Department of Medical Oncology and Haematology, Cantonal Hospital of St Gallen, St Gallen, Switzerland.
Division of Medical Oncology and Hematology, Princess Margaret Cancer Centre, Toronto, Canada.
JAMA Netw Open. 2020 Oct 1;3(10):e2021692. doi: 10.1001/jamanetworkopen.2020.21692.
DNA repair gene aberrations occur in 20% to 30% of patients with castration-resistant prostate cancer (CRPC), and some of these aberrations have been associated with sensitivity to poly(ADP-ribose) polymerase (PARP) inhibition platinum-based treatments. However, previous trials assessing platinum-based treatments in patients with CRPC have mostly included a biomarker-unselected population; therefore, efficacy in these patients is unknown.
To characterize the antitumor activity of platinum-based therapies in men with CRPC with or without DNA repair gene alterations.
DESIGN, SETTING, AND PARTICIPANTS: In this case series, data from 508 patients with CRPC treated with platinum-based therapy were collected from 25 academic centers from 12 countries worldwide. Patients were grouped by status of DNA repair gene aberrations (ie, cohort 1, present; cohort 2, not detected; and cohort 3, not tested). Data were collected from January 1986 to December 2018. Data analysis was performed in 2019, with data closure in April 2019.
Treatment with platinum-based compounds either as monotherapy or combination therapy.
The primary end points were as follows: (1) antitumor activity of platinum-based therapy, defined as a decrease in prostate-specific antigen (PSA) level of at least 50% and/or radiological soft tissue response in patients with measurable disease and (2) the association of response with the presence or absence of DNA repair gene aberrations.
A total of 508 men with a median (range) age of 61 (27-88) years were included in this analysis. DNA repair gene aberrations were present in 80 patients (14.7%; cohort 1), absent in 98 (19.3%; cohort 2), and not tested in 330 (65.0%; cohort 3). Of 408 patients who received platinum-based combination therapy, 338 patients (82.8%) received docetaxel, paclitaxel, or etoposide, and 70 (17.2%) received platinum-based combination treatment with another partner. A PSA level decrease of at least 50% was seen in 33 patients (47.1%) in cohort 1 and 26 (36.1%) in cohort 2 (P = .20). In evaluable patients, soft tissue responses were documented in 28 of 58 patients (48.3%) in cohort 1 and 21 of 67 (31.3%) in cohort 2 (P = .07). In the subgroup of 44 patients with BRCA2 gene alterations, PSA level decreases of at least 50% were documented in 23 patients (63.9%) and soft tissue responses in 17 of 34 patients (50.0%) with evaluable disease. In cohort 3, PSA level decreases of at least 50% and soft tissue responses were documented in 81 of 284 patients (28.5%) and 38 of 185 patients (20.5%) with evaluable disease, respectively.
In this study, platinum-based treatment was associated with relevant antitumor activity in a biomarker-positive population of patients with advanced prostate cancer with DNA repair gene aberrations. The findings of this study suggest that platinum-based treatment may be considered an option for these patients.
在接受去势抵抗性前列腺癌（CRPC）治疗的患者中，有 20%-30%存在 DNA 修复基因异常，其中一些异常与对聚（ADP-核糖）聚合酶（PARP）抑制剂铂类治疗的敏感性有关。然而，之前评估铂类治疗在 CRPC 患者中的试验大多包括了生物标志物未选择的人群；因此，这些患者的疗效尚不清楚。
描述 DNA 修复基因异常的 CRPC 患者接受铂类治疗的抗肿瘤活性。
设计、地点和参与者：在这项病例系列研究中，从全球 12 个国家的 25 个学术中心收集了 508 名接受铂类治疗的 CRPC 患者的数据。根据 DNA 修复基因异常的状态将患者分为三组（队列 1，存在；队列 2，未检测到；队列 3，未检测）。数据收集自 1986 年 1 月至 2018 年 12 月。数据分析于 2019 年进行，数据截止日期为 2019 年 4 月。
铂类化合物的治疗，无论是单药治疗还是联合治疗。
主要终点如下：（1）铂类治疗的抗肿瘤活性，定义为前列腺特异性抗原（PSA）水平下降至少 50%，和/或可测量疾病患者的影像学软组织反应；（2）反应与 DNA 修复基因异常的存在与否的关系。
本分析共纳入 508 名中位（范围）年龄为 61（27-88）岁的男性。80 名患者（14.7%；队列 1）存在 DNA 修复基因异常，98 名患者（19.3%；队列 2）不存在，330 名患者（65.0%；队列 3）未检测。在接受铂类联合治疗的 408 名患者中，338 名（82.8%）接受了多西他赛、紫杉醇或依托泊苷治疗，70 名（17.2%）接受了铂类联合治疗的其他药物。队列 1 中有 33 名（47.1%）患者 PSA 水平下降至少 50%，队列 2 中有 26 名（36.1%）患者 PSA 水平下降至少 50%（P=0.20）。在可评估的患者中，队列 1 中有 28 名（48.3%）患者的软组织反应得到了记录，队列 2 中有 21 名（31.3%）患者的软组织反应得到了记录（P=0.07）。在 44 名存在 BRCA2 基因突变的患者亚组中，有 23 名（63.9%）患者的 PSA 水平下降至少 50%，34 名（50.0%）患者的软组织反应得到了评估。在队列 3 中，有 81 名（28.5%）和 38 名（20.5%）可评估疾病的患者 PSA 水平下降至少 50%和软组织反应得到了记录。
在这项研究中，铂类治疗与 DNA 修复基因异常的晚期前列腺癌患者的生物标志物阳性人群的相关抗肿瘤活性相关。这项研究的结果表明，铂类治疗可能是这些患者的一种选择。
