High-dose Testosterone in Men with Metastatic Castration-resistant Prostate Cancer and ATM or CDK12 deficiency

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。同源重组中的DNA修复缺陷与CDK 12 途径增加肿瘤对高剂量睾酮的DNA损伤作用的敏感性， II期高剂量睾酮研究的早期生物标志物询问。高剂量的睾丸激素也非常 在适当选择的无症状患者人群中耐受良好。拟议的研究是一项 高剂量睾酮治疗转移性去势抵抗性前列腺癌男性的2组II期研究 含有ATM或CDK 12的突变。患者将接受间歇性高剂量睾酮 （每个月周期第1天肌肉注射），直至临床或放射学进展或不耐受。 雄激素剥夺持续进行，以维持稳定的最低睾酮水平，这对维持 通过将肿瘤细胞暴露于极高和极低的睾酮水平来诱导基因组不稳定性的概念 在周期的长度上。主要终点为PSA较基线下降50%。二次 终点为根据RECIST的放射学缓解、放射学无进展生存期、PSA进展 无瘤生存期、总生存期、每个基因组亚组的PSA 50缓解率、FACT-P生活质量， 国际勃起功能指数（IIEF）调查以及不良事件的发生率和严重程度， CTCAE 4.0版。这项研究将提供关于高剂量的疗效和毒性的关键信息。 在生物标志物选择的人群中进行睾酮治疗。高剂量睾酮在适当选择 患者的耐受性非常好，并将为那些在其他情况下无法接受治疗的患者提供治疗选择。 在他们的治疗序列中的适当点进行其他治疗。这项研究的重要性将是 建立特定基因中DNA修复缺陷的效用，作为高反应性的预测生物标志物。 剂量睾酮，并证明针对特定亚群的大型研究，特别是对于 尚未建立有效的治疗方法，例如ATM和CDK 12。

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 and CDK12 pathways increases sensitivity of tumors to the DNA damaging effects of high dose testosterone based on early biomarker interrogations of phase II high dose testosterone studies. High dose testosterone is also very well tolerated in appropriately selected patient populations who are asymptomatic. The proposed study is a two arm phase II study of high dose testosterone in men with metastatic, castration resistant prostate cancer containing mutations in ATM or CDK12. Patients would receive intermittent high dose testosterone (intramuscular injections Day 1 of each monthly cycle) until clinical or radiographic progression or intolerance. Androgen deprivation is continued in order to maintain consistent nadir testosterone levels which are critical to the concept of inducing genomic instability by exposing tumor cells to very high and low testosterone levels over the length of the cycle. The primary endpoint will be 50% decline in PSA from baseline. Secondary endpoints are radiographic response per RECIST, radiographic progression free survival, PSA progression free survival, overall survival, PSA50 response rate in each genomic subgroup, quality of life by FACT-P and International Index of Erectile Function (IIEF) surveys and incidence and severity of adverse events according to CTCAE version 4.0. This study will provide critical information regarding efficacy and toxicity of high dose testosterone therapy in a biomarker selected population. High dose testosterone in appropriately selected patients is very well tolerated and would provide treatment options for patients who are otherwise not at the appropriate point in their treatment sequence for other treatments. The importance of this study will be to establish the utility of DNA repair deficiency in specific genes as a predictive biomarker for response to high dose testosterone and to justify larger studies targeting specific subsets, particularly for subsets for which effective therapies have not yet been established such as ATM and CDK12.