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A phase II study of mifepristone (RU‐486) in castration‐resistant prostate cancer, with a correlative assessment of androgen‐related hormones
Author(s) -
Taplin MaryEllen,
Manola Judith,
Oh William K.,
Kantoff Philip W.,
Bubley Glenn J.,
Smith Matthew,
Barb Diana,
Mantzoros Christos,
Gelmann Edward P.,
Balk Steven P.
Publication year - 2008
Publication title -
bju international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.773
H-Index - 148
eISSN - 1464-410X
pISSN - 1464-4096
DOI - 10.1111/j.1464-410x.2008.07509.x
Subject(s) - medicine , testosterone (patch) , mifepristone , prostate cancer , endocrinology , androgen , androgen receptor , dihydrotestosterone , hormone , cancer , biology , pregnancy , genetics
OBJECTIVE To evaluate mifepristone (RU‐486) in patients with castration‐resistant prostate cancer (CRPC), with a correlative assessment of serum androgens and androgen metabolites PATIENTS AND 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 3α‐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 enrolment 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. CONCLUSION 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.