Adrenal androgen levels as predictors of outcome in castration‐resistant prostate cancer patients treated with combined androgen blockade using flutamide as a second‐line anti‐androgen

Objectives:  To analyze the clinical effects of flutamide as a second-line anti-androgen for combined androgen blockade in patients with castration-resistant prostate cancer (CRPC) initially treated with bicalutamide as a first-line anti-androgen. Methods:  Our study population consisted of 16 patients with CRPC who were treated with flutamide (375 mg daily) as second-line hormonal therapy. Dehydroepiandrosterone (DHEA), androstenedione, androstenediol, testosterone and dihydrotestosterone were measured to investigate the relationship between plasma androgens and outcome following treatment. Furthermore, adrenal androgen levels in a medium of adrenal cancer cell line were also measured. Results:  Second-line hormonal therapy using flutamide resulted in a reduction of the prostate-specific antigen (PSA) level in 14 (87.5%) of 16 patients. A PSA decline greater than 50% was observed in 8 (50%) of the 16 patients. The duration of median responsiveness was 6.25 months. PSA elevation of baseline androstenediol level was a predictive factor of PSA responsiveness. The lower DHEA group improved the duration of responsiveness to flutamide. In vitro, 3 µmol/L flutamide suppressed DHEA, androstenedione and androstenediol synthesis compared with bicalutamide in a medium of adrenal cancer cell line. Conclusions:  Our data show that flutamide suppresses the adrenal androgens in comparison with bicalutamide. The responsiveness and response duration of flutamide can be predicted in patients with a higher baseline androstenediol level and a lower DHEA level. Metabolites from adrenal androgens contribute to the progression of prostate cancer.