Urologic Oncology Program, University of California, San Francisco, San Francisco, CA 94115, USA.
J Clin Oncol. 2010 Mar 20;28(9):1481-8. doi: 10.1200/JCO.2009.24.1281. Epub 2010 Feb 16.
Abiraterone acetate is a prodrug of abiraterone, a selective inhibitor of CYP17, the enzyme catalyst for two essential steps in androgen biosynthesis. In castration-resistant prostate cancers (CRPCs), extragonadal androgen sources may sustain tumor growth despite a castrate environment. This phase I dose-escalation study of abiraterone acetate evaluated safety, pharmacokinetics, and effects on steroidogenesis and prostate-specific antigen (PSA) levels in men with CPRC with or without prior ketoconazole therapy.
Thirty-three men with chemotherapy-naïve progressive CRPC were enrolled. Nineteen patients (58%) had previously received ketoconazole for CRPC. Bone metastases were present in 70% of patients, and visceral involvement was present in 18%. Three patients (9%) had locally advanced disease without distant metastases. Fasted or fed cohorts received abiraterone acetate doses of 250, 500, 750, or 1,000 mg daily. Single-dose pharmacokinetic analyses were performed before continuous daily dosing.
Adverse events were predominantly grade 1 or 2. No dose-limiting toxicities were observed. Hypertension (grade 3, 12%) and hypokalemia (grade 3, 6%; grade 4, 3%) were the most frequent serious toxicities and responded to medical management. Confirmed > or = 50% PSA declines at week 12 were seen in 18 (55%) of 33 patients, including nine (47%) of 19 patients with prior ketoconazole therapy and nine (64%) of 14 patients without prior ketoconazole therapy. Substantial declines in circulating androgens and increases in mineralocorticoids were seen with all doses.
Abiraterone acetate was well tolerated and demonstrated activity in CRPC, including in patients previously treated with ketoconazole. Continued clinical study is warranted.
醋酸阿比特龙是阿比特龙的前体药物，是细胞色素 P45017（CYP17）的选择性抑制剂，该酶是雄激素生物合成两个关键步骤的酶催化剂。在去势抵抗性前列腺癌（CRPC）中，尽管存在去势环境，但外源性雄激素来源可能会维持肿瘤生长。这项醋酸阿比特龙的 I 期剂量递增研究评估了醋酸阿比特龙在有或没有酮康唑治疗史的 CRPC 男性中的安全性、药代动力学、对类固醇生成和前列腺特异性抗原（PSA）水平的影响。
33 名化疗初治进展性 CRPC 男性患者入组。19 名患者（58%）之前接受酮康唑治疗 CRPC。70%的患者存在骨转移，18%的患者存在内脏转移。3 名患者（9%）患有局部晚期疾病，无远处转移。空腹或进食组患者每天接受醋酸阿比特龙 250、500、750 或 1000mg 治疗。在连续每日给药前进行单次剂量药代动力学分析。
不良事件主要为 1 级或 2 级。未观察到剂量限制毒性。最常见的严重毒性为高血压（3 级，12%）和低钾血症（3 级，6%；4 级，3%），经医学治疗后得到缓解。33 名患者中有 18 名（55%）在第 12 周时确认 PSA 下降≥50%，其中 19 名有酮康唑治疗史的患者中有 9 名（47%），14 名无酮康唑治疗史的患者中有 9 名（64%）。所有剂量均可见循环雄激素显著下降和盐皮质激素增加。
醋酸阿比特龙耐受性良好，在 CRPC 中显示出疗效，包括在先前接受酮康唑治疗的患者中。需要进一步的临床研究。
