转移性去势抵抗性前列腺癌 (mCRPC) 通常采用直接或间接靶向雄激素受体 (AR) 途径的药物进行治疗。然而，这种治疗受到耐药机制的限制，包括 AR 配体结合域 (AR-LBD) 中激活突变的发展。这项研究评估了超过 15,000 名接受综合循环肿瘤治疗的晚期前列腺癌 (PC) 患者的数据库2014 年至 2021 年间的 DNA 分析（Guardant360，雷德伍德城，加利福尼亚州），以及来自行政索赔的相关临床信息（GuardantINFORM 数据库）。在 15,705 名 PC 患者中，54% 在抽血时患有 mCRPC。其中，49% 的人之前接受过 AR 通路抑制剂 (ARPi) 治疗。在未接受下一代 ARPi 治疗的 mCRPC 患者中，AR-LBD 突变患病率为 15%，在接受过一种 ARPi 治疗的患者中为 22%，在接受过两线 ARPi 治疗后的患者中为 24%。下一代 ARPi 治疗在阿比特龙治疗后导致 AR L702H 和 T878A/S 突变增加，在恩杂鲁胺治疗后导致 AR L702H 和 F877L 突变增加。 AR-LBD 患者表现出独特的生物学特性，包括细胞周期并发突变增加、无翅相关整合位点、同源重组修复和磷酸肌醇 3 激酶途径（所有 P < .0005），以及更大的低水平（拷贝数 <10) AR 扩增 (P = .0041)。相对于匹配的 AR-LBD 患者队列，AR-LBD 患者表现出更差的总生存期 (OS)（50.1 vs 60.7 个月，未经调整的对数秩 P = 0.013）。该大型数据库分析表明 AR-LBD 突变患病率增加下一代 ARPi 使用后。 AR-LBD 肿瘤表现出独特的生物学特性（更多的致癌途径突变和低水平的 AR 扩增）和降低的 OS。这些发现为开发旨在规避 AR 介导的治疗耐药性的新疗法提供了信息。

Metastatic castration-resistant prostate cancer (mCRPC) is typically treated with agents directly or indirectly targeting the androgen receptor (AR) pathway. However, such treatment is limited by resistance mechanisms, including the development of activating mutations in the AR ligand-binding domain (AR-LBD).This study evaluated a database of over 15,000 patients with advanced prostate cancer (PC) undergoing comprehensive circulating-tumor DNA analysis (Guardant360, Redwood City, CA) between 2014 and 2021, with associated clinical information from administrative claims (GuardantINFORM database).Of 15,705 patients with PC included, 54% had mCRPC at the time of their blood draw. Of those, 49% had previous treatment with an AR pathway inhibitor (ARPi). AR-LBD mutation prevalence was 15% in patients with mCRPC who were untreated with a next-generation ARPi, 22% in those after one line of ARPi therapy, and 24% in those after two lines of ARPi treatment. Next-generation ARPi treatment yielded an increase in AR L702H and T878A/S mutations after abiraterone, and an increase in AR L702H and F877L mutations after enzalutamide. AR-LBD+ patients demonstrated unique biology, including increased concurrent mutations in the cell-cycle, wingless-related integration site, homologous recombination repair, and phospho-inositide 3-kinase pathways (all P < .0005), and greater low-level (copy number <10) AR amplifications (P = .0041). AR-LBD+ patients exhibited worse overall survival (OS) relative to a matched cohort of AR-LBD- patients (50.1 v 60.7 months, unadjusted log-rank P = .013).This large database analysis demonstrates that AR-LBD mutation prevalence increases after next-generation ARPi use. AR-LBD+ tumors demonstrate unique biology (more oncogenic pathway mutations and low-level AR amplification) and reduced OS. These findings inform the development of novel therapies designed to circumvent AR-mediated therapeutic resistance.