Carboplatin or Olaparib for BRcA deficient prostate cancer (COBRA)

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。早期 数据表明，DNA损伤剂卡铂可能对DNA修复缺陷异常有效， 前列腺癌这项研究将确定使用DNA损伤剂卡铂是否更有效。 在同源重组缺陷型前列腺癌的一线治疗中比多西他赛有效， 在交叉时比较对替代药物的反应性。拟议的研究是一项随机II期研究， 一线卡铂与多西他赛治疗去势抵抗性转移性前列腺癌疗效比较 既往接受阿比特龙和/或enzalutamide治疗后含有BRCA1或BRCA2或PALB2突变， 化疗被认为是合适的。患者将接受一线治疗，直至 进展、不耐受或10个周期。在进展时，患者将交叉至替代方案 方案.主要终点将是一线治疗（PFS-1L）的无进展生存期， 二线治疗的无进展生存期（PFS-2L）和两种治疗的PFS的次要终点 组合以及每个方案的毒性。本研究将提供关于疗效的关键信息， 卡铂与标准化疗的毒性以及最初是否使用DNA靶向药物 PFS将比一线多西他赛更长。这项研究的重要性将是建立的效用， BRCA和PALB2作为卡铂的预测性生物标志物，并确定单独使用卡铂是否是有效的 和安全的治疗方法。这项研究还将确定卡铂是否是 适用于在未来的研究中针对靶向DNA修复途径缺陷的其他药物进行测试， 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 并且可能有毒。如果这项研究证明了卡铂的疗效，随机成本效益研究与 VA内的PARPi是合理的。

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.