Prostate cancer is dependent on androgen receptor (AR) activation. Optimal AR antagonism may effectively cytoreduce local disease and suppress or eliminate micrometastases. We evaluated neoadjuvant therapy prior to prostatectomy with the potent AR antagonist enzalutamide (enza) either alone or in combination with dutasteride and leuprolide (enza/dut/LHRHa).
Forty-eight of 52 men with intermediate or high-risk localized prostate cancer proceeded to prostatectomy after neoadjuvant enza or enza/dut/LHRHa for 6 months. We assessed pathologic complete response (pCR), minimal residual disease (MRD; ≤3 mm maximum diameter of residual disease), residual cancer burden (RCB), and expression of prostate-specific antigen (PSA) and serum and tissue androgen concentrations. We compared the proportion of patients with pCR in each treatment arm with a historical control rate of 5%, based on previous reports of flutamide with LHRHa.
In the enza arm, none of the 25 patients achieved pCR or MRD. In the enza/dut/LHRHa arm, one of 23 patients (4.3%) achieved pCR and three of 23 (13.0%) achieved MRD. Median RCB was higher in the enza arm than in the enza/dut/LHRHa arm (0.41 cm3 vs. 0.06 cm3, respectively). Tissue testosterone and dihydrotestosterone levels correlated with RCB. No adverse events leading to study drug discontinuation were reported.
Combination therapy with enza/dut/LHRHa resulted in pCR and MRD rates comparable to historical controls. Evidence of continued AR activity in residual tumor suggests that AR signaling may contribute to survival. Strategies to more effectively ablate AR activity are warranted to determine if more substantial antitumor effects are observed.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2016 Nov 09 [Epub ahead of print]
Bruce Montgomery, Maria S Tretiakova, Anthony Michael Joshua, Martin E Gleave, Neil Fleshner, Glenn J Bubley, Elahe A Mostaghel, Kim N Chi, Daniel Lin, Martin Sanda, William Novotny, Kenneth Wu, Philip W Kantoff, Brett Marck, Steve Plymate, Steven P Balk, Peter S Nelson, Alvin M Matsumoto, Rosina T Lis, Adam Kibel, Gabriel P Haas, Andrew Krivoshik, Alison Hannah, Mary-Ellen Taplin
Department of Medicine, University of Washington ., Pathology, University of Washington., Medical Oncology, Princess Margaret Cancer Centre., Vancouver Prostate Centre., Urology, Princess Margaret Hospital., Division of Hematology and Oncology, Department of Medicine, Beth Israel Deaconess Medical Center and Harvard Medical School., Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center., Medical Oncology, BC Cancer Agency., Urology, University of Washington., Department of Urology, Emory University., Clinical Development, Medivation, Inc., Biostatistics, Medivation, Inc., Department of Medicine, Memorial Sloan Kettering Cancer Center., GRECC, V.A. Puget sound., Medicine and Urology, University of Washington., Medicine, Beth Israel Deaconess., Division of Human Biology, Fred Hutchinson Cancer Research Center., Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System., Department of Pathology, Dana-Farber Cancer Institute., Department of Urology, Brigham and Women's Hospital., Medical Affairs, Astellas Pharma, Inc., N/A, Astellas Pharma Global Development, Inc., Oncology, Dana-Farber Cancer Institute.