Department of Pharmacy, Radboud university medical center, Radboud Institute for Health Sciences, Nijmegen, The Netherlands.
Department for Heath Evidence, Radboud university medical center, Nijmegen, The Netherlands.
Br J Clin Pharmacol. 2022 Mar;88(3):1170-1178. doi: 10.1111/bcp.15057. Epub 2021 Oct 8.
To assess whether the exposure-response relation for abiraterone is different in pre-chemotherapy patients compared to post-chemotherapy patients with metastatic castration-resistant prostate cancer (mCRPC).
Data were collected from three clinical studies in mCRPC patients treated with abiraterone acetate. Cox regression analysis was used to determine the relation between abiraterone exposure and survival (progression-free survival [PFS] and overall survival [OS]). An interaction term was used to test whether chemotherapy pretreatment was an effect modifier. To investigate the effect of the previously defined exposure threshold of 8.4 ng/mL on survival, Kaplan-Meier analysis was used.
In total, 98 mCRPC patients were included, of which 78 were pre-chemotherapy and 20 were post-chemotherapy patients. Chemotherapy pretreatment in mCRPC setting appears to be an effect modifier. In pre-chemotherapy patients, no significant association between abiraterone exposure and survival was observed (HR 0.68 [95% CI 0.42-1.10], P = .12 and HR 0.85 [95% CI 0.46-1.60], P = .61, PFS and OS, respectively) and no longer survival was seen for patients with an abiraterone exposure above the predefined threshold. In contrast, a significant association was seen in post-chemotherapy patients (HR 0.30 [95% CI 0.12-0.74], P = .01 and HR 0.38 [95% CI 0.18-0.82] P = .01, PFS and OS, respectively), with an increased survival when exposed above this threshold.
Chemotherapy pretreatment in mCRPC setting modifies the abiraterone exposure-response relation. No relation between abiraterone exposure and survival was seen for pre-chemotherapy patients. Therefore, potentially lower doses can be used in this setting to prevent overtreatment and reduce financial toxicity.
评估醋酸阿比特龙在转移性去势抵抗性前列腺癌（mCRPC）患者中的暴露-反应关系是否因化疗前和化疗后而有所不同。
从接受醋酸阿比特龙治疗的 mCRPC 患者的三项临床研究中收集数据。采用 Cox 回归分析来确定阿比特龙暴露与生存（无进展生存期[PFS]和总生存期[OS]）之间的关系。采用交互项检验化疗预处理是否为效应修饰因子。为了研究之前定义的 8.4ng/ml 暴露阈值对生存的影响，采用 Kaplan-Meier 分析。
共纳入 98 例 mCRPC 患者，其中 78 例为化疗前患者，20 例为化疗后患者。在 mCRPC 治疗中，化疗预处理似乎是一个效应修饰因子。在化疗前患者中，阿比特龙暴露与生存之间无显著相关性（HR 0.68 [95%CI 0.42-1.10]，P=0.12 和 HR 0.85 [95%CI 0.46-1.60]，P=0.61，PFS 和 OS），且预先设定的暴露阈值以上的患者生存情况未见改善。相比之下，在化疗后患者中观察到了显著的相关性（HR 0.30 [95%CI 0.12-0.74]，P=0.01 和 HR 0.38 [95%CI 0.18-0.82]，P=0.01，PFS 和 OS），且暴露于该阈值以上时，生存时间延长。
在 mCRPC 治疗中，化疗预处理改变了阿比特龙的暴露-反应关系。化疗前患者的阿比特龙暴露与生存之间无关联。因此，在这种情况下，可能可以使用较低的剂量，以防止过度治疗和降低经济毒性。
