Russell Z. Szmulewitz, Abiola Ibraheem, Elia Martinez, Mark F. Kozloff, Chadi Nabhan, Theodore Karrison, Walter M. Stadler, and Mark J. Ratain, The University of Chicago, Chicago; Mark F. Kozloff, Ingalls Hospital, Harvey; Paul Fishkin, Illinois Cancer Care, Peoria, IL; Cody J. Peer and William D. Figg, National Cancer Institute, Rockville, MD; Bradley Carthon and R. Donald Harvey, Winship Cancer Institute of Emory University, Atlanta, GA; and Wei Peng Yong and Edmund Chiong, National University Cancer Institute, Singapore, Singapore.
J Clin Oncol. 2018 May 10;36(14):1389-1395. doi: 10.1200/JCO.2017.76.4381. Epub 2018 Mar 28.
Purpose Abiraterone acetate (AA) is a standard of care for metastatic castration-resistant prostate cancer (CRPC). Despite a large food effect, AA was administered under fasting conditions in its pivotal trials. We sought to test the hypothesis that low-dose AA (LOW; 250 mg with a low-fat meal) would have comparable activity to standard AA (STD; 1,000 mg fasting) in patients with CRPC. Patients and Methods Patients (n = 72) with progressive CRPC from seven institutions in the United States and Singapore were randomly assigned to STD or LOW. Both arms received prednisone 5 mg twice daily. Prostate-specific antigen (PSA) was assessed monthly, and testosterone/dehydroepiandrosterone sulfate were assessed every 12 weeks with disease burden radiographic assessments. Plasma was collected for drug concentrations. Log change in PSA, as a pharmacodynamic biomarker for efficacy, was the primary end point, using a noninferiority design. Progression-free survival (PFS), PSA response (≥ 50% reduction), change in androgen levels, and pharmacokinetics were secondary end points. Results Thirty-six patients were accrued to both arms. At 12 weeks, there was a greater effect on PSA in the LOW arm (mean log change, -1.59) compared with STD (-1.19), and noninferiority of LOW was established according to predefined criteria. The PSA response rate was 58% in LOW and 50% in STD, and the median PFS was approximately 9 months in both groups. Androgen levels decreased similarly in both arms. Although there was no difference in PSA response or PFS, abiraterone concentrations were higher in STD. Conclusion Low-dose AA (with low-fat breakfast) is noninferior to standard dosing with respect to PSA metrics. Given the pharmacoeconomic implications, these data warrant consideration by prescribers, payers, and patients. Additional studies are indicated to assess the long-term efficacy of this approach.
目的 醋酸阿比特龙（AA）是转移性去势抵抗性前列腺癌（CRPC）的标准治疗方法。尽管存在较大的食物效应，但在其关键试验中，AA 仍在禁食条件下给药。我们试图检验以下假设，即低剂量 AA（LOW；250mg 与低脂肪餐）在 CRPC 患者中的活性与标准 AA（STD；1000mg 禁食）相当。
方法 来自美国和新加坡的 7 个机构的 72 例进展性 CRPC 患者被随机分配至 STD 或 LOW 组。两组均接受泼尼松 5mg，每日 2 次。每月评估前列腺特异性抗原（PSA），每 12 周评估一次睾酮/硫酸脱氢表雄酮，并进行疾病负担影像学评估。采集血浆用于药物浓度检测。作为疗效的药效学生物标志物，PSA 的对数变化是主要终点，采用非劣效性设计。无进展生存期（PFS）、PSA 反应（≥50%降低）、雄激素水平变化和药代动力学是次要终点。
结果 两组均入组 36 例患者。12 周时，LOW 组 PSA 下降更明显（平均对数变化为-1.59），而 STD 组为-1.19，根据预设标准，LOW 的非劣效性得到确立。LOW 组 PSA 反应率为 58%，STD 组为 50%，两组的中位 PFS 均约为 9 个月。两组的雄激素水平下降相似。尽管 PSA 反应或 PFS 无差异，但 STD 组的阿比特龙浓度较高。
结论 低剂量 AA（与低脂早餐一起）在 PSA 指标方面与标准剂量相当。鉴于药物经济学的影响，这一数据值得临床医生、支付者和患者考虑。需要进一步的研究来评估这种方法的长期疗效。
