A Phase II Trial of Abiraterone Combined with Dutasteride for Men with Metastatic Castration-Resistant Prostate Cancer.
Purpose:Despite the efficacy of abiraterone, a CYP17A1 inhibitor, in metastatic castration-resistant prostate cancer (CRPC), nearly all patients develop resistance. The purpose of this phase II study was to evaluate mechanisms of resistance to more complete androgen synthesis inhibition with abiraterone and dutasteride.Experimental Design:Eligible patients with metastatic CRPC underwent a baseline metastasis biopsy. Patients received abiraterone and prednisone for two 4-week cycles. After this time, high-dose dutasteride (3.5 mg daily) was added. Patients continued therapy until study withdrawal or radiographic progression. Repeat metastasis biopsy was obtained at progression. The primary endpoint was to assess mechanisms of resistance. Serum hormone and abiraterone levels were assessed. Tissue was assessed for androgen receptor (AR) and AR splice variant-7 (ARV7) expression.Results:Forty patients were enrolled. Sixty percent (n= 24) achieved a ≥50% reduction in prostate-specific antigen (PSA). The median time to radiographic progression was 11 months. Nearly all baseline (n= 29 of 31) and posttreatment (n= 16 of 16) tumors tested for AR nuclear expression were positive. Of those tested, ARV7 expression was present in 48% (n= 10 of 21) of baseline and 42% (n= 5 of 12) of treatment discontinuation specimens. Compared with patients with higher serum abiraterone levels at treatment discontinuation, patients with lower levels had higher circulating androgens.Conclusions:Despite increased androgen synthesis inhibition, we demonstrate that tumor AR axis remains important in disease progression. We highlight that abiraterone metabolism and pharmacokinetics may play a role in resistance. The noncomparative design limits conclusions on the efficacy of dual therapy with abiraterone and dutasteride, but the results support development of further multifaceted approaches toward AR inhibition.Clin Cancer Res; 23(4); 935-45. ©2016 AACR.
Dana-Farber Cancer Institute, Boston, Massachusetts.
Rana R
RR
McKay
Dana-Farber Cancer Institute, Boston, Massachusetts.
Lillian
L
Werner
University of Washington, Seattle, Washington.
Elahe A
EA
Mostaghel
Dana-Farber Cancer Institute, Boston, Massachusetts.
Rosina
R
Lis
Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Olga
O
Voznesensky
Dana-Farber Cancer Institute, Boston, Massachusetts.
Zhenwei
Z
Zhang
Veterans Affairs Puget Sound Health Care System, Seattle, Washington.
Brett T
BT
Marck
University of Washington, Seattle, Washington.|Veterans Affairs Puget Sound Health Care System, Seattle, Washington.
Alvin M
AM
Matsumoto
Beilinson Hospital, Petah Tikva, Israel.
Liran
L
Domachevsky
McMaster University, Ontario, Canada.
Katherine A
KA
Zukotynski
Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Manoj
M
Bhasin
Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Glenn J
GJ
Bubley
University of Washington, Seattle, Washington.
Bruce
B
Montgomery
Dana-Farber Cancer Institute, Boston, Massachusetts.|Memorial Sloan Kettering Cancer Center, New York, New York.
Philip W
PW
Kantoff
Beth Israel Deaconess Medical Center, Boston, Massachusetts.
Steven P
SP
Balk
Dana-Farber Cancer Institute, Boston, Massachusetts. Mary_Taplin@DFCI.harvard.edu.
Mary-Ellen
ME
Taplin
D000368:Aged; D000728:Androgens / Q000096:biosynthesis / Q000235:genetics; D000736:Androstenes / Q000008:administration & dosage* / Q000097:blood; D018450:Disease Progression; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D000068538:Dutasteride / Q000008:administration & dosage*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D064129:Prostatic Neoplasms, Castration-Resistant / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D011859:Radiography; D011944:Receptors, Androgen / Q000235:genetics*
C410798:AR protein, human; D000728:Androgens; D000736:Androstenes; D011944:Receptors, Androgen; C089740:abiraterone; D000068538:Dutasteride
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