PRESIDE (NCT02288247) 随机试验表明，在开始使用多西他赛的转移性去势抵抗性前列腺癌 (mCRPC) 患者中，持续使用恩杂鲁胺可延长无进展生存期 (PFS)。本研究旨在测试多西紫杉醇一个周期（周期 2 第 1 天 [C2D1]）前后 PFS 和循环肿瘤 DNA (ctDNA) 以及液体活检耐药生物标志物（LBRB；血浆雄激素受体 [AR] 增益）之间的关联和/或表达 AR 剪接变体 7 [CTC-AR-V7] 的循环肿瘤细胞 [CTC]，然后继续使用恩杂鲁胺/安慰剂。同意生物标志物亚组研究并在开始多西他赛与恩杂鲁胺/安慰剂之前献血的患者 (N = 157) ) 被包括在内。使用前列腺癌定制的下一代测序捕获面板 (PCF_SELECT) 对连续血浆 DNA 样本进行表征，并针对 AR-V7 评估 CTC（Epic Sc​​iences，圣地亚哥，加利福尼亚州，美国）。计算了 Cox 模型、Kaplan-Meier 和 18 个月的限制平均生存时间 (RMST)。不良 PFS 与多西紫杉醇前 ctDNA 检测存在显着相关性（N = 86 (55%)，8.1 vs 10.8 个月风险比[HR] = 1.78，p = 0.004) 或 C2D1 ctDNA 的持续/上升（N = 35/134，5.5 vs 10.9 个月，HR = 1.95，95% 置信区间 [CI] = 1.15-3.30，p = 0.019） 。 LBRB 阳性患者 (N = 62) 持续恩杂鲁胺联合多西他赛没有获益（HR = 0.78，95% CI = 0.41-1.48，p = 0.44；RMST：7.9 vs 7.1 个月，p = 0.50）。相反，耐药生物标志物阴性患者 (N = 87) 的 PFS 显着延长（HR = 0.49，95% CI = 0.29-0.82，p = 0.006；RMST：11.5 与 8.9 个月，p = 0.005）。八名患者无法评估。一项探索性分析发现，多西紫杉醇治疗进展时拷贝数增加 (CDK6/CDK4) 增加。局限性包括 CTC-AR-V7 的检出率相对较低。需要验证对总生存期的影响。液体活检可以早期表明多西他赛无效，可以指导患者选择继续恩杂鲁胺，并确定细胞周期基因改变是 mCRPC 中多西他赛耐药的潜在原因。在 PRESIDE 生物标志物研究中，我们研究发现，在开始用多西紫杉醇（化疗）治疗对雄激素剥夺疗法耐药的转移性前列腺癌后，检测血浆中的循环肿瘤 DNA 可以及早预测患者需要多长时间才能对治疗产生反应。液体活检耐药生物标志物呈阴性的患者（基于循环肿瘤细胞中雄激素受体 (AR) 基因和 AR 剪接变体 7 的状态）受益于持续恩杂鲁胺与多西紫杉醇的联合治疗，而耐药生物标志物呈阳性的患者则不然。此外，我们发现细胞周期基因 CDK6 和 CDK4 的改变是多西紫杉醇耐药的潜在遗传原因，这可能支持针对这些改变的特定药物的测试。版权所有 © 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

The PRESIDE (NCT02288247) randomized trial demonstrated prolonged progression-free survival (PFS) with continuing enzalutamide beyond progression in metastatic castration-resistant prostate cancer (mCRPC) patients starting docetaxel. This study aims to test the associations of PFS and circulating tumor DNA (ctDNA) prior to and after one cycle (cycle 2 day 1 [C2D1]) of docetaxel and with a liquid biopsy resistance biomarker (LBRB; plasma androgen receptor [AR] gain and/or circulating tumor cells [CTCs] expressing AR splice variant 7 [CTC-AR-V7]) prior to continuation of enzalutamide/placebo.Patients consenting to the biomarker substudy and donating blood before starting docetaxel with enzalutamide/placebo (N = 157) were included. Sequential plasma DNA samples were characterized with a prostate-cancer bespoke next-generation-sequencing capture panel (PCF_SELECT), and CTCs were assessed for AR-V7 (Epic Sciences, San Diego, CA, USA). Cox models, Kaplan-Meier, and restricted mean survival time (RMST) at 18 mo were calculated.There was a significant association of worse PFS with pre-docetaxel ctDNA detection (N = 86 (55%), 8.1 vs 10.8 mo hazard ratio [HR] = 1.78, p = 0.004) or persistence/rise of ctDNA at C2D1 (N = 35/134, 5.5 vs 10.9 mo, HR = 1.95, 95% confidence interval [CI] = 1.15-3.30, p = 0.019). LBRB-positive patients (N = 62) had no benefit from continuing enzalutamide with docetaxel (HR = 0.78, 95% CI = 0.41-1.48, p = 0.44; RMST: 7.9 vs 7.1 mo, p = 0.50). Conversely, resistance biomarker-negative patients (N = 87) had significantly prolonged PFS (HR = 0.49, 95% CI = 0.29-0.82, p = 0.006; RMST: 11.5 vs 8.9 mo, p = 0.005). Eight patients were unevaluable. An exploratory analysis identified increased copy-number gains (CDK6/CDK4) at progression on docetaxel. Limitations included relatively low detection of CTC-AR-V7. Validation of impact on overall survival is required.Liquid biopsy gives an early indication of docetaxel futility, could guide patient selection for continuing enzalutamide, and identifies cell cycle gene alterations as a potential cause of docetaxel resistance in mCRPC.In the PRESIDE biomarker study, we found that detecting circulating tumor DNA in plasma after starting treatment with docetaxel (chemotherapy) for metastatic prostate cancer resistant to androgen deprivation therapy can predict early how long patients will take to respond to treatment. Patients negative for a liquid biopsy resistance biomarker (based on the status of androgen receptor (AR) gene and AR splice variant 7 in circulating tumor cells) benefit from continuing enzalutamide in combination with docetaxel, while patients positive for the resistance biomarker did not. Additionally, we identified alterations in the cell cycle genes CDK6 and CDK4 as a potential genetic cause of resistance to docetaxel, which may support testing of specific drugs targeting these alterations.Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.