在一项多中心随机研究中，tasquinimod 对有轻微症状的转移性去势抵抗性前列腺癌男性患者的长期生存和生物标志物相关性分析。
Long-term survival and biomarker correlates of tasquinimod efficacy in a multicenter randomized study of men with minimally symptomatic metastatic castration-resistant prostate cancer.
机构信息
Authors' Affiliations: Duke Cancer Institute and the Duke Prostate Center, Duke University, Durham, North Carolina; University Hospital of Uppsala, Uppsala, Sweden; University of Chicago, Chicago, Illinois; University of Pittsburgh, Pittsburgh, Pennsylvania; Peachtree Hematology Oncology Consultants, Atlanta, Georgia; Kaiser Permanente Medical Group, San Diego, California; Sahlgrenska University Hospital, Gothenburg, Sweden; Urologic Consultants of SE PA, Bala Cynwyd, Pennsylvania; Active Biotech AB, Lund, Sweden; Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore Maryland; Roswell Park Cancer Institute, Buffalo, New York.
出版信息
Clin Cancer Res. 2013 Dec 15;19(24):6891-901. doi: 10.1158/1078-0432.CCR-13-1581. Epub 2013 Nov 19.
PURPOSE
Tasquinimod (Active Biotech) is an oral immunomodulatory, anti-angiogenic, and anti-metastatic agent that delayed metastatic disease progression in a randomized placebo-controlled phase II trial in men with metastatic castration-resistant prostate cancer (mCRPC). Here, we report long-term survival with biomarker correlates from this trial.
EXPERIMENTAL DESIGN
Two hundred and one (134 tasquinimod and 67 placebo) men with mCRPC were evaluated. Forty-one men randomized to placebo crossed over to tasquinimod. Survival data were collected with a median follow-up time of 37 months. Exploratory biomarker studies at baseline and over time were collected to evaluate potential mechanism-based correlates with tasquinimod efficacy including progression-free survival (PFS) and overall survival (OS).
RESULTS
With 111 mortality events, median OS was 33.4 months for tasquinimod versus 30.4 months for placebo overall, and 34.2 versus 27.1 months in men with bone metastases (n = 136), respectively. Multivariable analysis demonstrated an adjusted HR of 0.52 [95% confidence interval (CI), 0.35-0.78; P = 0.001] for PFS and 0.64 (95% CI, 0.42-0.97; P = 0.034) for OS, favoring tasquinimod. Time-to-symptomatic progression was improved with tasquinimod (P = 0.039, HR = 0.42). Toxicities tended to be mild in nature and improved over time. Biomarker analyses suggested a favorable impact on bone alkaline phosphatase and lactate dehydrogenase (LDH) over time and a transient induction of inflammatory biomarkers, VEGF-A, and thrombospondin-1 levels with tasquinimod. Baseline levels of thrombospondin-1 less than the median were predictive of treatment benefit.
CONCLUSIONS
The survival observed in this trial of men with minimally symptomatic mCRPC suggests that the prolongation in PFS with tasquinimod may lead to a survival advantage in this setting, particularly among men with skeletal metastases, and has a favorable risk:benefit ratio.
目的
Tasquinimod（Active Biotech）是一种口服免疫调节剂、抗血管生成剂和抗转移剂，在一项转移性去势抵抗性前列腺癌（mCRPC）男性的随机安慰剂对照 II 期试验中，该药物延迟了转移性疾病的进展。在这里，我们报告了来自该试验的长期生存数据及其与生物标志物的相关性。
实验设计
共评估了 201 名（134 名 tasquinimod 和 67 名安慰剂）mCRPC 男性患者。41 名随机分配至安慰剂的患者交叉至 tasquinimod 组。中位随访时间为 37 个月时收集了生存数据。在基线和随访时收集了探索性生物标志物研究，以评估 tasquinimod 疗效的潜在机制相关性，包括无进展生存期（PFS）和总生存期（OS）。
结果
在 111 例死亡事件中，tasquinimod 的中位 OS 为 33.4 个月，安慰剂组为 30.4 个月，在 136 例有骨转移的男性中，分别为 34.2 个月和 27.1 个月。多变量分析显示，在 PFS 方面，调整后的 HR 为 0.52（95%置信区间[CI]，0.35-0.78；P = 0.001），在 OS 方面，调整后的 HR 为 0.64（95%CI，0.42-0.97；P = 0.034），均有利于 tasquinimod。tasquinimod 组的症状性进展时间得到改善（P = 0.039，HR = 0.42）。毒性反应的性质倾向于轻微，并随时间推移而改善。生物标志物分析表明，随着时间的推移，骨碱性磷酸酶和乳酸脱氢酶（LDH）的水平有所改善，tasquinimod 可短暂诱导血管内皮生长因子-A（VEGF-A）和血栓反应蛋白-1（TSP-1）水平。基线 TSP-1 水平低于中位数与治疗获益相关。
结论
在这项对症状轻微的 mCRPC 男性的试验中观察到的生存结果表明，tasquinimod 延长 PFS 可能在这种情况下带来生存优势，特别是在有骨骼转移的男性中，并且具有良好的风险获益比。
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