A Phase 2 study of a Checkpoint Inhibitor in Men with Progressive Metastatic Castrate Resistant Prostate Cancer Characterized by a Mismatch Repair Deficiency or Biallelic CDK12 Inactivation

迫切需要替代治疗方法来改善患者的生活数量和质量 患有转移性去势抵抗前列腺癌(MCRPC)。检查点抑制形式的免疫治疗 在许多癌症方面取得了良好的结果，包括肺癌、黑色素瘤、肾癌和 淋巴瘤和其他几种疾病。肿瘤特异性体细胞突变和新抗原的频率 队形强烈预测对检查点抑制剂(CPIs)的客观反应。前列腺癌的典型特征是 突变负担相对较低，因此mCRPC的消费物价指数基本上无效也就不足为奇了，尽管 偶尔也能观察到一些反应。在过去的几年中，错配修复缺陷(DMMR)和 在一小部分mCRPC患者中观察到CDK12(CDK12-/-)双等位基因失活。重要的是 这些遗传损伤与由于点突变增加而增加的突变负担有关。 在dMMR的情况下，以及在CDK12-/-的情况下，焦点串联复制的形成增加。因此， 预计dMMR或CDK12-/-肿瘤对CPIs敏感。 由于检测分析的灵敏度较低，dMMR的频率被低估了，这可能 未能检测到MMR基因的等位基因失活。此外，dMMR或CDK12-/-的频率也不是 对检查点抑制或dMMR或CDK12-/-肿瘤的反应在退伍军人中进行了研究。这个 退伍军人的关键人口统计学差异突显了这种知识差距的相关性 与美国总体人口相比，这原则上可能会影响dMMR和CDK12的频率-/- 以及对检查点抑制的响应。使用灵敏的下一代测序平台 检测微卫星不稳定性的生物分析工具，dMMR的替代品，我们预测我们可以检测到dMMR或 CDK12-/-在至少15%的退伍军人中。此外，我们假设患有dMMR或CDK12-/-的退伍军人将 对检查点抑制表现出很高的应答率。我们提出三个目标： 1.确定由NGS和MSI敏感分析工具确定的dMMR和CDK12-/-的频率 用mCRPC对退伍军人进行检测。MSI生物分析，称为mSINGS(微卫星不稳定性 通过下一代测序)，以及包括CDK12在内的靶向基因测序 OncoPlex的组件，这是退伍军人事务部内实施的CLIA认证的NGS平台之一 前列腺癌精确肿瘤学计划(PopCap)网络。 2.进行抗PD1 CPI的pembrolizumab的开放标签2期临床试验，以确定 Pembrolizumab在dMMR和CDK12-/-mCRPC退伍军人中的应用 ≥ 抑制剂。主要终点将是响应率，其定义为以下各项的组合：客观响应率 IRECIST 1.1，12周PSA50，6个月无放射进展生存。 3.进行探索性分析，以确定dMMR中对培溴利珠单抗的反应和耐药性的生物标志物 和CDK12-/-mCRPC退伍军人。为此，我们将获取基线和进展中的活组织检查 转移以及系列血液样本以研究基因组、转录组、蛋白质组和免疫 影响反应的因素。 这项研究将使退伍军人和 确定对检查站抑制做出反应的退伍军人，从而受益于潜在的延长寿命 心理治疗。此外，探索性/相关性分析可以识别分子靶标，其调控 可增强检查点抑制的抗肿瘤作用。

Alternative treatment approaches are urgently needed to improve quantity and quality of life of patients with metastatic castration resistant prostate cancer (mCRPC). Immunotherapy in the form of checkpoint inhibition has yielded auspicious results in many cancers, including lung cancer, melanoma, renal cell carcinoma, and lymphoma amongst several others. The frequency of tumor-specific somatic mutations and hence neoantigen formation strongly predicts for objective response to checkpoint inhibitors (CPIs). Prostate cancer is typified by a relatively low mutational burden, so it is not surprising CPIs for mCRPC are largely ineffective, although occasional responses have been observed. Over the last few years, mismatch repair deficiency (dMMR) and biallelic inactivation of CDK12 (CDK12-/-) have been observed in a small subset of mCRPC patients. Importantly, these genetic lesions have been associated with increased mutational burden due to increased point mutations in the case of dMMR and heightened formation of focal tandem duplications in the case of CDK12-/-. Accordingly, dMMR or CDK12-/- tumors are expected to be sensitive to CPIs. The frequency of dMMR has been underestimated due to poor sensitivity of detection assays, which can fail to detect allelic inactivation of MMR genes. Moreover, neither the frequency of dMMR or CDK12-/- nor the response to checkpoint inhibition or dMMR or CDK12-/- tumors has been studied amongst Veterans. The relevance of this knowledge gap amongst Veterans is highlighted by key demographic differences in Veterans compared to the US population at large, which could in principle affect the frequencies of dMMR and CDK12-/- as well as response to checkpoint inhibition. Using a sensitive next generation sequencing platform and bioanalytic tool to detect microsatellite instability, a surrogate for dMMR, we predict that we can detect dMMR or CDK12-/- in at least 15% of Veterans. Furthermore, we hypothesize that Veterans with dMMR or CDK12-/- will exhibit a high response rate to checkpoint inhibition. We propose three aims: 1. Identify the frequency of dMMR and CDK12-/- as determined by NGS and a sensitive analytic tool for MSI detection amongst Veterans with mCRPC. The MSI bioanalysis, known as mSINGS (microsatellite instability by next generation sequencing), as well as targeted gene sequencing inclusive of CDK12 are built-in components of OncoPlex, one of the CLIA-certified NGS platforms being implemented within the VA Precision Oncology Program Cancer of the Prostate (POPCAP) network. 2. Perform an open label phase 2 clinical trial of pembrolizumab, an anti-PD1 CPI, to determine the efficacy of pembrolizumab amongst dMMR and CDK12-/- mCRPC Veterans who have received prior AR signaling ≥ inhibitors. The primary endpoint will be response rate, defined as a composite of: objective response rate by iRECIST 1.1, PSA50 at 12 weeks, radiographic progression free survival at 6 months. 3. Perform exploratory analyses to identify biomarkers of response and resistance to pembrolizumab in dMMR and CDK12-/- mCRPC Veterans. For this purpose, we will acquire baseline and at-progression biopsies of metastases as well as serial blood samples to investigate genomic, transcriptomic, proteomic, and immune factors that contribute to response. This study will result in enhanced understanding of the biology of mCRPCs amongst Veterans and the identification of Veterans who respond to checkpoint inhibition, thereby benefiting from potentially life extending therapy. In addition, exploratory/correlative analyses could identify molecular targets, the modulation of which could potentiate the anti-tumor effects of checkpoint inhibition..