Division of Hematology/Oncology, Department of Medicine, University of California San Francisco, San Francisco, California.
Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta, Canada.
Cancer. 2021 Jun 15;127(12):1965-1973. doi: 10.1002/cncr.33487. Epub 2021 Mar 10.
DNA damage repair mutations (DDRm) are common in patients with metastatic castration-resistant prostate cancer (mCRPC). The optimal standard therapy for this population is not well described.
A multi-institutional, retrospective study of patients with mCRPC and DDRm was conducted. Patient data, including systemic therapies and responses, were collected. The decline in prostate-specific antigen ≥ 50% from baseline (PSA50) and overall survival (OS) from the treatment start were compared by mutation and treatment type. A multivariable Cox proportional hazards model for OS was created that controlled for DDRm, first-line treatment received for mCRPC, and clinical factors.
The most common DDRm observed among 149 men with mCRPC were BRCA1/2 (44%), CDK12 (32%), and ATM (15%). The majority received first-line abiraterone (40%) or enzalutamide (30%). The PSA50 rate with first-line abiraterone was lower for CDK12 (52%) than BRCA1/2 (89%; P = .02). After first-line abiraterone or enzalutamide, the median OS was longest with second-line carboplatin-chemotherapy (38 months) in comparison with abiraterone or enzalutamide (33 months), docetaxel (17 months), or cabazitaxel (11 months; P = .02). PSA50 responses to carboplatin-based chemotherapy were higher for BRCA1/2 (79%) than ATM (14%; P = .02) or CDK12 (38%; P = .08). In a multivariable analysis, neither the specific DDRm type nor the first-line treatment was associated with improved OS.
Responses to standard therapies were generally superior in patients with BRCA1/2 mutations and inferior in patients with ATM or CDK12 mutations. The DDRm type did not independently predict OS. After progression on first-line abiraterone or enzalutamide, carboplatin-based chemotherapy was associated with the longest OS. These findings may inform treatment discussions and clinical trial design and require prospective validation.
DNA 损伤修复突变（DDRm）在转移性去势抵抗性前列腺癌（mCRPC）患者中很常见。该人群的最佳标准治疗方法尚未得到很好的描述。
对患有 mCRPC 和 DDRm 的患者进行了一项多机构、回顾性研究。收集了患者的数据，包括系统治疗和反应。通过突变和治疗类型比较了从基线开始前列腺特异性抗原（PSA）下降≥50%（PSA50）和总生存期（OS）。创建了一个 OS 的多变量 Cox 比例风险模型，该模型控制了 DDRm、mCRPC 的一线治疗以及临床因素。
在 149 名患有 mCRPC 的男性中，最常见的 DDRm 是 BRCA1/2（44%）、CDK12（32%）和 ATM（15%）。大多数人接受了一线阿比特龙（40%）或恩扎鲁胺（30%）治疗。一线阿比特龙治疗时，CDK12（52%）的 PSA50 率低于 BRCA1/2（89%；P=.02）。在一线阿比特龙或恩扎鲁胺之后，二线卡铂化疗的中位 OS 最长（38 个月），与阿比特龙或恩扎鲁胺（33 个月）、多西他赛（17 个月）或卡巴他赛（11 个月）相比；P=.02）。卡铂为基础的化疗对 BRCA1/2（79%）的 PSA50 反应高于 ATM（14%；P=.02）或 CDK12（38%；P=.08）。在多变量分析中，DDRm 类型或一线治疗均与 OS 改善无关。
标准治疗的反应在 BRCA1/2 突变患者中通常较好，在 ATM 或 CDK12 突变患者中较差。DDRm 类型不能独立预测 OS。一线阿比特龙或恩扎鲁胺治疗后进展，卡铂为基础的化疗与最长的 OS 相关。这些发现可能为治疗讨论和临床试验设计提供信息，并需要前瞻性验证。
