Efficacy and Mechanisms of Resistance to Neoadjuvant Intensive Androgen Signaling Inhibition

新辅助强化雄激素信号抑制的疗效和机制

• 批准号: 10628272
• 负责人: MARY ELLEN TAPLIN
• 金额: $ 49.26万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10628272
• 关键词: Acceleration; Acute; Address; Adjuvant Study; Adjuvant Therapy; Agonist; Androgens; Automobile Driving; Biological Markers; CDK4 gene; Castrate sensitive prostate cancer; Castration; Clinical Trials; Combined Modality Therapy; Cyclin D1; Dana-Farber Cancer Institute; Disease; Disease-Free Survival; Failure; GNRH1 gene; Genomics; Goals; In complete remission; Leuprolide; Malignant neoplasm of prostate; Mediating; Metastatic Prostate Cancer; Microscopic; Molecular; Molecular Analysis; Neoadjuvant Study; Neoadjuvant Therapy; Newly Diagnosed; Oncogenic; Operative Surgical Procedures; Pathologic; Patient Selection; Patients; Phase II Clinical Trials; Prediction of Response to Therapy; Proliferating; Prostate; Radical Prostatectomy; Randomized; Recurrent disease; Relapse; Residual Neoplasm; Residual state; Resistance; Sampling; Series; Signal Transduction; Specimen; Systemic Therapy; Testing; Translating; Tumor Biology; abiraterone; antagonist; clinical efficacy; clinically significant; deprivation; disorder risk; efficacy evaluation; enzalutamide; high risk; improved; inhibitor; insight; men; non-genomic; novel; novel therapeutic intervention; patient derived xenograft model; phase 3 study; phase II trial; prevent; prostate cancer risk; resistance mechanism; response; tumor

PROJECT SUMMARY – PROJECT 1 Localized high-risk prostate cancer (PCa) comprises ~15% of newly diagnosed localized PCa, and the cure rate for these tumors after primary surgical treatment by radical prostatectomy (RP) is low, with recurrent disease in up to ~50%. Neoadjuvant trials for these localized high-risk PCa may provide valuable opportunities to increase cure rates and our understanding of response and resistance. However, previous studies of neoadjuvant androgen deprivation using GnRH agonists alone have generally shown infrequent pathological complete responses (pCRs) and have not shown evidence of clinical efficacy. We have hypothesized that responses to neoadjuvant ADT have been limited due to substantial residual androgen in the prostate, and that more intensive neoadjuvant androgen signaling inhibition (ASI) therapy, in addition to increasing pCR rates, will translate into an improvement in disease free survival (DFS) and ultimately overall survival (OS). We have been testing this hypothesis in a series of phase 2 trials examining the efficacy of neoadjuvant intensive ASI using leuprolide in combination with abiraterone (ABI) and/or enzalutamide (ENZ) or apalutamide (APA) for 6 months prior to radical prostatectomy (RP). Responses appear to be improved relative to previous neoadjuvant trials, but it remains unclear whether the cases with pCR/MRD reflect tumors that have less metastatic potential. Moreover, the molecular basis for residual disease in prostate, and its relationship to metastatic disease in patients who progress, remain to be determined. To address the genomic basis of response versus resistance, we propose comprehensive genomic analyses of tumors with exceptional responses (pCR/MRD) to intensive neoadjuvant ASI therapy, and of residual disease in RP specimens in men who do not achieve pCR/MRD (Aim 1). These studies will leverage samples from our previous trials, as well as a large multicenter phase 3 study of neoadjuvant GnRH agonist/antagonist combined with APA in comparison with GnRH agonist/antagonist alone (PROTEUS trial, supported by Janssen, NCT03767244). Aim 2 will identify actionable acute nongenomic adaptations that mediate initial resistance to intensive ASI therapy, and specifically test the hypothesis that these adaptations converge on expression of D cyclins and activation of CDK4/6 to drive proliferation. Aim 3 is a randomized phase 2 trial of intensive ASI (leuprolide plus darolutamide), alone or in combination with the CDK4/6 inhibitor abemaciclib. Our long-term goal is to establish neoadjuvant trials as a platform for assessing the efficacy of novel combination therapies in castration-sensitive PCa.

项目摘要-项目1 局限性高危前列腺癌（PCa）占新诊断的局限性PCa的约15%， 对于这些肿瘤，经根治性膀胱切除术（RP）初次手术治疗后的复发率低， 高达~ 50%。针对这些局部高危PCa的新辅助治疗试验可能提供了宝贵的机会， 治愈率和我们对反应和耐药性的理解。然而，以前的新辅助治疗研究 单独使用GnRH激动剂的雄激素剥夺通常表现出罕见的病理性完全性 pCRs，并且尚未显示出临床疗效的证据。我们假设， 新辅助ADT由于前列腺中大量残留雄激素而受到限制， 新辅助雄激素信号抑制（ASI）治疗，除了增加pCR率，将转化为 无病生存期（DFS）和最终总生存期（OS）的改善。我们一直在测试 一系列II期试验中的假设，这些试验检查了使用亮丙瑞林的新辅助强化ASI在 根治性治疗前联合阿比特龙（ABI）和/或Enzalutamide（ENZ）或阿帕鲁胺（APA）治疗6个月 腰椎切除术（RP）。相对于以前的新辅助治疗试验，反应似乎有所改善，但仍然存在 不清楚pCR/MRD病例是否反映了转移潜力较低的肿瘤。而且 前列腺残留疾病的分子基础及其与前列腺癌患者转移性疾病的关系 进展，有待确定。为了解决响应与抗性的基因组基础，我们建议 对强化新辅助治疗具有特殊应答（pCR/MRD）的肿瘤的全面基因组分析 ASI治疗，以及未达到pCR/MRD的男性RP标本中的残留疾病（目标1）。这些 研究将利用我们以前试验的样本，以及一项新辅助治疗的大型多中心III期研究。 GnRH激动剂/拮抗剂联合阿帕与单独GnRH激动剂/拮抗剂的比较（PROTEUS 试验，由Janssen，NCT 03767244支持）。目标2将确定可采取行动的急性非基因组适应， 介导对强化ASI治疗的初始抵抗，并专门测试这些适应性的假设， 聚集于D细胞周期蛋白的表达和CDK 4/6的活化以驱动增殖。目标3是随机化阶段 2项强化ASI（亮丙瑞林+达罗鲁米特）单药治疗或与CDK 4/6抑制剂联合治疗的试验 Abemaciclib。我们的长期目标是建立新辅助治疗试验，作为评估新辅助治疗有效性的平台。 去势敏感性前列腺癌的联合治疗。