Background Five-year survival of patients with inoperable, advanced urothelial carcinoma treated with the first-line chemotherapy is 5%-15%. We assessed whether the Hsp27 inhibitor apatorsen combined with gemcitabine plus cisplatin (GC) could improve overall survival (OS) in these patients. Patients and methods This placebo-controlled, double-blind, phase II trial randomized 183 untreated urothelial carcinoma patients (North America and Europe) to receive GC plus either placebo (N = 62), 600 mg apatorsen (N = 60), or 1000 mg apatorsen (N = 61). In the experimental arm, treatment included loading doses of apatorsen followed by up to six cycles of apatorsen plus GC. Patients receiving at least four cycles could continue apatorsen monotherapy as maintenance until progression or unacceptable toxicity. The primary end point was OS. Results OS was not significantly improved in the single or combined 600- or 1000-mg apatorsen arms versus placebo [hazard ratio (HR), 0.86 and 0.90, respectively]. Exploratory study of specific statistical modeling showed a trend for improved survival in patients with baseline poor prognostic features treated with 600 mg apatorsen compared with placebo (HR = 0.72). Landmark analysis of serum Hsp27 (sHsp27) levels showed a trend toward survival benefit for poor-prognosis patients in 600- and 1000-mg apatorsen arms who achieved lower area under the curve sHsp27 levels, compared with the placebo arm (HR = 0.45 and 0.62, respectively). Higher baseline circulating tumor cells (≥5 cells/7.5 ml) was observed in patients with poor prognosis in correlation with poor survival. Treatment-emergent adverse events were manageable and more common in both apatorsen-treatment arms. Conclusions Even though apatorsen combined with standard chemotherapy did not demonstrate a survival benefit in the overall study population, patients with poor prognostic features might benefit from this combination. Serum Hsp27 levels may act as a biomarker to predict treatment outcome. Further exploration of apatorsen in poor-risk patients is warranted.

中文翻译：

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Borealis-1：一项随机、一线、安慰剂对照、II 期研究，评估晚期尿路上皮癌患者的 apatorsen 和化疗。

背景 无法手术的晚期尿路上皮癌患者接受一线化疗的 5 年生存率为 5%-15%。我们评估了 Hsp27 抑制剂 apatorsen 联合吉西他滨加顺铂 (GC) 是否可以提高这些患者的总生存期 (OS)。患者和方法 这项安慰剂对照、双盲、II 期试验将 183 名未经治疗的尿路上皮癌患者（北美和欧洲）随机分配接受 GC 加安慰剂（N = 62）、600 mg apatorsen（N = 60）或 1000毫克 apatorsen (N = 61)。在实验组中，治疗包括加载剂量的 apatorsen，然后是多达 6 个周期的 apatorsen 加 GC。接受至少四个周期的患者可以继续使用 apatorsen 单药治疗作为维持治疗，直至疾病进展或出现不可接受的毒性。主要终点是 OS。结果 与安慰剂相比，单独或联合 600 或 1000 毫克 apatorsen 组的 OS 没有显着改善 [风险比 (HR) 分别为 0.86 和 0.90]。对特定统计模型的探索性研究表明，与安慰剂相比，接受 600 mg apatorsen 治疗的基线预后不良的患者有改善生存率的趋势（HR = 0.72）。血清 Hsp27 (sHsp27) 水平的标志性分析显示，与安慰剂组相比，600 和 1000 毫克 apatoren 组的 sHsp27 水平曲线下面积较低的预后不良患者的生存获益趋势（HR = 0.45 和 0.62 ， 分别）。在预后较差的患者中观察到较高的基线循环肿瘤细胞（≥5 个细胞/7.5 ml）与较差的生存期相关。治疗中出现的不良事件是可控的，并且在两个 apatorsen 治疗组中更为常见。结论 尽管 apatoren 联合标准化疗并未显示出对整个研究人群的生存益处，但预后不良的患者可能会从这种组合中受益。血清 Hsp27 水平可作为预测治疗结果的生物标志物。有必要在低风险患者中进一步探索 apatorsen。