尽管不同的肾癌代表一组异质性恶性肿瘤，但多种亚型包括 Von Hippel-Lindau (VHL) 改变的透明细胞肾细胞癌 (ccRCC)、富马酸水合酶 (FH) 和琥珀酸脱氢酶 (SDH) 缺陷型肾细胞癌。 RCC）和肾髓样癌（RMC）受基因组不稳定性的影响。在这些亚型的临床前模型中已表明聚 ADP-核糖聚合酶抑制剂 (PARPis) 具有合成致死作用，并且将 PARPis 与免疫检查点阻断 (ICB) 配对可能对既往接受过治疗的晚期肾癌患者实现相加和/或协同作用。评估治疗 - 难治性转移性肾癌中的parpi ICB合并。我们在两个基因组选择的晚期肾癌同类中进行了单中心，研究者引发的2期试验：（1）（1）与至少一个先前的ICB剂和一个ICB剂和一个vhl的RCC血管内皮生长因子 (VEGF) 抑制剂，以及 (2) FH 或 SDH 缺陷性 RCC 接受过至少一种既往 ICB 药物或 VEGF 抑制剂，以及 RMC 接受过至少一种既往化疗。患者每天接受 1 mg talazoparib 加 avelumab 800 28 天周期中，每 14 天静脉注射一次。主要终点是 4 个月时实体瘤免疫反应评估标准的客观缓解率 (ORR)，次要终点包括无进展生存期 (PFS)、总生存期和安全性。第 1 组由 10 名患有 VHL 改变的 ccRCC 患者组成。所有患者之前均接受过 ICB。患者的 ORR 为 0/9；一名患者因漏服剂量而无法进行评估。在该队列中，七名患者达到了疾病稳定 (SD) 作为最佳反应。中位 PFS 为 3.5 个月（95% 置信区间 [CI] 1.0, 3.9 个月）。第 2 组由 8 名患者组成； 4 例患有 FH 缺陷型 RCC，1 例患有 SDH 缺陷型 RCC，3 例患有 RMC。在该队列中，有 6 名患者之前接受过 ICB。患者的 ORR 为 0/8；两名患者达到 SD 作为最佳缓解，中位 PFS 为 1.2 个月（95% CI 0.4，2.9 个月）。所有级别中最常见的治疗相关不良事件是疲劳（61%）、贫血（28%）、恶心（22%）和头痛（22%）。有 7 例 3-4 级事件，没有 5 级事件。第一项 PARPi 和 ICB 联合治疗晚期肾癌的临床研究在多个基因组定义的转移性 RCC 队列或 RMC 中没有显示出临床益处。我们进行了一项研究来观察两种药物（talazoparib 和 avelumab）对标准治疗后疾病进展的转移性肾癌患者的影响。 Talazoparib 阻断聚 ADP-核糖聚合酶分子的正常活性，从而阻止肿瘤细胞自我修复和生长，而 avelumab 则帮助免疫系统识别并杀死癌细胞。我们发现这些药物的组合是安全的，但对特定类型的肾癌无效。版权所有 © 2023 欧洲泌尿外科协会。由 Elsevier B.V. 出版。保留所有权利。

Although different kidney cancers represent a heterogeneous group of malignancies, multiple subtypes including Von Hippel-Lindau (VHL)-altered clear cell renal cell carcinoma (ccRCC), fumarate hydratase (FH)- and succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC), and renal medullary carcinoma (RMC) are affected by genomic instability. Synthetic lethality with poly ADP-ribose polymerase inhibitors (PARPis) has been suggested in preclinical models of these subtypes, and paired PARPis with immune checkpoint blockade (ICB) may achieve additive and/or synergistic effects in patients with previously treated advanced kidney cancers.To evaluate combined PARPi + ICB in treatment-refractory metastatic kidney cancer.We conducted a single-center, investigator-initiated phase 2 trial in two genomically selected advanced kidney cancer cohorts: (1) VHL-altered RCC with at least one prior ICB agent and one vascular endothelial growth factor (VEGF) inhibitor, and (2) FH- or SDH-deficient RCC with at least one prior ICB agent or VEGF inhibitor and RMC with at least one prior line of chemotherapy.Patients received talazoparib 1 mg daily plus avelumab 800 mg intravenously every 14 d in 28-d cycles.The primary endpoint was objective response rate (ORR) by Immune Response Evaluation Criteria in Solid Tumors at 4 mo, and the secondary endpoints included progression-free survival (PFS), overall survival, and safety.Cohort 1 consisted of ten patients with VHL-altered ccRCC. All patients had previously received ICB. The ORR was 0/9 patients; one patient was not evaluable due to missed doses. In this cohort, seven patients achieved stable disease (SD) as the best response. The median PFS was 3.5 mo (95% confidence interval [CI] 1.0, 3.9 mo). Cohort 2 consisted of eight patients; four had FH-deficient RCC, one had SDH-deficient RCC, and three had RMC. In this cohort, six patients had previously received ICB. The ORR was 0/8 patients; two patients achieved SD as the best response and the median PFS was 1.2 mo (95% CI 0.4, 2.9 mo). The most common treatment-related adverse events of all grades were fatigue (61%), anemia (28%), nausea (22%), and headache (22%). There were seven grade 3-4 and no grade 5 events.The first clinical study of combination PARPi and ICB therapy in advanced kidney cancer did not show clinical benefit in multiple genomically defined metastatic RCC cohorts or RMC.We conducted a study to look at the effect of two medications, talazoparib and avelumab, in patients with metastatic kidney cancer who had disease progression on standard treatment. Talazoparib blocks the normal activity of molecules called poly ADP-ribose polymerase, which then prevents tumor cells from repairing themselves and growing, while avelumab helps the immune system recognize and kill cancer cells. We found that the combination of these agents was safe but not effective in specific types of kidney cancer.Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.