Carboplatin or Olaparib for BRcA deficient prostate cancer (COBRA)

卡铂或奥拉帕尼治疗 BRcA 缺陷型前列腺癌 (COBRA)

• 批准号: 10417024
• 负责人: Bruce Montgomery
• 金额: --
• 依托单位: VA PUGET SOUND HEALTHCARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10417024
• 关键词: Address; Affect; BRCA deficient; BRCA1 gene; BRCA2 gene; Biological Markers; Cancer Etiology; Carboplatin; Cessation of life; DNA; DNA Damage; DNA Repair; DNA Repair Disorder; DNA Repair Pathway; Data; Decision Making; Defect; Disease; Disease Progression; Effectiveness; FDA approved; Future; Genes; Histology; Individual; Lesion; Malignant Neoplasms; Malignant neoplasm of ovary; Malignant neoplasm of prostate; Measurable Disease; Metastatic Prostate Cancer; Molecular; Mutation; Older Population; Outcome; PALB2 gene; Pathway interactions; Patient Agents; Patients; Pharmaceutical Preparations; Phase; Platinum; Poly(ADP-ribose) Polymerases; Prior Therapy; Progression-Free Survivals; Randomized; Regimen; Reporting; Resistance; Screening for Prostate Cancer; Testing; Therapeutic; Time; Toxic effect; Treatment-related toxicity; Veterans; Work; abiraterone; advanced prostate cancer; base; biomarker performance; bone imaging; brca gene; castration resistant prostate cancer; chemotherapy; comparative efficacy; cost effectiveness; design; docetaxel; effectiveness study; effectiveness testing; efficacy evaluation; enzalutamide; homologous recombination; inhibitor; malignant breast neoplasm; men; objective response rate; personalized care; phase 2 study; potential biomarker; predicting response; predictive marker; primary endpoint; response; response biomarker; secondary endpoint; standard of care; targeted agent; time interval; tumor

Abstract Advanced prostate cancer is a universally lethal disease and one for which no biomarkers have yet been found to inform therapeutic decision making. DNA repair deficiency in the homologous recombination pathway increases sensitivity of tumors to DNA damaging agents for patients with breast and ovarian cancers. Early data suggests that the DNA damaging agent carboplatin may be exceptionally effective in DNA repair deficient prostate cancer. This study would determine if the use of the DNA damaging agent carboplatin is more effective than docetaxel in homologous recombination deficient prostate cancers in the first line setting and compare responsiveness to the alternate drug at crossover. The proposed study is a randomized phase II study of first line carboplatin vs. docetaxel in men with metastatic, castration resistant prostate cancer containing BRCA1 or BRCA2 or PALB2 mutations after prior therapy with abiraterone and/or enzalutamide and for whom chemotherapy is considered appropriate. Patients will be treated with first line therapy until progression, intolerance or 10 cycles. At the time of progression, patients will cross over to the alternative regimen. The primary endpoint will be progression free survival with the first line therapy (PFS-1L) with secondary endpoints of progression free survival with second line therapy (PFS-2L) and PFS to both therapies combined as well as toxicity of each regimen. This study will provide critical information regarding efficacy and toxicity of carboplatin vs. the standard of care chemotherapy and whether use of DNA targeting agents initially will provide longer PFS than first line docetaxel. The importance of this study will be to establish the utility of BRCA and PALB2 as predictive biomarkers for carboplatin and to determine if carboplatin alone is an effective and safe therapy in men with resistant prostate cancer. The study would also establish whether carboplatin is appropriate to test in future studies against other agents targeting DNA repair pathway deficiency such as poly(ADP-ribose)polymerase inhibitors (PARPi). PARPi are very effective in early studies but are expensive and can be toxic. If this study demonstrates efficacy of carboplatin, randomized cost effectiveness studies vs. PARPi within the VA would be justified.

摘要 晚期前列腺癌是一种普遍致命的疾病，目前还没有发现其生物标志物。 为治疗决策提供信息。同源重组途径中的DNA修复缺陷 增加乳腺癌和卵巢癌患者肿瘤对DNA损伤剂的敏感性。早些时候 数据表明，dna损伤剂卡铂对dna修复缺陷可能特别有效。 前列腺癌。这项研究将确定DNA损伤剂卡铂的使用是否更多 在一线治疗同源重组缺陷前列腺癌方面比多西他赛更有效 比较交叉试验中替代药物的反应性。建议的研究是随机的第二阶段。 一线卡铂与多西紫杉醇治疗男性转移性去势抵抗前列腺癌的对比研究 在之前使用阿比特龙和/或苯扎鲁胺治疗后含有BRCA1或BRCA2或PALB2突变，以及 他们认为化疗对他们来说是合适的。患者将接受一线治疗，直到 进展、不耐受或10个周期。在病情进展的时候，患者会转向另一种选择 养生法。主要终点将是一线治疗(PFS-1L)的无进展生存 二线治疗(PFS-2L)和两种治疗的PFS的无进展生存期的次要终点 每种方案的联合用药以及毒性反应。这项研究将提供有关疗效和 卡铂的毒性与护理化疗的标准以及最初是否使用DNA靶向药物 将提供比一线多西紫杉醇更长的PFS。这项研究的重要性将是确定 BRCA和PALB2作为卡铂的预测生物标志物并确定卡铂是否单独有效 对患有耐药前列腺癌的男性进行安全治疗。这项研究还将确定卡铂是否可以 适合在未来的研究中针对其他针对DNA修复途径缺陷的药物进行测试，例如 聚(ADP-核糖)聚合酶抑制剂(PARPI)。PARPI在早期研究中非常有效，但价格昂贵 而且可能是有毒的。如果这项研究证明了卡铂的疗效，那么随机成本效益研究与 退伍军人事务部内的PARPI将是合理的。