A phase II study of mifepristone (RU-486) in castration-resistant prostate cancer, with a correlative assessment of androgen-related hormones.
OBJECTIVE
To evaluate mifepristone (RU-486) in patients with castration-resistant prostate cancer (CRPC), with a correlative assessment of serum androgens and androgen metabolites


METHODS
The androgen receptor (AR) is critical in the development and progression of prostate cancer, but available antiandrogens incompletely abrogate AR signalling. Mifepristone is a potent AR antagonist that functions by competing with androgen, preventing AR coactivator binding and by enhancing binding of AR corepressors. Patients with CRPC were treated with mifepristone 200 mg/day oral until disease progression. Testosterone, dihydrotestosterone (DHT), androstenedione, dihydroepiandrosterone sulphate and the testosterone metabolite 3 alpha-diol G, were measured at baseline and during therapy.


RESULTS
Nineteen patients were enrolled between April and August 2005; they were treated for a median (range) of 85 (31-338) days. The median prostate-specific antigen (PSA) level at enrollment was 22.0 (3.0-937.2) ng/mL. No patient had a PSA response (>50% reduction in PSA). Six patients had stable disease for a median of 5.5 months. After 1 month, adrenal androgens were increased and testosterone and DHT increased by 91% and 80%, respectively, compared to baseline.


CONCLUSIONS
Mifepristone had limited activity in patients with CRPC, and stimulated a marked increase in adrenal androgens, testosterone and DHT. We hypothesise that inhibition of glucocorticoid receptor by mifepristone resulted in an increase in adrenocorticotropic hormone and subsequent increase in adrenal androgens, and that their conversion by tumour cells to testosterone and DHT probably limited the efficacy of mifepristone. These data emphasize the continued importance of alternative androgen sources in AR signalling in CRPC.
Taplin
Mary-Ellen
ME
Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. mtaplin@partners.org
Manola
Judith
J
Oh
William K
WK
Kantoff
Philip W
PW
Bubley
Glenn J
GJ
Smith
Matthew
M
Barb
Diana
D
Mantzoros
Christos
C
Gelmann
Edward P
EP
Balk
Steven P
SP
D000368:Aged; D000369:Aged, 80 and over; D000728:Androgens / Q000378:metabolism; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D002369:Castration / Q000379:methods; D002450:Cell Communication / Q000187:drug effects; D018450:Disease Progression; D006727:Hormone Antagonists / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015735:Mifepristone / Q000627:therapeutic use*; D009362:Neoplasm Metastasis; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy*; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011944:Receptors, Androgen / Q000187:drug effects*; D016896:Treatment Outcome
D000728:Androgens; D018931:Antineoplastic Agents, Hormonal; D006727:Hormone Antagonists; D011944:Receptors, Androgen; D015735:Mifepristone; D017430:Prostate-Specific Antigen