利用时间无关的g-速率方法评估美国退伍军人中转移性前列腺癌患者的奥拉帕尼疗效，适用于真实世界分析

本研究旨在利用国家数据仓库评估PARP抑制剂奥拉帕尼在美国转移性前列腺癌（mPC）患者中的真实世界疗效，并探索一种新颖的评价肿瘤治疗效果的方法，特别适用于罕见或携带罕见突变的肿瘤。纳入的退伍军人符合以下条件：1）伴有同源重组修复（HRR）相关基因突变或变异的mPC；2）接受奥拉帕尼单药治疗及/或新型激素疗法/雄激素受体通路抑制剂（NHT/ARPI）和/或化疗；3）在治疗期间通过血清前列腺特异抗原（PSA）值评估肿瘤增长速率（g-速率）。已有研究显示，g-速率与存活率高度相关。我们利用g-速率计算肿瘤倍增时间（DT）及其比值（DT在奥拉帕尼治疗期间/先前治疗期间），假设DT比值≥1代表治疗获益。共识别出139名退伍军人，其中包括42名黑人男性，肿瘤携带HRR基因突变或变异：BRCA2（50例）、ATM（32例）、BRCA1（10例）及其他突变（47例）。其中45%（62/139）和50%（21/42）的黑人退伍军人在奥拉帕尼治疗期间的DT比值≥1，具体包括BRCA2（31例）、ATM（10例）、BRCA1（2例）及其他突变（19例）（p=0.006）。DT比值≥1的中位生存期更优，为24.5个月，而DT比值<1者为11.4个月（p=0.01，HR 0.50，95% CI 0.29-0.85）。奥拉帕尼的疗效（DT比值≥1）与胚系突变状态、起始PSA值、既往治疗次数或最近一次治疗无关。与匹配队列相比，奥拉帕尼组肿瘤在一线使用恩扎鲁胺的DT较短（367天对884天；p=0.0043）。利用适合真实世界疗效分析的时间无关的方程，我们发现DT比值≥1表示奥拉帕尼相较于先前治疗能减缓肿瘤生长，且与生存改善相关。在携带HRR基因突变的mPC退伍军人中，奥拉帕尼的疗效与临床试验结果一致。黑人男性的结果也类似。与匹配队列相比，一线治疗中，恩扎鲁胺在携带HRR突变的肿瘤中的疗效较差。美国临床肿瘤学会（ASCO CCF）、布拉瓦特尼克家族基金会和前列腺癌基金会（PCF）共同支持这一研究。

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).