Quantifying and Personalizing the Clinical Benefit of Metastasis-Directed Therapy in Men with De Novo Oligometastatic Prostate Cancer

项目概要/摘要 本项目的长期目标是确定转移导向放疗（MDT）的临床影响 在患有原发性寡转移性前列腺癌（PCa）的男性中，并确定哪些男性可以治愈和受益 大多数来自MDT。我们的目标是通过进行一项3期随机对照试验来实现这一目标， 前瞻性成像和生物样本（例如组织和血液）采集。这次审判是新颖的，因为它是一个 国际里程碑多项研究的下一个组（M组）的随机化北美子研究（n=200） 组、多阶段、STAMPEDE试验。能够通过全面的生物标本采集进行本试验 和成像分析将通过我们独特的研究团队在校外和校内实现 中心，由预后和预测生物标志物特征鉴定，生物信息学， 生物统计学、基因组学、成像和临床试验执行。我们将利用北美的机会 参与STAMPEDE试验，不仅仅是在首次大型III期试验中确定MDT的真正影响， 在PCa中试验MDT，但使用这种与NCI合作的临床试验来开发第一个 使用常规和分子PET成像的放射组学预测MDT获益的生物标志物，以及 作为原发性、转移性和液体活检的测序。这一目标将通过三个具体的 目标。目标1将重点关注III期随机化北美子研究的开展，以确定 在标准全身治疗和原发灶治疗中加入MDT可提高无失败生存率。五 中心将参与，包括NIH临床中心。这些患者将全部纳入国际 STAMPEDE试验，主要终点为总生存期。目标2将利用基线CT和骨 收集所有患者的扫描，以及将发送给NCI进行治疗前18F的子集- 进行DCFPyL PET/CT扫描（n=50）。将进行放射组学分析和图像特征提取， 这些信息将用于确定哪些男性从MDT中获益最多。我们假设一个子集 的男性将从MDT中获益最多，并可通过成像生物标志物进行识别。目标3将利用 基线前列腺活检、转移性活检、根治性前列腺切除术标本和液体活检（循环 肿瘤细胞和无细胞DNA），以注释寡转移性PCa的分子景观。这些数据将 然后用于开发预测性生物标志物，以确定哪些男性从MDT中获益最多。国际 将储存患者样本以供日后验证。我们假设一个离散的分子图谱 描述哪些男性最有可能从MDT中治愈。这项工作的影响非常大，因为它 有可能治愈目前无法治愈的转移性前列腺癌患者。成功完成 这些目标将产生预测性生物标志物，这些生物标志物可以直接影响患有糖尿病的男性的临床管理。 寡转移性PCa，并改变目前的治疗模式。

Project Summary/Abstract The long-term goal of this project is to determine the clinical impact of metastasis-directed radiotherapy (MDT) in men with de novo oligometastatic prostate cancer (PCa), and identify which men may be cured and benefit most from MDT. We aim to achieve this goal through the conduct of a phase 3 randomized controlled trial with prospective imaging and biospecimen (e.g. tissue and blood) collection. This trial is novel in that it is a randomized North American sub-study (n=200) of the next arm (Arm M) of the international landmark multi- arm, multi-stage, STAMPEDE trial. The ability to conduct this trial with comprehensive biospecimen collection and imaging analysis will be achieved through our unique research team across extramural and intramural centers, comprised of experts in prognostic and predictive biomarker signature identification, bioinformatics, biostatistics, genomics, imaging, and clinical trial execution. We will leverage the opportunity for North America to participate in the STAMPEDE trial to not simply identify the true impact of MDT in the first ever large phase 3 trial testing MDT in PCa, but use this one of a kind clinical trial working with the NCI to develop the first predictive biomarkers of benefit of MDT using radiomics of conventional and molecular PET imaging, as well as sequencing of primary, metastatic, and liquid biopsies. This goal will be carried out through three specific aims. Aim 1 will focus on the conduct of the phase 3 randomized North American sub-study to determine if the addition of MDT to standard systemic therapy and treatment of the primary improves failure-free survival. Five centers will participate, including the NIH Clinical Center. These patients will all be included in the international STAMPEDE trial with the primary endpoint of overall survival. Aim 2 will leverage the baseline CT and bone scans collected on all patients, as well as a subset that will be sent to the NCI to have pre-treatment 18F- DCFPyL PET/CT scans performed (n=50). Radiomic analyses and image feature extraction will be performed, and this information will be used to identify which men benefit most from MDT. We hypothesize that a subset of men will benefit most from MDT and be identifiable through an imaging biomarker. Aim 3 will utilize the baseline prostate biopsy, metastatic biopsies, radical prostatectomy specimens, and liquid biopsies (circulating tumor cells and cell-free DNA), to annotate the molecular landscape of oligometastatic PCa. This data will then be used to develop a predictive biomarker to identify which men benefit most from MDT. International patient samples will be banked for later validation. We hypothesize that a discrete molecular profile will characterize which men are most likely to be cured from MDT. The impact of this work is extremely large, as it has the potential to cure a currently incurable subset of men with metastatic PCa. Successful completion of these aims would result in predictive biomarkers that could directly impact the clinical management of men with oligometastatic PCa, and transform current treatment paradigms.