Primary resistance to androgen receptor (AR)–directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naïve mCRPC to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers.

Significance: Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice. Cancer Discov; 8(4); 444–57. ©2018 AACR.

See related commentary by Jayaram et al., p. 392.

This article is highlighted in the In This Issue feature, p. 371

人们对转移性去势抵抗性前列腺癌（mCRPC）中对雄激素受体（AR）指导疗法的主要耐药性了解甚少。我们将202例未接受过治疗的mCRPC患者随机分为阿比特龙或enzalutamide，并在治疗前对血浆无细胞DNA进行了全外显子和深度靶向72基因测序。对于从未直接比较过的这些药物，进展时间相似。与临床预后因素和循环肿瘤DNA丰度无关，BRCA2和ATM的缺陷与不良的临床结果密切相关。TP53的体细胞改变先前与减少的肿瘤对AR信号传导的依赖性有关，也与快速耐药相关。虽然检测AR扩增并没有优于标准的预后生物标志物，在几例原发性耐药的患者中发现了AR基因结构重排截短了配体结合域。这些发现建立了对mCRPC中针对一线AR导向治疗的耐药性的基因组驱动力，并确定了潜在的微创生物标志物。

意义：利用大型随机II期试验中收集的血浆标本，我们报告了常见循环肿瘤DNA改变对患者对晚期前列腺癌最广泛使用的疗法的反应的相对影响。我们的发现表明，液体活检分析可以指导一般实践中以AR为靶标的治疗方法的使用。巨蟹座Discov; 8（4）; 444–57。©2018 AACR。

参见Jayaram等人的相关评论，第1页。392。

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