Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer.
Phase II study of androgen synthesis inhibition with ketoconazole, hydrocortisone, and dutasteride in asymptomatic castration-resistant prostate cancer.
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DOI：
10.1158/1078-0432.ccr-09-1722
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发表时间：
2009-11-15
期刊：
影响因子：
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通讯作者：
Balk SP
中科院分区：
文献类型：
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作者：
Taplin ME;Regan MM;Ko YJ;Bubley GJ;Duggan SE;Werner L;Beer TM;Ryan CW;Mathew P;Tu SM;Denmeade SR;Oh WK;Sartor O;Mantzoros CS;Rittmaster R;Kantoff PW;Balk SP
越来越多的证据表明，增强瘤内雄激素合成有助于雄激素剥夺治疗后前列腺癌的进展。这项II期研究旨在评估去势抵抗性前列腺癌（CRPC）患者使用CYP 17 A1（酮康唑）以及I型和II型5α-还原酶（度他雄胺）抑制剂阻断雄激素合成多个步骤的反应。57例CRPC男性患者继续接受性腺抑制治疗，并接受酮康唑（400 mg，每日三次）、氢化可的松（30 mg/AM，10 mg/PM）和度他雄胺（0.5 mg/d）治疗。前列腺特异性抗原应答率（下降≥50%）为56%（32/57; 95%置信区间，42.4-69.3%）;中位应答持续时间为20个月。在具有可测量疾病的患者中，20例患者中有6例（30%）根据实体瘤缓解评价标准缓解。中位治疗持续时间为8个月; 9例患者仍在接受治疗，治疗持续时间删失为18 - 32个月。中位进展时间为14.5个月。32%的患者发生3级毒性，仅报告1例4级（血栓形成）毒性。与单独睾丸抑制的基线水平相比，硫酸脱氢表雄酮下降了89%，雄烯二酮下降了56%，睾酮下降了66%，双氢睾酮下降到低于可检测水平。中位基线水平和硫酸脱氢表雄酮，雄烯二酮，睾酮和双氢睾酮下降无统计学差异的反应者与无反应者，激素水平没有显着增加，从最低水平复发。对酮康唑、氢化可的松和度他雄胺的反应比例至少与既往单用酮康唑的研究相当，而至进展时间显著延长。针对雄激素合成多个步骤的联合治疗需要进一步研究。(Clin Cancer Res 2009;15：7099-105）
Increasing evidence indicates that enhanced intratumoral androgen synthesis contributes to prostate cancer progression after androgen deprivation therapy. This phase II study was designed to assess responses to blocking multiple steps in androgen synthesis with inhibitors of CYP17A1 (ketoconazole) and type I and II 5α-reductases (dutasteride) in patients with castration-resistant prostate cancer (CRPC). Fifty-seven men with CRPC were continued on gonadal suppression and treated with ketoconazole (400 mg thrice daily), hydrocortisone (30 mg/AM, 10 mg/PM), and dutasteride (0.5 mg/d). Prostate-specific antigen response rate (≥50% decline) was 56% (32 of 57; 95% confidence interval, 42.4–69.3%); the median duration of response was 20 months. In patients with measurable disease, 6 of 20 (30%) responded by the Response Evaluation Criteria in Solid Tumors. Median duration of treatment was 8 months; 9 patients remained on therapy with treatment durations censored at 18 to 32 months. Median time to progression was 14.5 months. Grade 3 toxicities occurred in 32% with only one reported grade 4 (thrombosis) toxicity. Dehydroepiandrosterone sulfate declined by 89%, androstenedione by 56%, and testosterone by 66%, and dihydrotestosterone declined to below detectable levels compared with baseline levels with testicular suppression alone. Median baseline levels and declines in dehydroepiandrosterone sulfate, androstenedione, testosterone, and dihydrotestosterone were not statistically different in the responders versus nonresponders, and hormone levels were not significantly increased from nadir levels at relapse. The response proportion to ketoconazole, hydrocortisone, and dutasteride was at least comparable with previous studies of ketoconazole alone, whereas time to progression was substantially longer. Combination therapies targeting multiple steps in androgen synthesis warrant further investigation. (Clin Cancer Res 2009;15:7099–105)