Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer.
OBJECTIVE
Increasing evidence indicates that enhanced intratumoral androgen synthesis contributes to prostate cancer progression after androgen deprivation therapy. This phase II study was designed to assess responses to blocking multiple steps in androgen synthesis with inhibitors of CYP17A1 (ketoconazole) and type I and II 5alpha-reductases (dutasteride) in patients with castration-resistant prostate cancer (CRPC).


METHODS
Fifty-seven men with CRPC were continued on gonadal suppression and treated with ketoconazole (400 mg thrice daily), hydrocortisone (30 mg/AM, 10 mg/PM), and dutasteride (0.5 mg/d).


RESULTS
Prostate-specific antigen response rate (> or =50% decline) was 56% (32 of 57; 95% confidence interval, 42.4-69.3%); the median duration of response was 20 months. In patients with measurable disease, 6 of 20 (30%) responded by the Response Evaluation Criteria in Solid Tumors. Median duration of treatment was 8 months; 9 patients remained on therapy with treatment durations censored at 18 to 32 months. Median time to progression was 14.5 months. Grade 3 toxicities occurred in 32% with only one reported grade 4 (thrombosis) toxicity. Dehydroepiandrosterone sulfate declined by 89%, androstenedione by 56%, and testosterone by 66%, and dihydrotestosterone declined to below detectable levels compared with baseline levels with testicular suppression alone. Median baseline levels and declines in dehydroepiandrosterone sulfate, androstenedione, testosterone, and dihydrotestosterone were not statistically different in the responders versus nonresponders, and hormone levels were not significantly increased from nadir levels at relapse.


CONCLUSIONS
The response proportion to ketoconazole, hydrocortisone, and dutasteride was at least comparable with previous studies of ketoconazole alone, whereas time to progression was substantially longer. Combination therapies targeting multiple steps in androgen synthesis warrant further investigation.
Taplin
Mary-Ellen
ME
Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA 02115, USA.
Regan
Meredith M
MM
Ko
Yoo-Joung
YJ
Bubley
Glenn J
GJ
Duggan
Stephen E
SE
Werner
Lillian
L
Beer
Tomasz M
TM
Ryan
Christopher W
CW
Mathew
Paul
P
Tu
Shi-Ming
SM
Denmeade
Samuel R
SR
Oh
William K
WK
Sartor
Oliver
O
Mantzoros
Christos S
CS
Rittmaster
Roger
R
Kantoff
Philip W
PW
Balk
Steven P
SP
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000378:metabolism*; D001378:Azasteroids / Q000008:administration & dosage*; D042944:Cholestenone 5 alpha-Reductase / Q000378:metabolism; D000068538:Dutasteride; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage*; D007654:Ketoconazole / Q000008:administration & dosage*; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
D000728:Androgens; D001378:Azasteroids; C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase; D042944:Cholestenone 5 alpha-Reductase; D000068538:Dutasteride; D007654:Ketoconazole; D006854:Hydrocortisone