderson Cancer Center, Houston, Texas
3. West Virginia University School of Public Health, Morgantown, West Virginia

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