我们的目的是通过利用国家数据存储库来评估 PARP 抑制剂奥拉帕尼对患有转移性前列腺癌 (mPC) 的美国退伍军人的真实疗效，并评估一种新方法来评估罕见或含有罕见突变的肿瘤的治疗效果。退伍军人 1) 患有同源重组修复 (HRR) 相关基因体细胞或种系改变/突变的 mPC，2) 接受奥拉帕尼单一疗法以及新型激素疗法/雄激素受体途径抑制剂 (NHT/ARPI) 和/或化疗，和 3) 使用接受治疗时获得的 PSA 值估计肿瘤生长率（g 率）。之前的研究表明，g 率与生存率存在极好的负相关性。使用 g 速率，我们确定了肿瘤倍增时间 (DT) 和 DT 比率（奥拉帕尼的 DT/先前用药的 DT）。我们假设 DT 比率≥ 1 与获益相关。我们确定了 139 名退伍军人，其中包括 42 名患有 HRR 基因突变/改变肿瘤的黑人男性，他们接受了奥拉帕尼治疗：BRCA2 (50)、ATM (32)、BRCA1 (10)、其他突变（47）。 62/139 (45%) 的黑人退伍军人和 21/42 (50%) 的黑人退伍军人的 DT 比率≥1，其中分别有 31、10、2 和 19 人携带 BRCA2、ATM、BRCA1 和其他突变 (p = 0.006）。 DT 比率≥1 的中位生存期较高，为 24.5 个月，而 DT 比率 <1 的中位生存期为 11.4 个月（p = 0.01，HR 0.50，95% CI 0.29-0.85）。奥拉帕尼的获益（定义为 DT 比率≥1）未观察到种系状态、起始 PSA 值、先前治疗次数或先前治疗。与匹配队列相比，奥拉帕尼队列中的肿瘤在一线使用恩杂鲁胺时的 DT 较短（367 天与 884 天；p = 0.0043）。使用与现实世界疗效分析理想的评估时间无关的方程，我们显示 DT 比率 ≥图 1 代表奥拉帕尼治疗后肿瘤生长较之前治疗减慢与生存率提高相关。奥拉帕尼对患有 HRR 基因突变/改变的 mPC 退伍军人的疗效模拟了临床试验结果。黑人男性也有类似的结果。与匹配队列相比，在一线治疗中，恩杂鲁胺对 HRR 基因突变/改变的肿瘤的疗效较差。美国临床肿瘤学会征服癌症基金会 (ASCO CCF)、Blavatnik 家庭基金会和前列腺癌基金会 (PCF)。版权所有© 2024 作者。由 Elsevier B.V. 出版。保留所有权利。

We aimed to assess real-world efficacy of the PARP inhibitor, olaparib, in US Veterans with metastatic prostate cancer (mPC) by leveraging the national data repository and evaluate a novel approach to assess treatment efficacy in tumors considered rare or harboring rare mutations.Included Veterans had 1) mPC with somatic or germline alterations/mutations in genes involved in homologous recombination repair (HRR), 2) received olaparib monotherapy as well as a novel hormonal therapy/androgen receptor pathway inhibitors (NHT/ARPI), and/or chemotherapy, and 3) estimable rates of tumor growth (g-rate) using PSA values obtained while receiving treatment. Previous work has shown an excellent inverse correlation of g-rate with survival. Using g-rate, we determined tumor doubling time (DT) and DT ratios (DT on olaparib/DT on prior medication). We postulated that a DT ratio≥ 1 was associated with benefit.We identified 139 Veterans, including 42 Black males with tumors harboring mutations/alterations in HRR genes who received olaparib: BRCA2 (50), ATM (32), BRCA1 (10), other mutations (47). 62/139 (45%) of all and 21/42 (50%) of Black Veterans had DT ratios ≥1, including 31, 10, 2, and 19 with BRCA2, ATM, BRCA1, and other mutations, respectively (p = 0.006). Median survival with DT ratios ≥1 was superior, being 24.5 vs. 11.4 months for DT ratio <1 (p = 0.01, HR 0.50, 95% CI 0.29-0.85). Benefit from olaparib, defined as DT ratio ≥1, was not observed for germline status, starting PSA value, number of prior therapies, or immediate prior therapy. Compared to matched cohorts, tumors in the olaparib cohort had shorter DTs with enzalutamide in first line (367 vs. 884 days; p = 0.0043).Using equations indifferent to timing of assessments ideal for real-world efficacy analyses, we showed DT ratio ≥1 representing slower tumor growth on olaparib relative to the prior therapy correlates with improved survival. Olaparib efficacy in Veterans with mPC harboring mutations/alterations in HRR genes emulates clinical trial results. Black men had comparable results. Compared to matched cohorts, in first line, enzalutamide was less efficacious in tumors harboring mutations/alterations in HRR genes.American Society of Clinical Oncology Conquer Cancer Foundation (ASCO CCF), the Blavatnik Family Foundation and the Prostate Cancer Foundation (PCF).Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.