IMPORTANCE Preclinical studies suggest that inhibition of single-stranded DNA repair by ataxia telangiectasia and Rad3 (ATR) may enhance the cytotoxicity of cisplatin, gemcitabine, and other chemotherapeutic agents. Cisplatin with gemcitabine remains the standard up-front therapy for treatment in patients with metastatic urothelial cancer. OBJECTIVE To determine whether the use of the selective ATR inhibitor, berzosertib, could augment the activity of cisplatin with gemcitabine. DESIGN, SETTING, AND PARTICIPANTS In a phase 2 randomized clinical trial, 87 patients across 23 centers in the National Cancer Institute Experimental Therapeutics Clinical Trials Network were randomized to receive either cisplatin with gemcitabine alone (control arm) or cisplatin with gemcitabine plus berzosertib (experimental arm). Key eligibility criteria included confirmed metastatic urothelial cancer, no prior cytotoxic therapy for metastatic disease, 12 months or more since perioperative therapy, and eligibility for cisplatin receipt based on standard criteria. The study was conducted from January 27, 2017, to December 15, 2020. INTERVENTIONS In the control arm, cisplatin, 70 mg/m2, was given on day 1 and gemcitabine, 1000 mg/m2, was given on days 1 and 8 of a 21-day cycle. In the experimental arm, cisplatin, 60 mg/m2, was given on day 1; gemcitabine, 875 mg/m2, on days 1 and 8; and berzosertib, 90 mg/m2, on days 2 and 9 of a 21-day cycle. MAIN OUTCOMES AND MEASURES The primary end point of the study was progression-free survival. The analysis was on all patients who started therapy. RESULTS Of the total of 87 patients randomized, 41 patients received cisplatin with gemcitabine alone and 46 received cisplatin with gemcitabine plus berzosertib. Median age was 67 (range, 32-84) years, and 68 patients (78%) were men. Median progression-free survival was 8.0 months for both arms (Bajorin risk-adjusted hazard ratio, 1.22; 95% CI, 0.72-2.08). Median overall survival was shorter with cisplatin with gemcitabine plus berzosertib compared with cisplatin with gemcitabine alone (14.4 vs 19.8 months; Bajorin risk-adjusted hazard ratio, 1.42; 95% CI, 0.76-2.68). Higher rates of grade 3 vs grade 4 thrombocytopenia (59% vs 39%) and neutropenia (37% vs 27%) were observed with cisplatin with gemcitabine and berzosertib compared with cisplatin with gemcitabine alone; consequently, more dose reductions were needed in the experimental arm. Patients in the experimental arm received a median cisplatin dose of 250 mg/m2, which was significantly lower than the median dose of 370 mg/m2 in the control arm (P < .001). CONCLUSIONS AND RELEVANCE The addition of berzosertib to cisplatin with gemcitabine did not prolong progression-free survival relative to cisplatin with gemcitabine alone in patients with metastatic urothelial cancer, and a trend toward inferior survival was observed with this combination. Berzosertib plus cisplatin with gemcitabine was associated with significantly higher hematologic toxicities despite attenuated dosing of cisplatin with gemcitabine. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT02567409.

中文翻译：

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顺铂和吉西他滨联合或不联合 Berzosertib 对晚期尿路上皮癌患者的影响：一项 2 期随机临床试验。

重要性 临床前研究表明，共济失调毛细血管扩张症和 Rad3 (ATR) 抑制单链 DNA 修复可能会增强顺铂、吉西他滨和其他化疗药物的细胞毒性。顺铂联合吉西他滨仍然是治疗转移性尿路上皮癌患者的标准前期疗法。目的 确定使用选择性 ATR 抑制剂 berzosertib 是否可以增强吉西他滨顺铂的活性。设计、设置和参与者 在一项 2 期随机临床试验中，国家癌症研究所实验治疗临床试验网络 23 个中心的 87 名患者被随机分配接受顺铂单独吉西他滨治疗（对照组）或顺铂联合吉西他滨加 berzosertib 治疗（实验组）。手臂）。关键资格标准包括确诊的转移性尿路上皮癌、既往未接受过针对转移性疾病的细胞毒治疗、围手术期治疗后 12 个月或更长时间，以及根据标准接受顺铂的资格。该研究于 2017 年 1 月 27 日至 2020 年 12 月 15 日进行。 干预措施 在对照组中，第 1 天给予顺铂 70 mg/m2，第 1 天和第 8 天给予吉西他滨 1000 mg/m2。 21天为一个周期。实验组在第一天给予顺铂 60 mg/m2；吉西他滨，875 mg/m2，第 1 天和第 8 天；和 berzosertib，90 mg/m2，在 21 天周期的第 2 天和第 9 天。主要结果和措施 该研究的主要终点是无进展生存期。该分析针对所有开始治疗的患者。结果 在总共 87 名随机分组的患者中，41 名患者接受顺铂联合吉西他滨治疗，46 名患者接受顺铂联合吉西他滨联合 berzosertib 治疗。中位年龄为 67 岁（范围 32-84），68 名患者 (78%) 为男性。两组的中位无进展生存期均为 8.0 个月（Bajorin 风险调整风险比，1.22；95% CI，0.72-2.08）。与顺铂单独使用吉西他滨相比，顺铂联合吉西他滨联合 berzosertib 的中位总生存期较短（14.4 个月与 19.8 个月；Bajorin 风险调整风险比，1.42；95% CI，0.76-2.68）。与单用顺铂联合吉西他滨相比，顺铂联合吉西他滨和 berzosertib 观察到的 3 级血小板减少症（59% 比 39%）和中性粒细胞减少症（37% 比 27%）的发生率更高；因此，实验组需要进一步减少剂量。实验组患者接受的顺铂中位剂量为 250 mg/m2，显着低于对照组的中位剂量 370 mg/m2 (P < .001)。结论和相关性 在转移性尿路上皮癌患者中，在顺铂联合吉西他滨的基础上加用 berzosertib 并不能延长转移性尿路上皮癌患者的无进展生存期，并且观察到这种组合存在生存期较差的趋势。尽管减少了顺铂与吉西他滨的剂量，但 Berzosertib 加顺铂与吉西他滨的血液学毒性显着较高。试验注册 ClinicalTrials.gov 标识符：NCT02567409。结论和相关性 在转移性尿路上皮癌患者中，在顺铂联合吉西他滨的基础上加用 berzosertib 并不能延长转移性尿路上皮癌患者的无进展生存期，并且观察到这种组合存在生存期较差的趋势。尽管减少了顺铂与吉西他滨的剂量，但 Berzosertib 加顺铂与吉西他滨的血液学毒性显着较高。试验注册 ClinicalTrials.gov 标识符：NCT02567409。结论和相关性 在转移性尿路上皮癌患者中，在顺铂联合吉西他滨的基础上加用 berzosertib 并不能延长转移性尿路上皮癌患者的无进展生存期，并且观察到这种组合存在生存期较差的趋势。尽管减少了顺铂与吉西他滨的剂量，但 Berzosertib 加顺铂与吉西他滨的血液学毒性显着较高。试验注册 ClinicalTrials.gov 标识符：NCT02567409。尽管减少了顺铂与吉西他滨的剂量，但 Berzosertib 加顺铂与吉西他滨的血液学毒性显着较高。试验注册 ClinicalTrials.gov 标识符：NCT02567409。尽管减少了顺铂与吉西他滨的剂量，但 Berzosertib 加顺铂与吉西他滨的血液学毒性显着较高。试验注册 ClinicalTrials.gov 标识符：NCT02567409。