Division of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, Canada.
Department of Medical Oncology, St. Claraspital, Basel, Switzerland.
Oncologist. 2019 Sep;24(9):1188-1194. doi: 10.1634/theoncologist.2018-0621. Epub 2019 Apr 5.
Enhancing the effectiveness of docetaxel for men with metastatic castration-resistant prostate cancer (mCRPC) is an unmet clinical need. Preclinical studies demonstrated that high-dose pantoprazole can prevent or delay resistance to docetaxel via the inhibition of autophagy in several solid tumor xenografts.
Men with chemotherapy-naive mCRPC with a prostate-specific antigen (PSA) >10 ng/mL were eligible for enrolment. Men received intravenous pantoprazole (240 mg) prior to docetaxel (75 mg/m) every 21 days, with continuous prednisone 5 mg twice daily. Primary endpoint was a confirmed ≥50% decline of PSA. The trial used a Simon's two-stage design.
Between November 2012 and March 2015, 21 men with a median age of 70 years (range, 58-81) were treated (median, 6 cycles; range, 2-11). Men had received prior systemic therapies (median, 1; range, 0-3), and 14 had received abiraterone and/or enzalutamide. PSA response rate was 52% (11/21), which did not meet the prespecified criterion (≥13/21 responders) to proceed to stage 2 of the study. At interim analysis with a median follow-up of 17 months, 18 (86%) men were deceased (15 castration-resistant prostate cancer, 2 unknown, 1 radiation complication). Of the men with RECIST measurable disease, the radiographic partial response rate was 31% (4/13). The estimated median overall survival was 15.7 months (95% confidence interval [CI], 9.3-19.6) and median PFS was 5.3 months (95% CI, 2.6-12.9). There were no toxic deaths, and all adverse events were attributed to docetaxel.
The combination of docetaxel and pantoprazole was tolerable, but the resultant clinical activity was not sufficient to meet the ambitious predefined target to warrant further testing.
To date, no docetaxel combination regimen has reported superior efficacy over docetaxel alone in men with metastatic castration-resistant prostate cancer (mCRPC). The PANDORA trial has demonstrated that the combination of high dose pantoprazole with docetaxel is tolerable, but the clinical activity was not sufficient to warrant further testing. The chemotherapy standard of care for men with mCRPC remains docetaxel with prednisone. Future studies of autophagy inhibitors will need to measure autophagy inhibition accurately and determine the degree of autophagy inhibition required to produce a meaningful clinical response.
提高转移性去势抵抗性前列腺癌（mCRPC）男性患者多西他赛的疗效是未满足的临床需求。临床前研究表明，高剂量泮托拉唑可通过抑制几种实体肿瘤异种移植物中的自噬来预防或延迟对多西他赛的耐药性。
符合条件的患者为化疗初治 mCRPC 且 PSA＞10ng/ml 的男性。患者在每 21 天接受一次多西他赛（75mg/m）前静脉注射泮托拉唑（240mg），同时每日口服泼尼松 5mg，每日两次。主要终点为 PSA 确证下降≥50%。该试验采用 Simon 的两阶段设计。
2012 年 11 月至 2015 年 3 月，共 21 名中位年龄为 70 岁（范围 58-81）的男性接受了治疗（中位 6 个周期；范围 2-11）。男性曾接受过系统治疗（中位 1 次；范围 0-3），14 名男性接受过阿比特龙和/或恩杂鲁胺治疗。PSA 缓解率为 52%（21/41），未达到研究第二阶段的预设标准（≥13/21 名应答者）。中期分析时中位随访时间为 17 个月，18 名（86%）男性死亡（15 名死于去势抵抗性前列腺癌，2 名死因不明，1 名死于放射并发症）。在 RECIST 可测量疾病的男性中，影像学部分缓解率为 31%（4/13）。估计的中位总生存期为 15.7 个月（95%置信区间 [CI]，9.3-19.6），中位无进展生存期为 5.3 个月（95%CI，2.6-12.9）。无治疗相关死亡，所有不良事件均归因于多西他赛。
多西他赛联合泮托拉唑耐受性良好，但产生的临床活性不足以满足有野心的预设目标，因此无需进一步检测。
迄今为止，在转移性去势抵抗性前列腺癌（mCRPC）男性中，没有多西他赛联合治疗方案的疗效优于多西他赛单药治疗。PANDORA 试验表明，高剂量泮托拉唑联合多西他赛是可耐受的，但临床活性不足以进一步检测。mCRPC 男性的化疗标准治疗仍然是多西他赛联合泼尼松。未来对自噬抑制剂的研究需要准确测量自噬抑制，并确定产生有意义临床反应所需的自噬抑制程度。
