Coquan Elodie, Penel Nicolas, Lequesne Justine, Leman Raphaël, Lavaud Pernelle, Neviere Zoé, Brachet Pierre-Emmanuel, Meriaux Emeline, Carnot Aurélien, Boutrois Jérémy, Castera Marie, Goardon Nicolas, Muller Etienne, Leconte Alexandra, Thiery-Vuillemin Antoine, Clarisse Bénédicte, Joly Florence
Department of Medical Oncology, Centre François Baclesse, Caen, France.
Department of Clinical Research, Centre François Baclesse, Caen, France.
Ther Adv Urol. 2024 Feb 28;16:17562872241229876. doi: 10.1177/17562872241229876. eCollection 2024 Jan-Dec.
DNA damage repair genes are altered in 20-35% of metastatic castration-resistant prostate cancer (mCRPC). Poly-ADP (Adénosine Diphosphate)-ribose polymerase inhibitors (PARPi) showed significant activity for these selected tumors, especially with homologous recombination repair (HRR) deficiency. These alterations could also predict platinum sensitivity. Although carboplatin was inconclusive in unselected mCRPC, the literature suggests an anti-tumoral activity in mCRPC with HHR gene alterations. We aimed to assess the efficacy of carboplatin monotherapy in mCRPC patients with HRR deficiency.
This prospective multicenter single-arm two-stage phase II addressed mCRPC men with HRR somatic and/or germline alterations, pretreated with ⩾2 taxane chemotherapy regimens and one androgen receptor pathway inhibitor. Prior PARPi treatment was allowed. Enrolled patients received intravenous carboplatin (AUC5) every 21 days for 6-9 cycles. The primary endpoint was the best response rate according to adapted PCWG3 guidelines: radiological response (RECIST 1.1 criteria) and/or biological response [⩾50% prostate-specific antigen (PSA) decline].
A total of 15 out of 16 enrolled patients started carboplatin treatment. Genomic alterations were identified for ( = 5), ( = 3), ( = 3) ( = 2), ( = 1), and ( = 1) genes. Objective response (partial biological response + stable radiological response) was achieved in one patient (6.7%), carrying a BRCA2 mutation and not pre-treated with PARPi; stable disease was observed for five patients (33.5%). Among seven patients (46.7%) with previous PARPi treatment, four patients (57.1%) had a stable disease. The median progression-free and overall survivals were 1.9 [95% confidence interval (95% CI), 1.8-9.5] and 8.6 months (95% CI, 4.3-19.5), respectively. The most common severe (grade 3-4) treatment-related toxicities were thrombocytopenia (66.7%), anemia (66.7%), and nausea (60%). Overall, 8 (53.3%) patients experienced a severe hematological event.
The study was prematurely stopped as pre-planned considering the limited activity of carboplatin monotherapy in heavily pre-treated, HHR-deficient mCRPC patients. Larger experience is needed in mCRPC with BRCA alterations.
NCT03652493, EudraCT ID number 2017-004764-35.
20%-35%的转移性去势抵抗性前列腺癌（mCRPC）中存在DNA损伤修复基因改变。聚-ADP（二磷酸腺苷）-核糖聚合酶抑制剂（PARPi）对这些特定肿瘤显示出显著活性，尤其是在同源重组修复（HRR）缺陷的情况下。这些改变也可预测铂敏感性。尽管卡铂在未选择的mCRPC中效果不明确，但文献表明其在伴有HHR基因改变的mCRPC中具有抗肿瘤活性。我们旨在评估卡铂单药治疗HRR缺陷的mCRPC患者的疗效。
这项前瞻性多中心单臂两阶段II期研究针对患有HRR体细胞和/或种系改变的mCRPC男性患者，这些患者之前接受过≥2种紫杉烷化疗方案和1种雄激素受体途径抑制剂治疗。允许之前接受过PARPi治疗。入组患者每21天接受一次静脉注射卡铂（AUC5），共6-9个周期。主要终点是根据修订后的PCWG3指南确定的最佳缓解率：放射学缓解（RECIST 1.1标准）和/或生物学缓解[前列腺特异性抗原（PSA）下降≥50%]。
16名入组患者中有15名开始接受卡铂治疗。鉴定出 （=5）、 （=3）、 （=3）、 （=2）、 （=1）和 （=1）基因的基因组改变。1名携带BRCA2突变且未接受过PARPi治疗的患者实现了客观缓解（部分生物学缓解+稳定的放射学缓解）（6.7%）；5名患者（33.5%）病情稳定。在7名之前接受过PARPi治疗的患者（46.7%）中，4名患者（57.1%）病情稳定。无进展生存期和总生存期的中位数分别为1.9个月[95%置信区间（95%CI），1.8-9.5]和8.6个月（95%CI，4.3-19.5）。最常见的严重（3-4级）治疗相关毒性为血小板减少（66.7%）、贫血（66.7%）和恶心（60%）。总体而言，8名（53.3%）患者发生了严重血液学事件。
鉴于卡铂单药治疗在预处理严重、HRR缺陷的mCRPC患者中的活性有限，该研究按预先计划提前终止。对于伴有BRCA改变的mCRPC，需要更多经验。
NCT03652493，EudraCT识别号2017-004764-35。
