Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: A phase III trial (CALGB 9583). Small EJ, Halabi S, Dawson NA, Stadler WM, Rini BI, Picus J, Gable P, Torti FM, Kaplan E, Vogelzang NJ, UCSF Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA.J Clin Oncol 2004;22:1025–33

Abstract

Antiandrogen withdrawal (AAWD) results in a prostate-specific antigen (PSA) response (decline in PSA level of ≥50%) in 15% to 30% of androgen-independent prostate cancer (AiPCa) patients. Thereafter, adrenal androgen ablation with agents such as ketoconazole (K) is commonly utilized. The therapeutic effect of AAWD alone was compared with simultaneous AAWD and K therapy. AiPCa patients were randomized to undergo AAWD alone (n = 132), or together with K (400 mg orally [po] tid) and hydrocortisone (30 mg po each morning, 10 mg po each evening; n = 128). Patients who developed progressive disease after AAWD alone were eligible for deferred treatment with K. Eleven percent of patients undergoing AAWD alone had a PSA response, compared to 27% of patients who underwent AAWD and simultaneous K (P = .0002). Objective responses were observed in 2% of patients treated with AAWD alone compared to 20% in patients treated with AAWD/K (P = .02). There was no difference in survival. PSA and objective responses were observed in 32% and 7%, respectively, of patients receiving deferred K, and were more common in patients with prior AAWD response. Treatment with K was well tolerated, and resulted in a decline in adrenal androgen levels, which rose at the time of disease progression. K has modest activity in AiPCa patients, while AAWD alone has minimal activity. Adrenal androgen levels fall with treatment with K and then climb at the time of progression, suggesting that progressive disease while on K may be due to tachyphylaxis to the adrenolytic properties of K.