Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, North Carolina.
Division of Medical Oncology, Department of Medicine, Duke University, Durham, North Carolina.
Prostate. 2019 Nov;79(15):1752-1761. doi: 10.1002/pros.23899. Epub 2019 Sep 9.
Docetaxel prednisone is a standard of care for men with metastatic castration-resistant prostate cancer (mCRPC), and plasma vascular endothelial growth factor (VEGF) levels are a poor prognostic factor in this population; therefore, we evaluated the combination of docetaxel prednisone with pazopanib, an oral VEGF receptor inhibitor, for safety and preliminary efficacy.
This is a two-site phase 1b Department of Defense Prostate Cancer Clinical Trials Consortium trial of docetaxel, prednisone, and pazopanib once daily and ongoing androgen deprivation therapy and prophylactic pegfilgrastim in men with mCRPC. The primary endpoint was safety and the determination of a maximum tolerated dose (MTD) through a dose-escalation and expansion design; secondary endpoints included progression-free and overall survival (OS), prostate specific antigen (PSA) declines, radiographic responses, and pharmacokinetic and plasma angiokine biomarker analyses.
Twenty-five men were treated over six dose levels. Pegfilgrastim was added to the regimen after myelosuppression limited dose escalation. With pegfilgrastim, our target MTD of docetaxel 75 mg/m q3 weeks; prednisone 10 mg daily; and pazopanib 800 mg daily was reached. Eleven additional patients were accrued at this dose level for a total of 36 patients. Dose-limiting toxicities included neutropenia, syncope, and hypertension. Three deaths attributed to study treatment occurred. The objective response rate was 31%; median PFS was 14.1 months (95% confidence interval [CI]: 7.1 and 22.2); and OS was 18.6 months (95% CI: 11.8 and 22.2).
The combination of docetaxel, prednisone, and pazopanib (with pegfilgrastim) was tolerable at full doses and demonstrated promising efficacy in a relatively poor risk patients with mCRPC. Further development of predictive biomarkers may enrich for patients who receive clinical benefit from this regimen.
多西他赛泼尼松是转移性去势抵抗性前列腺癌（mCRPC）患者的标准治疗方法，而该人群中血浆血管内皮生长因子（VEGF）水平是预后不良的因素；因此，我们评估了多西他赛泼尼松与口服 VEGF 受体抑制剂帕唑帕尼联合用于该人群的安全性和初步疗效。
这是一项由国防部前列腺癌临床试验联盟进行的、在两个地点开展的 1b 期试验，评估了多西他赛、泼尼松和帕唑帕尼每日一次联合持续雄激素剥夺治疗和预防性培非格司亭在 mCRPC 男性患者中的安全性和初步疗效。主要终点是安全性，并通过剂量递增和扩展设计确定最大耐受剂量（MTD）；次要终点包括无进展生存期（PFS）和总生存期（OS）、前列腺特异性抗原（PSA）下降、影像学反应以及药代动力学和血浆血管生成素生物标志物分析。
25 名男性接受了 6 个剂量水平的治疗。在骨髓抑制限制剂量递增后，加入培非格司亭。培非格司亭加入后，我们达到了多西他赛 75mg/m q3 周、泼尼松 10mg 每日和帕唑帕尼 800mg 每日的目标 MTD。在该剂量水平上又入组了 11 名患者，总共 36 名患者。剂量限制性毒性包括中性粒细胞减少症、晕厥和高血压。有 3 例与研究治疗相关的死亡。客观缓解率为 31%；中位 PFS 为 14.1 个月（95%CI：7.1 和 22.2）；OS 为 18.6 个月（95%CI：11.8 和 22.2）。
多西他赛、泼尼松和帕唑帕尼（联合培非格司亭）在全剂量下可耐受，并且在 mCRPC 预后较差的患者中显示出有希望的疗效。进一步开发预测性生物标志物可能会使从该方案中获得临床获益的患者受益。
