Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY.
Alliance Statistics and Data Management Center, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY.
J Clin Oncol. 2023 Jun 20;41(18):3352-3362. doi: 10.1200/JCO.22.02394. Epub 2023 Mar 30.
Enzalutamide and abiraterone both target androgen receptor signaling but via different mechanisms. The mechanism of action of one drug may counteract the resistance pathways of the other. We sought to determine whether the addition of abiraterone acetate and prednisone (AAP) to enzalutamide prolongs overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the first-line setting.
Men with untreated mCRPC were randomly assigned (1:1) to receive first-line enzalutamide with or without AAP. The primary end point was OS. Toxicity, prostate-specific antigen declines, pharmacokinetics, and radiographic progression-free survival (rPFS) were also examined. Data were analyzed using an intent-to-treat approach. The Kaplan-Meier estimate and the stratified log-rank statistic were used to compare OS between treatments.
In total, 1,311 patients were randomly assigned: 657 to enzalutamide and 654 to enzalutamide plus AAP. OS was not statistically different between the two arms (median, 32.7 [95% CI, 30.5 to 35.4] months for enzalutamide 34.2 [95% CI, 31.4 to 37.3] months for enzalutamide and AAP; hazard ratio [HR], 0.89; one-sided = .03; boundary nominal significance level = .02). rPFS was longer in the combination arm (median rPFS, 21.3 [95% CI, 19.4 to 22.9] months for enzalutamide 24.3 [95% CI, 22.3 to 26.7] months for enzalutamide and AAP; HR, 0.86; two-sided = .02). However, pharmacokinetic clearance of abiraterone was 2.2- to 2.9-fold higher when administered with enzalutamide, compared with clearance values for abiraterone alone.
The addition of AAP to enzalutamide for first-line treatment of mCRPC was not associated with a statistically significant benefit in OS. Drug-drug interactions between the two agents resulting in increased abiraterone clearance may partly account for this result, although these interactions did not prevent the combination regimen from having more nonhematologic toxicity.
恩扎鲁胺和阿比特龙均靶向雄激素受体信号，但作用机制不同。一种药物的作用机制可能会抵消另一种药物的耐药途径。我们旨在确定在一线治疗转移性去势抵抗性前列腺癌（mCRPC）患者中，加用醋酸阿比特龙和泼尼松（AAP）是否能延长恩扎鲁胺的总生存期（OS）。
未经治疗的 mCRPC 男性患者被随机（1:1）分配接受一线恩扎鲁胺联合或不联合 AAP 治疗。主要终点为 OS。还检查了毒性、前列腺特异性抗原下降、药代动力学和放射学无进展生存期（rPFS）。采用意向治疗分析数据。Kaplan-Meier 估计和分层对数秩检验用于比较两种治疗方法的 OS。
共有 1311 例患者被随机分配：657 例接受恩扎鲁胺治疗，654 例接受恩扎鲁胺联合 AAP 治疗。两组之间的 OS 无统计学差异（中位 OS，恩扎鲁胺组为 32.7 [95% CI，30.5 至 35.4] 个月；恩扎鲁胺和 AAP 组为 34.2 [95% CI，31.4 至 37.3] 个月；风险比 [HR]，0.89；单侧 =.03；边界名义显著性水平 =.02）。联合组的 rPFS 更长（中位 rPFS，恩扎鲁胺组为 21.3 [95% CI，19.4 至 22.9] 个月；恩扎鲁胺和 AAP 组为 24.3 [95% CI，22.3 至 26.7] 个月；HR，0.86；双侧 =.02）。然而，与单独使用阿比特龙相比，当与恩扎鲁胺联合使用时，阿比特龙的药代动力学清除率增加了 2.2 至 2.9 倍。
在一线治疗 mCRPC 中，加用 AAP 不能显著提高恩扎鲁胺的 OS。两种药物之间的药物相互作用导致阿比特龙清除率增加，可能部分解释了这一结果，尽管这些相互作用并未阻止联合治疗方案产生更多的非血液学毒性。
