Use of adrenal androgen levels to predict response to ketoconazole in patients with androgen independent prostate cancer: Results from CALGB 9583.

4558 Background Adrenal androgens can activate the androgen receptor and stimulate prostate cancer growth. Because of its adrenolytic properties, ketoconazole (keto) is active as a secondary hormonal therapy in men with androgen-independent prostate cancer (AiPCa). The relationship between pre-treatment adrenal androgen levels and outcome after therapy with keto was therefore evaluated. Methods 260 patients with AiPCa were enrolled on CALGB 9583, a randomized trial of antiandrogen withdrawal (AAWD) compared to AAWD plus keto. 133 patients received initial keto, of which 103 had available baseline adrenal androgen levels, performed by a central laboratory. Androstedione (AON), dehydroepiandrostendione (DHEA) and DHEA-sulfate levels were measured. All patients were treated with antiandrogen withdrawal, keto 400 mg po tid, and hydrocortisone 40 mg po qd. Regression models (logistic and proportional hazard) were used to assess the prognostic significance of baseline adrenal androgen levels in predicting overall survival and PSA response defined by Consensus Criteria. Results In patients with available adrenal androgen levels, PSA response rate was 28% and median response duration was 4.76 months (Interquartile range 2.76-9.07). The median baseline AON level was 640 mcg/mL. The median AON for patients with and without a PSA response was 880 mcg/mL vs. 530 mcg/mL, Wilcoxon p = .034; and for patients with a duration of PSA response ≥ median vs. < median was 1080 vs. 550 mcg/dL, Wilcoxon p = .007. Conversely, elevation of baseline AON levels was predictive of PSA response (odds ratio = 2.26 [95% CI = 1.03-5.00, p = 0.043]). In a multivariate analysis, patients with AON levels > median had improved survival (hazard ratio for death 0.62, [95% CI = 0.39-0.96, log rank p = 0.032]). Conclusions AiPCa patients with higher baseline AON levels have a higher likelihood of response to keto, a longer duration of response, and improved survival compared with patients with lower AON levels. These data support a risk adapted approach to ketoconazole therapy based on baseline AON levels. No significant financial relationships to disclose.

Duke Scholars

Author Susan Halabi Biostatistics & Bioinformatics, Division of Biostatistics