Targeting the DNA Damage Repair Pathway in Non-Castrate Prostate Cancers

项目总结/摘要 BRCA 2、ATM和其他DNA损伤的生殖系（~12%）和体细胞（~25%）改变的频率 已经描述了去势抵抗性前列腺癌（CRPC）患者中的DDR修复基因。DDR- 改变的PC具有更高的转移进展率，并且对雄激素剥夺的反应减弱 治疗（ADT）低风险非去势PC的DDR改变频率约为10-15% （主要是生殖细胞）。我们认为，特殊的反应或治愈可能会获得与治疗 靶向与ADT一起进一步抑制DDR通路（PARP抑制），根治性椎间盘切除术 (RP)以及扩大淋巴结清扫术（LND）和放射治疗可见转移。 我们团队的经验表明，在非去势，高风险， 局限性和寡转移性PC可导致前列腺的病理完全反应，沿着 PSA持久缓解（非去势睾酮检测不到PSA）。受此鼓舞， 奥拉帕尼在DDR改变的CRPC中观察到的活性，该项目的目的1提出了一种新的，灵活的，随机的， 多组临床试验平台（MetaCURE试验），用于检测PARP靶向全身治疗的能力 抑制剂与ADT+阿比特龙、RP和LND以及放射治疗可见转移瘤，以消除PC。 具有和不具有DDR途径改变的患者（根据途径中单个基因的改变分类）。 该方案得到了杨森制药的支持，试验于2018年第2季度开始。该新型结构 允许在不编写新方案的情况下添加新的治疗组。 目标2和3由MetaCURE平台的前瞻性嵌入式相关科学计划实现， 肿瘤组织样品（来自诊断性前列腺活检、RP、淋巴结和转移部位）和 在治疗前后将系统地收集用于无细胞DNA分析的血液样品。所有患者 将使用MSK-IMPACT进行配对肿瘤/生殖系测序，以确认局部肿瘤分析的结果 并评估DDR途径突变的杂合性丢失。全外显子组深入分析 将对特殊的应答者/无应答者进行测序和RNA-Seq，以确定潜在的 反应/耐药性的生物标志物和非DDR改变的肿瘤反应，新的基因型，反映 DDR改变状态。目标3中的游离DNA分析将通过跟踪DDR水平来补充目标2 改变以评估微小残留病并确定潜在的耐药机制。的 评价与PARP抑制和ADT耐药相关的可操作突变， 治疗对基因组突变负担的影响，以及本补助金中其他项目的观察结果（项目1和 项目3）将为MetaCURE试验中后续治疗队列的开发提供信息。

PROJECT SUMMARY/ABSTRACT The frequency of germline (~12%) and somatic (~25%) alterations in BRCA2, ATM, and other DNA damage repair (DDR) genes in patients with castration-resistant prostate cancer (CRPC) has been described. DDR- altered PC has higher metastatic progression rates, and an attenuated response to androgen deprivation therapy (ADT). The frequency of DDR alterations in poor-risk non-castrate PC is approximately 10-15% (predominantly germline). We propose that exceptional responses or cure may be obtained with therapy targeted at further inhibition of the DDR pathway (PARP inhibition) together with ADT, radical prostatectomy (RP) and extended lymph node dissection (LND), and radiation to visible metastases. Our teams’ experience has demonstrated that aggressive, multimodality therapy in non-castrate, high-risk localized and oligometastatic PC can result in pathologic complete responses in the prostate, along with durable PSA remissions (undetectable PSA with non-castrate testosterone). Encouraged by this and the activity seen with olaparib in DDR-altered CRPC, Aim 1 of this project proposes a novel, flexible, randomized, multi-arm clinical trial platform (MetaCURE trial) to test the ability of targeted systemic therapy with a PARP inhibitor, together with ADT+abiraterone, RP and LND, and radiation to visible metastases, to eliminate PC in patients with and without DDR pathway alterations (as classified by alterations in single genes in the pathway). The protocol is supported by Janssen Pharmaceuticals and the trial opened Q2 2018. The novel structure allows new treatment arms to be added without writing a new protocol. Aims 2 and 3 are enabled by the MetaCURE platform’s prospectively embedded correlative science program in which tumor tissue samples (from diagnostic prostate biopsy, RP, lymph nodes, and metastatic sites) and blood samples for cell-free DNA analysis will be systematically collected before and after therapy. All patients will have paired tumor/germline sequencing using MSK-IMPACT to confirm the result of local tumor profiling and to assess for loss of heterozygosity of DDR pathway mutations. In-depth analyses with whole exome sequencing and RNA-Seq will be carried out on exceptional responders/nonresponders to identify potential biomarkers of response/resistance and in non-DDR altered tumors that respond, new genotypes that reflect DDR-altered status. Analysis of cell-free DNA in Aim 3 will complement Aim 2, by tracking levels of DDR alterations to assess for minimal residual disease and to identify potential mechanisms of drug resistance. The evaluation of actionable mutations associated with resistance to PARP inhibition and ADT, the evaluation of treatment effect on genomic mutation burden, and observations from other projects in this grant (Project 1 and Project 3) will inform the development of subsequent treatment cohorts in the MetaCURE trial.