Lack of Effect of Aminoglutethimide and Hydrocortisone Added to High-Dose Bicalutamide for Androgen-Independent Prostate Cancer

Objectives: To determine whether hormones derived from the adrenal gland affected the progression of androgen-independent (AI) prostate cancer for patients already receiving treatment with high-dose bicalutamide. This was accomplished by using a sequential trial design in which medically or surgically castrated patients with AI prostate cancer whose cancers were progressing while receiving bicalutamide were treated with adrenolytic therapy in the form of aminoglutethimide (AM) and hydrocortisone (HC). Materials and Methods: Sixteen patients with AI prostate cancer were enrolled into this trial. All patients had metastatic disease in the bone, and two patients had additional metastases at other sites. Using prostate specific antigen (PSA) level as an indicator of disease activity, patients initially received bicalutamide therapy, then AM and HC were added to the regimen, and then bicalutamide therapy was discontinued, with each documented PSA level increase (see Figure 1). Figure 1. Clinical Trial Study Design: Patients were treated with sequential hormonal interventions according to the scheme depicted above. Download figure to PowerPoint Results: Four (25%) patients demonstrated PSA level reductions of at least 50% after the initiation of bicalutamide, 150 mg/day. No patient demonstrated a PSA or obvious clinical response to the addition of AM and HC to the regimen. This includes the four patients who were initially sensitive to bicalutamide. Therapy with AM and HC was associated with fatigue and skin rashes. These side effects persisted after the withdrawal of bicalutamide therapy and were therefore attributed to AM and HC therapy. Conclusions: Bicalutamide at high doses seems to effectively block the androgen receptor (AR) from the growth stimulation derived from adrenal hormones. Therefore, the inhibition of adrenal hormone production by AM is not a useful therapeutic maneuver in this setting and is associated with moderate side effects. The activation of the AR pathway in these patients may occur by a mechanism other than stimulation by the androgens derived from the testes or adrenal gland.