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) 约占新诊断局限性前列腺癌的 15%，治愈率 根治性前列腺切除术 (RP) 进行初次手术治疗后，这些肿瘤的复发率较低 高达~50%。针对这些局部高风险 PCa 的新辅助试验可能会提供宝贵的机会来增加 治愈率以及我们对反应和耐药性的理解。然而，之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很少表现出病理完全性 反应（pCR），但尚未显示出临床疗效的证据。我们假设响应 由于前列腺中存在大量残留雄激素，新辅助 ADT 受到限制，并且需要加强治疗 新辅助雄激素信号抑制 (ASI) 治疗除了提高 pCR 率外，还将转化为 无病生存期 (DFS) 和最终总生存期 (OS) 的改善。我们一直在测试这个 一系列 2 期试验的假设，检验使用亮丙瑞林进行新辅助强化 ASI 的疗效 根治前联合阿比特龙 (ABI) 和/或恩杂鲁胺 (ENZ) 或阿帕鲁胺 (APA) 6 个月 前列腺切除术（RP）。相对于之前的新辅助试验，反应似乎有所改善，但仍然存在 尚不清楚 pCR/MRD 病例是否反映了转移潜力较小的肿瘤。此外， 前列腺残留疾病的分子基础及其与患者转移性疾病的关系 进展情况，尚待确定。为了解决反应与耐药性的基因组基础，我们建议 对强化新辅助治疗具有特殊反应 (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 标本中残留疾病的治疗（目标 1）。这些 研究将利用我们之前试验的样本，以及新辅助疗法的大型多中心 3 期研究 GnRH 激动剂/拮抗剂联合 APA 与单独使用 GnRH 激动剂/拮抗剂的比较 (PROTEUS 试验，由 Janssen 支持，NCT03767244）。目标 2 将确定可行的急性非基因组适应措施 介导对强化 ASI 治疗的初始抵抗，并专门检验这些适应的假设 集中于 D 细胞周期蛋白的表达和 CDK4/6 的激活以驱动增殖。目标 3 是一个随机阶段 2 次强化 ASI 试验（亮丙瑞林加达洛鲁胺），单独或与 CDK4/6 抑制剂联合使用 abemaciclib。我们的长期目标是建立新辅助试验作为评估新辅助疗法疗效的平台 联合疗法治疗去势敏感的前列腺癌。