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Antiandrogen Withdrawal Alone or in Combination With Ketoconazole in Androgen-Independent Prostate Cancer Patients: A Phase III Trial (CALGB 9583)

From the University of California San Francisco, San Francisco, and US Naval Medical Center, University of California San Diego, San Diego, CA; Cancer and Leukemia Group B Statistical Center, Duke University Medical Center, Durham, and Wake Forest Comprehensive Cancer Center, Winston-Salem, NC; Greenebaum Cancer Center, University of Maryland, Baltimore, MD; University of Chicago Medical Center, Chicago, IL; and Washington University Barnard Cancer Center, St Louis, MO

Address reprint requests to Eric J. Small, MD, UCSF Comprehensive Cancer Center, University of California San Francisco, 1600 Divisadero St, Room A-718, San Francisco, CA 94115; e-mail: smalle{at}medicine.ucsf.edu

PURPOSE: 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.

PATIENTS AND METHODS: 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.

RESULTS: 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.

CONCLUSION: 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.

Supported by grants CA60138 (E.J.S. and B.I.R.), CA47577 (S.H. and E.K.), CA31983 (N.A.D.), CA41287 (W.M.S. and N.J.V.), CA77440 (J.P.), CA11789 (P.G.), and CA03927 (F.M.T.). The research for Cancer and Leukemia Group B Trial 9583 was supported, in part, by grants from the National Cancer Institute (CA31946) to the Cancer and Leukemia Group B (Richard L. Schilsky, MD, Chairman). The research was also supported by Janssen Pharmaceutica Products, LP.

Presented in part at the American Society of Clinical Oncology annual meeting, San Francisco, CA, May 12-15, 2001.

The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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