Phase I clinical trial of a selective inhibitor of CYP17, abiraterone acetate, confirms that castration-resistant prostate cancer commonly remains hormone driven.
OBJECTIVE
Studies indicate that castration-resistant prostate cancer (CRPC) remains driven by ligand-dependent androgen receptor (AR) signaling. To evaluate this, a trial of abiraterone acetate-a potent, selective, small-molecule inhibitor of cytochrome P (CYP) 17, a key enzyme in androgen synthesis-was pursued.


METHODS
Chemotherapy-naïve men (n = 21) who had prostate cancer that was resistant to multiple hormonal therapies were treated in this phase I study of once-daily, continuous abiraterone acetate, which escalated through five doses (250 to 2,000 mg) in three-patient cohorts.


RESULTS
Abiraterone acetate was well tolerated. The anticipated toxicities attributable to a syndrome of secondary mineralocorticoid excess-namely hypertension, hypokalemia, and lower-limb edema-were successfully managed with a mineralocorticoid receptor antagonist. Antitumor activity was observed at all doses; however, because of a plateau in pharmacodynamic effect, 1,000 mg was selected for cohort expansion (n = 9). Abiraterone acetate administration was associated with increased levels of adrenocorticotropic hormone and steroids upstream of CYP17 and with suppression of serum testosterone, downstream androgenic steroids, and estradiol in all patients. Declines in prostate-specific antigen >or= 30%, 50%, and 90% were observed in 14 (66%), 12 (57%), and 6 (29%) patients, respectively, and lasted between 69 to >or= 578 days. Radiologic regression, normalization of lactate dehydrogenase, and improved symptoms with a reduction in analgesic use were documented.


CONCLUSIONS
CYP17 blockade by abiraterone acetate is safe and has significant antitumor activity in CRPC. These data confirm that CRPC commonly remains dependent on ligand-activated AR signaling.
Attard
Gerhardt
G
Royal Marsden NHS Foundation Trust, Sutton, Surrey, United Kingdom.
Reid
Alison H M
AH
Yap
Timothy A
TA
Raynaud
Florence
F
Dowsett
Mitch
M
Settatree
Sarah
S
Barrett
Mary
M
Parker
Christopher
C
Martins
Vanessa
V
Folkerd
Elizabeth
E
Clark
Jeremy
J
Cooper
Colin S
CS
Kaye
Stan B
SB
Dearnaley
David
D
Lee
Gloria
G
de Bono
Johann S
JS
D000230:Adenocarcinoma / Q000188:drug therapy*; D000284:Administration, Oral; D000368:Aged; D000369:Aged, 80 and over; D000736:Androstenes; D000737:Androstenols / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D002369:Castration; D018450:Disease Progression; D006801:Humans; D008297:Male; D008875:Middle Aged; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D011446:Prospective Studies; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D016896:Treatment Outcome
D000736:Androstenes; D000737:Androstenols; C089740:abiraterone