Efficacy and Mechanisms of Resistance to Neoadjuvant Intensive Androgen Signaling Inhibition

项目摘要--项目1 局限性高危前列腺癌(PCa)占新诊断的局限性前列腺癌的15%，治愈率 这些肿瘤在初次手术后根治性前列腺切除术(RP)的发生率很低，有复发的疾病 高达~50%。这些局部高危PCa的新辅助试验可能会提供宝贵的机会来增加 治愈率和我们对反应和耐药性的理解。然而，之前对新佐剂的研究 单独使用促性腺激素释放激素激动剂的雄激素剥夺通常表现出罕见的病理完全 反应(PCR)，尚未显示出临床疗效的证据。我们已经假设了对 由于雄激素在前列腺中的大量残留，新辅助ADT已经受到限制，而更密集的 新辅助性雄激素信号抑制(ASI)治疗，除了增加PCR率外，还将转化为 无病存活率(DFS)和最终总存活率(OS)的改善。我们一直在测试这一点 在一系列2期试验中使用亮丙瑞林检验新佐剂强化ASI疗效的假说 在自由基前与阿比特龙(ABI)和/或苯扎鲁胺(ENZ)或阿帕鲁胺(APA)联合治疗6个月 前列腺摘除(RP)。与以前的新佐剂试验相比，反应似乎有所改善，但它仍然 不清楚PCRMRD的病例是否反映了转移潜力较小的肿瘤。此外， 前列腺癌残留病变的分子基础及其与转移性疾病的关系 进展如何，还有待确定。为了解决应答与抵抗的基因组基础，我们提出 对对强化新佐剂有特殊反应的肿瘤的综合基因组分析(PCR/MRD) ASI治疗，以及未能实现PCR/MRD的男性RP样本中的残留疾病(目标1)。这些 研究将利用我们先前试验的样本，以及新佐剂的大型多中心3期研究。 GnRH激动剂/拮抗剂与APA合用与单独使用GnRH激动剂/拮抗剂(Proteus)的比较 试验，由Janssen支持，NCT03767244)。目标2将确定可操作的急性非基因组适应 调节对强化ASI治疗的初始抵抗，并具体测试这些适应的假设 趋同于D细胞周期蛋白的表达和CDK4/6的激活，从而推动细胞增殖。目标3是一个随机阶段 2单独或与CDK4/6抑制剂联合应用强化ASI(亮丙瑞林加达鲁他胺)的试验 阿贝米卡利布。我们的长期目标是建立新辅助试验作为评估新诺菲疗效的平台 去势敏感型前列腺癌的联合治疗。

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.