A DNA repair deficiency (DRD) phenotype exists within a subset of metastatic urothelial carcinomas (mUC) predicting benefit from platinum-based chemotherapy. We tested switch maintenance therapy with the poly ADP-ribose polymerase inhibitor rucaparib, following chemotherapy, for DRD biomarker–positive mUC.

DRD biomarker–positive mUC patients, within 10 weeks of chemotherapy, and without cancer progression, were randomly assigned (1:1) to maintenance rucaparib 600 mg twice a day orally, or placebo, until disease progression. The primary end point was progression-free survival (PFS). Statistical analysis targeted a hazard ratio of 0.5 with a 20% one-sided α for this signal-seeking trial. PFS (RECIST 1.1) was compared between trial arms, by intention to treat, within a Cox model.

Out of 248 patients, 74 (29.8%) were DRD biomarker–positive and 40 were randomly assigned. A total of 12 (60%) and 20 (100%) PFS events occurred in the rucaparib and placebo arms, respectively (median follow-up was 94.6 weeks in those still alive). Median PFS was 35.3 weeks (80% CI, 11.7 to 35.6) with rucaparib and 15.1 weeks (80% CI, 11.9 to 22.6) with placebo (hazard ratio, 0.53; 80% CI, 0.30 to 0.92; one-sided P = .07). In the safety population (n = 39) treatment-related adverse events were mostly low grade. Patients received a median duration of 10 rucaparib or six placebo cycles on treatment. Treatment-related adverse events (all grades) of fatigue (63.2% v 30.0%), nausea (36.8% v 5.0%), rash (21.1% v 0%), and raised alanine aminotransferase (57.9% v 10%) were more common with rucaparib.

Maintenance rucaparib, following platinum-based chemotherapy, extended PFS in DRD biomarker-selected patients with mUC and was tolerable. Further investigation of poly ADP-ribose polymerase inhibition in selected patients with mUC is warranted.

DNA 修复缺陷 (DRD) 表型存在于转移性尿路上皮癌 (mUC) 的一个子集中，预测铂类化疗的益处。我们测试了化疗后使用聚 ADP-核糖聚合酶抑制剂 rucaparib 的转换维持疗法，以治疗 DRD 生物标志物阳性 mUC。

化疗后 10 周内且无癌症进展的 DRD 生物标志物阳性 mUC 患者被随机分配 (1:1) 接受每日两次口服 rucaparib 600 mg 维持治疗或安慰剂治疗，直至疾病进展。主要终点是无进展生存期（PFS）。对于此信号搜索试验，统计分析的目标风险比为 0.5，单侧 α 为 20%。在 Cox 模型中，通过意向治疗在试验组之间比较 PFS (RECIST 1.1)。

在 248 名患者中，74 名 (29.8%) 为 DRD 生物标志物阳性，40 名被随机分配。rucaparib 组和安慰剂组分别发生了 12 起 (60%) 和 20 起 (100%) 的 PFS 事件（仍然存活的患者的中位随访时间为 94.6 周）。rucaparib 组的中位 PFS 为 35.3 周（80% CI，11.7 至 35.6），安慰剂组为 15.1 周（80% CI，11.9 至 22.6）（风险比，0.53；80% CI，0.30 至 0.92；单侧 P = . 07). 在安全人群 (n = 39) 中，与治疗相关的不良事件大多是低级别的。患者在治疗中接受了 10 个 rucaparib 或 6 个安慰剂周期的中位持续时间。疲劳（63.2%对30.0%）、恶心（36.8%对5.0%）、皮疹（21.1%对0%）和丙氨酸氨基转移酶升高（57.9%对10%）在 rucaparib 中更常见。

含铂化疗后的维持性 rucaparib 延长了 DRD 生物标志物选择的 mUC 患者的 PFS，并且是可以耐受的。有必要对选定的 mUC 患者进行聚 ADP-核糖聚合酶抑制的进一步研究。