随机、双盲、生物标志物选择、Ⅱ期临床试验：在转移性尿路上皮癌化疗后用芦卡帕利维持多聚 ADP-核糖聚合酶抑制。

A Randomized, Double-Blind, Biomarker-Selected, Phase II Clinical Trial of Maintenance Poly ADP-Ribose Polymerase Inhibition With Rucaparib Following Chemotherapy for Metastatic Urothelial Carcinoma.

机构信息

Southampton Experimental Cancer Medicine Centre, University of Southampton, Southampton, United Kingdom.

University of Sheffield and Sheffield Teaching Hospitals, Sheffield, United Kingdom.

出版信息

J Clin Oncol. 2023 Jan 1;41(1):54-64. doi: 10.1200/JCO.22.00405. Epub 2022 Aug 12.

PURPOSE

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.

METHODS

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.

RESULTS

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 = .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% 30.0%), nausea (36.8% 5.0%), rash (21.1% 0%), and raised alanine aminotransferase (57.9% 10%) were more common with rucaparib.

CONCLUSION

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.

目的

存在一种 DNA 修复缺陷（DRD）表型，存在于一部分转移性尿路上皮癌（mUC）患者中，这些患者对铂类化疗有获益。我们检测了在铂类化疗后，用多聚 ADP-核糖聚合酶抑制剂芦卡帕尼（rucaparib）进行维持治疗，用于 DRD 生物标志物阳性的 mUC。

方法

在化疗后 10 周内且无癌症进展的 DRD 生物标志物阳性 mUC 患者，按 1:1 随机分配（随机分组）接受芦卡帕尼 600 mg 每日两次口服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）。该信号探索性试验的目标是，针对该试验，风险比为 0.5，单侧 20%的 α 值。通过意向治疗，在 Cox 模型中比较试验臂之间的 PFS（RECIST 1.1）。

结果

在 248 例患者中，74 例（29.8%）为 DRD 生物标志物阳性，40 例被随机分配。在芦卡帕尼和安慰剂组中，分别有 12 例（60%）和 20 例（100%）发生了 PFS 事件（仍存活患者的中位随访时间为 94.6 周）。芦卡帕尼组的中位 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 =.07）。在安全性人群（n=39）中，治疗相关不良事件大多为低级别。患者接受了中位数为 10 个周期的芦卡帕尼或 6 个周期的安慰剂治疗。芦卡帕尼组的治疗相关不良事件（所有级别）更常见，包括疲劳（63.2% 30.0%）、恶心（36.8% 5.0%）、皮疹（21.1% 0%）和丙氨酸氨基转移酶升高（57.9% 10%）。