Mary-Ellen Taplin1, Bruce Montgomery2, Christopher J Logothetis2, Glenn J Bubley2, Jerome P Richie2, Bruce L Dalkin2, Martin G Sanda2, John W Davis2, Massimo Loda2, Lawrence D True2, Patricia Troncoso2, Huihui Ye2, Rosina T Lis2, Brett T Marck2, Alvin M Matsumoto2, Steven P Balk2, Elahe A Mostaghel2, Trevor M Penning2, Peter S Nelson2, Wanling Xie2, Zhenyang Jiang2, Christopher M Haqq2, Daniel Tamae2, NamPhuong Tran2, Weimin Peng2, Thian Kheoh2, Arturo Molina2, Philip W Kantoff2. 1. Mary-Ellen Taplin, Massimo Loda, Rosina T. Lis, Wanling Xie, Zhenyang Jiang, and Philip W. Kantoff, Dana-Farber Cancer Institute, Harvard Medical School; Glenn J. Bubley, Huihui Ye, and Steven P. Balk, Beth Israel Deaconess Medical Center; Jerome P. Richie, Massimo Loda, and Rosina T. Lis, Brigham and Women's Hospital, Boston, MA; Bruce Montgomery, Bruce L. Dalkin, Lawrence D. True, and Alvin M. Matsumoto, University of Washington; Brett T. Marck and Alvin M. Matsumoto, Geriatric Research, Education and Clinical Center, Veterans' Affairs Puget Sound Health Care System; Elahe A. Mostaghel and Peter S. Nelson, Fred Hutchinson Cancer Research Center, Seattle, WA; Christopher J. Logothetis, John W. Davis, and Patricia Troncoso, University of Texas MD Anderson Cancer Center, Houston, TX; Martin G. Sanda, Emory University School of Medicine, Atlanta, GA; Massimo Loda, King's College London, London, United Kingdom; Trevor M. Penning and Daniel Tamae, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; and Christopher M. Haqq, NamPhuong Tran, Weimin Peng, Thian Kheoh, and Arturo Molina, Janssen Research and Development, Los Angeles, CA. mary_taplin@dfci.harvard.edu. 2. Mary-Ellen Taplin, Massimo Loda, Rosina T. Lis, Wanling Xie, Zhenyang Jiang, and Philip W. Kantoff, Dana-Farber Cancer Institute, Harvard Medical School; Glenn J. Bubley, Huihui Ye, and Steven P. Balk, Beth Israel Deaconess Medical Center; Jerome P. Richie, Massimo Loda, and Rosina T. Lis, Brigham and Women's Hospital, Boston, MA; Bruce Montgomery, Bruce L. Dalkin, Lawrence D. True, and Alvin M. Matsumoto, University of Washington; Brett T. Marck and Alvin M. Matsumoto, Geriatric Research, Education and Clinical Center, Veterans' Affairs Puget Sound Health Care System; Elahe A. Mostaghel and Peter S. Nelson, Fred Hutchinson Cancer Research Center, Seattle, WA; Christopher J. Logothetis, John W. Davis, and Patricia Troncoso, University of Texas MD Anderson Cancer Center, Houston, TX; Martin G. Sanda, Emory University School of Medicine, Atlanta, GA; Massimo Loda, King's College London, London, United Kingdom; Trevor M. Penning and Daniel Tamae, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA; and Christopher M. Haqq, NamPhuong Tran, Weimin Peng, Thian Kheoh, and Arturo Molina, Janssen Research and Development, Los Angeles, CA.
Abstract
PURPOSE:Cure rates for localized high-risk prostate cancers (PCa) and some intermediate-risk PCa are frequently suboptimal with local therapy. Outcomes are improved by concomitant androgen-deprivation therapy (ADT) with radiation therapy, but not by concomitant ADT with surgery. Luteinizing hormone-releasing hormone agonist (LHRHa; leuprolide acetate) does not reduce serum androgens as effectively as abiraterone acetate (AA), a prodrug of abiraterone, a CYP17 inhibitor that lowers serum testosterone (< 1 ng/dL) and improves survival in metastatic PCa. The possibility that greater androgen suppression in patients with localized high-risk PCa will result in improved clinical outcomes makes paramount the reassessment of neoadjuvant ADT with more robust androgen suppression. PATIENTS AND METHODS: A neoadjuvant randomized phase II trial of LHRHa with AA was conducted in patients with localized high-risk PCa (N = 58). For the first 12 weeks, patients were randomly assigned to LHRHa versus LHRHa plus AA. After a research prostate biopsy, all patients received 12 additional weeks of LHRHa plus AA followed by prostatectomy. RESULTS: The levels of intraprostatic androgens from 12-week prostate biopsies, including the primary end point (dihydrotestosterone/testosterone), were significantly lower (dehydroepiandrosterone, Δ(4)-androstene-3,17-dione, dihydrotestosterone, all P <; .001; testosterone, P < .05) with LHRHa plus AA compared with LHRHa alone. Prostatectomy pathologic staging demonstrated a low incidence of complete responses and minimal residual disease, with residual T3- or lymph node-positive disease in the majority. CONCLUSION:LHRHa plus AA treatment suppresses tissue androgens more effectively than LHRHa alone. Intensive intratumoral androgen suppression with LHRHa plus AA before prostatectomy for localized high-risk PCa may reduce tumor burden.
RCT Entities:
PURPOSE: Cure rates for localized high-risk prostate cancers (PCa) and some intermediate-risk PCa are frequently suboptimal with local therapy. Outcomes are improved by concomitant androgen-deprivation therapy (ADT) with radiation therapy, but not by concomitant ADT with surgery. Luteinizing hormone-releasing hormone agonist (LHRHa; leuprolide acetate) does not reduce serum androgens as effectively as abiraterone acetate (AA), a prodrug of abiraterone, a CYP17 inhibitor that lowers serum testosterone (< 1 ng/dL) and improves survival in metastatic PCa. The possibility that greater androgen suppression in patients with localized high-risk PCa will result in improved clinical outcomes makes paramount the reassessment of neoadjuvant ADT with more robust androgen suppression. PATIENTS AND METHODS: A neoadjuvant randomized phase II trial of LHRHa with AA was conducted in patients with localized high-risk PCa (N = 58). For the first 12 weeks, patients were randomly assigned to LHRHa versus LHRHa plus AA. After a research prostate biopsy, all patients received 12 additional weeks of LHRHa plus AA followed by prostatectomy. RESULTS: The levels of intraprostatic androgens from 12-week prostate biopsies, including the primary end point (dihydrotestosterone/testosterone), were significantly lower (dehydroepiandrosterone, Δ(4)-androstene-3,17-dione, dihydrotestosterone, all P < .001; testosterone, P < .05) with LHRHa plus AA compared with LHRHa alone. Prostatectomy pathologic staging demonstrated a low incidence of complete responses and minimal residual disease, with residual T3- or lymph node-positive disease in the majority. CONCLUSION:LHRHa plus AA treatment suppresses tissue androgens more effectively than LHRHa alone. Intensive intratumoral androgen suppression with LHRHa plus AA before prostatectomy for localized high-risk PCa may reduce tumor burden.
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