Neoadjuvant Enzalutamide Prior to Prostatectomy.
Purpose: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 (dut) and leuprolide (enza/dut/luteinizing hormone-releasing hormone analogues [LHRHa]).Experimental Design:Forty-eight of 52 men with intermediate or high-risk localized prostate cancer proceeded to prostatectomy after neoadjuvant enzalutamide 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 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.Results:In the enzalutamide 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 3 of 23 (13.0%) achieved MRD. Median RCB was higher in the enzalutamide arm than in the enza/dut/LHRHa arm (0.41 cm3vs. 0.06 cm3, respectively). Tissue testosterone and dihydrotestosterone levels correlated with RCB. No adverse events leading to study drug discontinuation were reported.Conclusions:Combination therapy with enza/dut/LHRHa resulted in pCR and MRD rates comparable with 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 whether more substantial antitumor effects are observed.Clin Cancer Res; 23(9); 2169-76. ©2016 AACR.
Department of Medicine, University of Washington, Seattle, Washington. rbmontgo@uw.edu.
Bruce
B
Montgomery
Department of Pathology, University of Washington, Seattle, Washington.
Maria S
MS
Tretiakova
Princess Margaret Cancer Centre, Toronto, Canada.
Anthony M
AM
Joshua
Department of Urologic Sciences, University of British Columbia, Vancouver, Canada.
Martin E
ME
Gleave
Princess Margaret Cancer Centre, Toronto, Canada.
Neil
N
Fleshner
Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Glenn J
GJ
Bubley
Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.|Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington.
Elahe A
EA
Mostaghel
BC Cancer Agency and University of British Columbia, Vancouver, Canada.
Kim N
KN
Chi
Department of Urology, University of Washington, Seattle, Washington.
Daniel W
DW
Lin
Department of Urology, Emory University, Atlanta, Georgia.
Martin
M
Sanda
Medivation, Inc., San Francisco, California.
William
W
Novotny
Medivation, Inc., San Francisco, California.
Kenneth
K
Wu
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.|Memorial Sloan Kettering Cancer Center, New York, New York.
Philip W
PW
Kantoff
Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, and Department of Medicine, Division of Gerontology & Geriatric Medicine, University of Washington, Seattle, Washington.
Brett T
BT
Marck
Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, and Department of Medicine, Division of Gerontology & Geriatric Medicine, University of Washington, Seattle, Washington.
Stephen
S
Plymate
Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Steven P
SP
Balk
Department of Medicine, University of Washington, Seattle, Washington.|Department of Pathology, University of Washington, Seattle, Washington.|Division of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, Washington.|Department of Urology, University of Washington, Seattle, Washington.
Peter S
PS
Nelson
Department of Medicine, University of Washington, Seattle, Washington.|Geriatric Research, Education and Clinical Center, VA Puget Sound Health Care System, and Department of Medicine, Division of Gerontology & Geriatric Medicine, University of Washington, Seattle, Washington.
Alvin M
AM
Matsumoto
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Rosina T
RT
Lis
Brigham and Women's Hospital, Boston, Massachusetts.
Adam
A
Kibel
Astellas Pharma, Inc., Northbrook, Illinois.
Gabriel P
GP
Haas
Astellas Pharma, Inc., Northbrook, Illinois.
Andrew
A
Krivoshik
Medivation, Inc., San Francisco, California.
Alison
A
Hannah
Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
Mary-Ellen
ME
Taplin
D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage* / Q000009:adverse effects; D001549:Benzamides; D003131:Combined Modality Therapy; D000068538:Dutasteride / Q000008:administration & dosage; D006801:Humans; D016729:Leuprolide / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy / Q000009:adverse effects; D018365:Neoplasm, Residual / Q000097:blood / Q000139:chemically induced / Q000473:pathology; D009570:Nitriles; D010669:Phenylthiohydantoin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D017430:Prostate-Specific Antigen / Q000097:blood; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D011944:Receptors, Androgen / Q000235:genetics*
D001549:Benzamides; D009570:Nitriles; D011944:Receptors, Androgen; D010669:Phenylthiohydantoin; C540278:enzalutamide; D017430:Prostate-Specific Antigen; D016729:Leuprolide; D000068538:Dutasteride