TY - JOUR
T1 - Contemporary experience with ketoconazole in patients with metastatic castration-resistant prostate cancer
T2 - Clinical factors associated with PSA response and disease progression
AU - Keizman, Daniel
AU - Huang, Peng
AU - Carducci, Michael A.
AU - Eisenberger, Mario A.
PY - 2012/3
Y1 - 2012/3
N2 - BACKGROUND Adrenal/intratumoral androgen biosynthesis contributes to ligand-dependent androgen receptor activation in metastatic castration-resistant prostate cancer (mCRCP). Compounds targeting CYP-17 hydroxylase and lyase, as ketoconazole and abiraterone, block adrenal/intratumoral androgen biosynthesis, and are used as sequential endocrine approaches in mCRCP. We aimed to describe contemporary experience and association of clinical factors with Prostate specific antigen (PSA) response and disease progression, in mCRPC progressing on GnRH-agonist, antiandrogen, antiandrogen withdrawal, and treated with ketoconazole. METHODS Data were retrospectively analyzed in all mCRPC patients treated with ketoconazole. Patients continued GnRH-agonist, and treated with ketoconazole 200-400 mg 3Ã- a day until dose-limiting toxicity or disease progression. A multivariate cox regression model was used to identify clinical factors associated with PSA response and disease progression. RESULTS From 1999 to 2010, 114 mCRPC patients were treated with ketoconazole. With a median follow-up time of 31 months (range 5-129), 25 patients (22%) had grade 3/4 toxicity, most commonly fatigue, abdominal discomfort, nausea, and dizziness. Sixty-one patients (54%) had ≥50% PSA decline. Median time to progression was 8 months (range 1-129). Factors associated with PSA response and disease progression were response to prior antiandrogen (≥6 vs. <6 months), pre-treatment PSADT (≥3 vs. <3 months) and extent of disease (limited-axial skeleton and/or nodal vs. extensive-appendicular skeleton and/or visceral). CONCLUSIONS Ketoconazole is effective and safe in mCRPC. Prior response to antiandrogen, pre-treatment PSADT, and disease extent are associated with PSA response and disease progression, and further supports a therapeutic role in suppressing adrenal androgens in mCRPC.
AB - BACKGROUND Adrenal/intratumoral androgen biosynthesis contributes to ligand-dependent androgen receptor activation in metastatic castration-resistant prostate cancer (mCRCP). Compounds targeting CYP-17 hydroxylase and lyase, as ketoconazole and abiraterone, block adrenal/intratumoral androgen biosynthesis, and are used as sequential endocrine approaches in mCRCP. We aimed to describe contemporary experience and association of clinical factors with Prostate specific antigen (PSA) response and disease progression, in mCRPC progressing on GnRH-agonist, antiandrogen, antiandrogen withdrawal, and treated with ketoconazole. METHODS Data were retrospectively analyzed in all mCRPC patients treated with ketoconazole. Patients continued GnRH-agonist, and treated with ketoconazole 200-400 mg 3Ã- a day until dose-limiting toxicity or disease progression. A multivariate cox regression model was used to identify clinical factors associated with PSA response and disease progression. RESULTS From 1999 to 2010, 114 mCRPC patients were treated with ketoconazole. With a median follow-up time of 31 months (range 5-129), 25 patients (22%) had grade 3/4 toxicity, most commonly fatigue, abdominal discomfort, nausea, and dizziness. Sixty-one patients (54%) had ≥50% PSA decline. Median time to progression was 8 months (range 1-129). Factors associated with PSA response and disease progression were response to prior antiandrogen (≥6 vs. <6 months), pre-treatment PSADT (≥3 vs. <3 months) and extent of disease (limited-axial skeleton and/or nodal vs. extensive-appendicular skeleton and/or visceral). CONCLUSIONS Ketoconazole is effective and safe in mCRPC. Prior response to antiandrogen, pre-treatment PSADT, and disease extent are associated with PSA response and disease progression, and further supports a therapeutic role in suppressing adrenal androgens in mCRPC.
KW - PSA response
KW - disease progression
KW - ketoconazole
KW - metastatic castration-resistant prostate cancer
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U2 - 10.1002/pros.21447
DO - 10.1002/pros.21447
M3 - Review article
C2 - 21688281
AN - SCOPUS:84856053991
SN - 0270-4137
VL - 72
SP - 461
EP - 467
JO - Prostate
JF - Prostate
IS - 4
ER -