Mifepristone (RU-486) in androgen independent prostate cancer

Abstract

14508 Background: The androgen receptor (AR) plays a critical role in the development and progression of prostate cancer, and available antiandrogens do not turn off AR transcription completely. Mifepristone (RU-486) is a potent inhibitor of AR and acts by both competing with dihydrotestosterone (DHT) and binding with the AR co-repressor nuclear receptor co-repressor (NCoR), converting AR from a transcriptional activator to a transcriptional repressor. Methods: 22 patients with AIPC, PSA ≥5 ng/mL, and documented bone metastases were treated with mifepristone 200 mg PO QD until disease progression. Correlative studies include measurement of testosterone, cortisol, androstenedione, DHT, DHEA (dehydroepiandrosterone), and DHEA sulfate levels at baseline and during therapy. Results: Patients were treated a median of 84 days (range 10–182 d). Median PSA at time of enrollment was 41.9 ng/mL (range 5.2–1930.9 ng/mL). No patients demonstrated a PSA response. 13 patients have discontinued treatment, 12 for progressive disease (11 PSA progression and 1 bony progression) and 1 for grade 3 toxicity (GI bleed after 10 d on treatment). 6 patients are still on therapy with stable disease after a median 98 d. In 11 patients, baseline testosterone levels were mean 28.4 ng/dL (range <20–49 ng/dL). After one month of therapy, testosterone increased to mean 66.6 ng/dL (range 16–104 ng/dL) (p = 0.001). Compared to baseline, one month androstenedione and DHEAS levels were elevated in the majority of patients. Conclusions: Mifepristone demonstrated limited activity in AIPC patients. Potential efficacy was most likely limited by a rapid elevation in testosterone levels. We hypothesize that inhibition of glucocorticoid receptor led to an increase in ACTH with subsequent elevation of adrenal androgens and conversion to DHT. These preliminary data suggest that even moderate increases in systemic testosterone levels may stimulate tumor growth. These data also emphasize the continued importance of adrenal androgens and AR transcription in prostate cancer biology. No significant financial relationships to disclose.