Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, Houston, TX, USA; Department of Clinical Therapeutics, University of Athens, Athens, Greece.
Department of Genitourinary Medical Oncology, Stanford Alexander Tissue Derivatives Laboratory, David H. Koch Center for Applied Research of Genitourinary Cancers, Houston, TX, USA.
Eur Urol Oncol. 2020 Feb;3(1):119-127. doi: 10.1016/j.euo.2019.01.008. Epub 2019 Apr 20.
It is hypothesised that cotargeting the androgen receptor (AR) and paracrine androgen biosynthesis with enzalutamide and abiraterone acetate in metastatic castration-resistant prostate cancer (mCRPC) will dissipate adaptive feedback loops observed with either agent alone.
To assess the safety, efficacy, androgen signalling/metabolome, and drug-drug interactions (DDIs) of enzalutamide with abiraterone acetate in progressive bone mCRPC (bmCRPC).
DESIGN, SETTING, AND PARTICIPANTS: This open-label, single-centre interventional study was conducted in bmCRPC patients.
Enzalutamide 160mg and abiraterone acetate 1000mg once daily; prednisone 5mg twice daily.
Adverse events (AEs), prostate-specific antigen (PSA) response, progression-free survival (PFS), tumour biomarker/metabolite expression, and C plasma concentrations were evaluated.
Sixty patients were enrolled. Common AEs independent of grade/causality included fatigue (72%), hyperglycaemia (67%), alkaline phosphatase (ALP) elevation (53%), and hot flush (43%). Grade 3 AEs included hypertension (17%), alanine aminotransferase elevation (12%), ALP elevation (5%), and arthralgia (5%). No treatment-related grade 4 AEs or deaths were reported. Median treatment-discontinuation time was 312d (95% confidence interval [CI] 196.0-483.0). Maximal PSA decline ≥50% and ≥90% occurred in 46 (77%) and 29 (48%) patients, respectively. Median PFS was 251d (95% CI 147-337). At week 9, median tumour microenvironment androgens, precursors, and nuclear AR expression decreased (p<0.001). The baseline tumour AR C/N terminal ratio of ≥80% was associated with treatment benefit. At enzalutamide steady state, abiraterone acetate C was ∼23% lower (range 14.05-200.5ng/ml) than when given alone.
Enzalutamide combined with abiraterone acetate has a manageable safety profile, without a meaningful DDI. Both agents are pharmacodynamically active with no feedback. Efficacy findings do not support significant benefit of combined treatment for unselected bmCRPC.
This is the first study combining enzalutamide plus abiraterone in bone metastatic castration-resistant prostate cancer. Results show that this combination is safe.
雄激素受体（AR）和旁分泌雄激素生物合成的双重靶向治疗在转移性去势抵抗性前列腺癌（mCRPC）中，可能会消除单独使用任一药物时观察到的适应性反馈回路。
评估恩扎卢胺联合醋酸阿比特龙在进展性骨转移去势抵抗性前列腺癌（bmCRPC）中的安全性、疗效、雄激素信号/代谢组学和药物相互作用（DDI）。
设计、地点和参与者：这是一项在 bmCRPC 患者中进行的开放标签、单中心干预性研究。
恩扎卢胺 160mg 和醋酸阿比特龙 1000mg 每日一次；泼尼松 5mg 每日两次。
评估不良事件（AE）、前列腺特异性抗原（PSA）反应、无进展生存期（PFS）、肿瘤生物标志物/代谢物表达和 C 血浆浓度。
共纳入 60 例患者。与等级/因果关系无关的常见 AE 包括疲劳（72%）、高血糖（67%）、碱性磷酸酶（ALP）升高（53%）和热潮红（43%）。3 级 AE 包括高血压（17%）、丙氨酸氨基转移酶升高（12%）、ALP 升高（5%）和关节痛（5%）。未报告与治疗相关的 4 级 AE 或死亡。中位治疗停药时间为 312d（95%置信区间 [CI] 196.0-483.0）。最大 PSA 下降≥50%和≥90%分别发生在 46（77%）和 29（48%）例患者中。中位 PFS 为 251d（95% CI 147-337）。在第 9 周时，肿瘤微环境雄激素、前体和核 AR 表达均下降（p<0.001）。基线肿瘤 AR C/N 端比值≥80%与治疗获益相关。在恩扎卢胺稳态时，阿比特龙 C 降低约 23%（范围 14.05-200.5ng/ml），低于单独使用时的水平。
恩扎卢胺联合醋酸阿比特龙具有可管理的安全性，无明显药物相互作用。两种药物均具有药效学活性，无反馈。疗效结果不支持联合治疗对未选择的 bmCRPC 有显著获益。
这是第一项联合恩扎卢胺加阿比特龙治疗骨转移去势抵抗性前列腺癌的研究。结果表明该联合治疗是安全的。
