Department of Oncology, Wayne State University School of Medicine and Karmanos Cancer Institute, Detroit, Michigan, USA
Department of Oncology, Wayne State University School of Medicine and Karmanos Cancer Institute, Detroit, Michigan, USA.
Oncologist. 2019 Sep;24(9):1149-e807. doi: 10.1634/theoncologist.2019-0331. Epub 2019 May 31.
The negative results are consistent with the negative results of large phase III trials in which docetaxel plus antiangiogenic agents were used in patients with metastatic castrate-resistant prostate cancer (mCRPC).The negative data underscore that, despite a sound biological rationale and supportive early-phase clinical results, adding antiangiogenic agents to docetaxel for mCRPC is a great challenge.
Inhibition of vascular endothelial growth factor (VEGF) signaling abrogates tumor-induced angiogenesis to constrain tumor growth, and can be exploited therapeutically by using cediranib, an oral tyrosine kinase inhibitor of VEGF receptor signaling. Our preliminary phase I trial data showed that adding cediranib to docetaxel plus prednisone (DP) was safe and feasible, with early evidence for efficacy in patients with metastatic castrate-resistant prostate cancer (mCRPC).
This multicenter phase II trial assessed whether adding cediranib to DP improves efficacy of DP in patients with mCRPC. Chemotherapy-naive patients with mCRPC were randomly assigned to receive either docetaxel (75 mg/m intravenously every 3 weeks) with prednisone (5 mg twice daily) plus cediranib (30 mg once daily; the DP+C arm) or DP only (the DP arm). The primary endpoint was to compare 6-month progression-free survival (PFS) rate between the two arms. Secondary endpoints included 6-month overall survival (OS), objective tumor and prostate-specific antigen (PSA) response rates, biomarkers, and adverse events.
The 6-month PFS rate in a total of 58 patients was only numerically higher in the DP+C arm (61%) compared with the DP arm (57%). Similarly, the 6-month OS rate, objective tumor and PSA response rates, and biomarkers were not significantly different between the two arms. Increased baseline levels of interleukin 6 (IL-6), however, were significantly associated with increased risk of progression. Neutropenia was the only grade 4 toxicity (38% in the DP+C arm vs. 18% in the DP arm).
Combining cediranib with docetaxel + prednisone failed to demonstrate superior efficacy, compared with docetaxel + prednisone, and added toxicity. Our data do not support pursuing the combination further in patients with mCRPC.
这些阴性结果与大型三期临床试验的阴性结果一致，这些试验中在转移性去势抵抗性前列腺癌（mCRPC）患者中使用多西他赛联合抗血管生成药物。这些阴性数据强调，尽管有合理的生物学基础和早期临床结果的支持，将抗血管生成药物添加到多西他赛中用于 mCRPC 仍然是一个巨大的挑战。
抑制血管内皮生长因子（VEGF）信号可阻断肿瘤诱导的血管生成，从而限制肿瘤生长，并可通过使用西地尼布（一种 VEGF 受体信号的口服酪氨酸激酶抑制剂）进行治疗。我们的初步 I 期试验数据表明，将西地尼布添加到多西他赛加泼尼松（DP）中是安全且可行的，并且在转移性去势抵抗性前列腺癌（mCRPC）患者中具有早期疗效证据。
这项多中心 II 期试验评估了在 DP 中添加西地尼布是否能提高 DP 在 mCRPC 患者中的疗效。化疗初治的 mCRPC 患者被随机分配接受多西他赛（75mg/m 静脉注射，每 3 周一次）加泼尼松（5mg 每日两次）加西地尼布（30mg 每日一次；DP+C 组）或 DP 单药（DP 组）。主要终点是比较两组患者 6 个月无进展生存期（PFS）率。次要终点包括 6 个月总生存期（OS）、客观肿瘤和前列腺特异性抗原（PSA）反应率、生物标志物和不良事件。
58 例患者的总 6 个月 PFS 率仅在 DP+C 组（61%）略高于 DP 组（57%）。同样，两组患者的 6 个月 OS 率、客观肿瘤和 PSA 反应率以及生物标志物均无显著差异。然而，基线白细胞介素 6（IL-6）水平升高与进展风险增加显著相关。中性粒细胞减少是唯一的 4 级毒性（DP+C 组 38%，DP 组 18%）。
与多西他赛+泼尼松相比，西地尼布联合多西他赛+泼尼松并未显示出更好的疗效，且毒性增加。我们的数据不支持进一步在 mCRPC 患者中探索该联合治疗。
