Background

Biomarkers predicting second-generation novel hormonal therapy (NHT) benefit relative to taxanes are critical for optimized treatment decisions for metastatic castration-resistant prostate cancer (mCRPC) patients. These associations have not been reported simultaneously for common mCRPC genomic biomarkers.

Objective

To evaluate predictive associations of common genomic aberrations in mCRPC using an established comprehensive genomic profiling (CGP) system.

Design, setting, and participants

A retrospective cohort study used data from a deidentified US-based clinicogenomic database comprising patients treated in routine clinical practice between 2011 and 2020, evaluated with Foundation Medicine CGP in tissue biopsies obtained around the time of treatment decision. The main cohort included 180 NHT and 179 taxane lines of therapy (LOTs) from 308 unique patients. The sequential cohort comprised a subset of the main cohort NHT LOTs immediately followed by taxane from 55 unique patients.

Outcome measurements and statistical analysis

Prostate-specific antigen (PSA) response, time to next treatment (TTNT), and overall survival (OS) were assessed. Main cohort analyses were adjusted for known treatment assignment biases via inverse probability of treatment weighting (IPTW) in treatment interaction models.

Results and limitations

In the main cohort, patients with AR amplification (ARamp) or PTEN aberrations (PTENalt) had worse relative PSA response on NHT versus taxanes compared with patients without. Patients with ARamp, PTENalt, or RB1 aberrations (RB1alt) also had worse relative TTNT and OS on NHT but not on taxanes. In multivariable models for TTNT and OS adjusted via IPTW, ARamp, PTENalt, and RB1alt were shown as poor prognostic factors overall and demonstrated significant treatment interactions, indicating reduced hazards of therapy switch and death on taxanes versus NHT. Consistent associations favoring increased benefit from subsequent taxane despite prior NHT treatment line were observed only for ARamp in the sequential cohort, in which very few patients had RB1alt for assessment.

Conclusions

ARamp status is a candidate biomarker to predict poor effectiveness of NHT relative to taxanes in mCRPC in scenarios where both options are considered.

Patient summary

Specific alterations in the DNA of tumors may assist in choosing between novel oral hormonal therapies and standard chemotherapy in advanced prostate cancer patients.

中文翻译：

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激素治疗与化疗在转移性去势抵抗性前列腺癌中获益的预测基因组生物标志物

背景

预测第二代新型激素疗法 (NHT) 相对于紫杉烷类的益处的生物标志物对于转移性去势抵抗性前列腺癌 (mCRPC) 患者的优化治疗决策至关重要。对于常见的 mCRPC 基因组生物标志物，这些关联尚未同时报道。

客观的

使用已建立的综合基因组分析 (CGP) 系统评估 mCRPC 中常见基因组畸变的预测关联。

设计、设置和参与者

一项回顾性队列研究使用了来自美国临床基因组数据库的数据，该数据库包括 2011 年至 2020 年间在常规临床实践中接受治疗的患者，并在治疗决定时获得的组织活检中使用 Foundation Medicine CGP 进行了评估。主要队列包括来自 308 名独特患者的 180 名 NHT 和 179 名紫杉烷治疗线 (LOT)。顺序队列包括主要队列 NHT LOT 的一个子集，紧随其后的是来自 55 名独特患者的紫杉烷。

结果测量和统计分析

评估了前列腺特异性抗原 (PSA) 反应、下次治疗时间 (TTNT) 和总生存期 (OS)。通过治疗相互作用模型中的治疗加权逆概率 (IPTW) 针对已知的治疗分配偏差调整主要队列分析。

结果和局限性

在主要队列中，与没有的患者相比，具有AR扩增 ( AR amp) 或PTEN畸变 ( PTEN alt) 的患者对 NHT 的相对 PSA 反应与紫杉烷相比更差。患有AR amp、PTEN alt 或RB1畸变 ( RB1 alt) 的患者在 NHT 上的相对 TTNT 和 OS 也较差，但在紫杉类药物上则没有。在通过 IPTW、AR amp、PTEN alt 和RB1调整的 TTNT 和 OS 的多变量模型中alt 总体上显示为不良预后因素，并显示出显着的治疗相互作用，表明与 NHT 相比，紫杉烷类药物的治疗转换和死亡风险降低。尽管先前的 NHT 治疗线仅在AR amp 中观察到有利于后续紫杉烷增加益处的一致关联，但仅在顺序队列中观察到，其中很少有患者使用RB1 alt 进行评估。

结论

AR amp 状态是一种候选生物标志物，可在同时考虑两种选择的情况下预测 NHT 相对于 mCRPC 中紫杉烷类的有效性较差。

患者总结

肿瘤 DNA 的特定改变可能有助于在晚期前列腺癌患者中选择新型口服激素疗法和标准化学疗法。