Antiandrogen withdrawal alone or in combination with ketoconazole in androgen-independent prostate cancer patients: a phase III trial (CALGB 9583).
OBJECTIVE
Antiandrogen withdrawal (AAWD) results in a prostate-specific antigen (PSA) response (decline in PSA level of > or =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.


METHODS
AiPCa patients were randomized to undergo AAWD alone (n=132), or together with K (400 mg orally [p.o.] tid) and hydrocortisone (30 mg p.o. each morning, 10 mg p.o. 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.


CONCLUSIONS
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.
Small
Eric J
EJ
UCSF Comprehensive Cancer Center, University of California San Francisco, 1600 Divisadero St, Room A-718, San Francisco, CA 94115, USA. smalle@medicine.ucsf.edu
Halabi
Susan
S
Dawson
Nancy A
NA
Stadler
Walter M
WM
Rini
Brian I
BI
Picus
Joel
J
Gable
Preston
P
Torti
Frank M
FM
Kaplan
Ellen
E
Vogelzang
Nicholas J
NJ
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000556:secondary / Q000601:surgery; D000368:Aged; D000726:Androgen Antagonists / Q000008:administration & dosage* / Q000009:adverse effects; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D018572:Disease-Free Survival; D006801:Humans; D006854:Hydrocortisone / Q000008:administration & dosage; D007654:Ketoconazole / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D011446:Prospective Studies; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016019:Survival Analysis
D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D017430:Prostate-Specific Antigen; D007654:Ketoconazole; D006854:Hydrocortisone