[ASCO 2017]巅峰对话:LATITUDE研究者Fizazi解读阿比特龙治疗转移性前列腺癌

作者:  张宇   日期:2017/6/9 10:30:17  浏览量:24595

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编者按:本届ASCO年会全体大会上,法国Paris-Sud大学的Karim Fizazi教授报告的一项国际多中心研究(LATITUDE)引起了各方热议,该研究结果显示:雄激素剥夺治疗(ADT)联合醋酸阿比特龙能够显著延长高危未经治疗的转移性前列腺癌(mHNPC)患者的总生存期和影像学无进展生存期。本刊特邀请研究第一作者Fizazi教授分享研究成果、对临床实践的影响,及未来研究计划。

 
 Karim Fizazi教授:“这是一项全球试验,近1200名男性患者被随机入组。两个主要终点均获得了显著改善。对于总生存期,我们看到死亡风险降低了38%,这是空前的……基于LATITUDE数据,阿比特龙可能会成为激素敏感型疾病的治疗新标准。换言之,我们将在疾病更早期给予患者阿比特龙治疗。” 
 
 
ASCO专家Sumanta Kumar Pal博士点评:“对于被诊断为晚期前列腺癌的患者而言,仍有有效的治疗可以选择,从前是化疗,而现在是阿比特龙。该研究带来了一个好消息,其结果提示阿比特龙可以帮助前列腺癌患者活得更长,而副作用很少。”
 
 研究详述:
 
 “It was a global trial with about 1200 men being randomized.”
 
 LATITUDE是一项III期、双盲、随机试验,研究阿比特龙在未经治疗转移性前列腺癌男性患者中的作用。 研究纳入1199例新诊断(≤3个月)的mHNPC患者,美国东部肿瘤协作组体能状态评分(ECOG PS)0~2分,≥2项风险因素(Gleason ≥ 8、≥3处骨病变、可测量的内脏转移)。这些患者最初接受标准ADT治疗,后按1:1随机分配至接受阿比特龙加泼尼松[ADT+AA (1g QD) + P (5mg QD)]或安慰剂[ADT+PBOs]治疗(图1)。
图1.研究设计
 
 “The findings support significant improvement for both primary endpoints.”
 
研究主要终点为总生存(OS)和影像学无进展生存(rPFS)。“对于这两个主要终点,研究发现显著改善:对于OS,我们看到了死亡风险降低了38%,这是空前的;对于rPFS,我们观察到了进展或死亡风险降低了53%。”
 
中位随访30.4 个月时,与接受安慰剂的患者相比较,接受阿比特龙的男性死亡风险降低38%(图2)。与安慰剂组相比,阿比特龙组的OS和rPFS均显著更优[中位OS:ADT+AA+P组尚未达到,PBOs组34.7个月(HR 0.62,P<0.0001);中位rPFS: ADT+AA+P组33.0个月,ADT+PBOs组14.8个月(HR 0.47,P<0.0001)]。此外,与安慰剂相比,阿比特龙降低53%的癌症恶化风险,导致肿瘤生长延迟中位数18.2个月(图3)。所有次要终点,阿比特龙组均显著更优(表1)。
 
图2.OS
 
图3.rPFS
 
表1.研究主要和次要终点
 
 “Those are side effects that are very well known in patients with resistant disease.”
 
在安全性方面,阿比特龙组与更高的高血压和低钾血症发生有关,这与基于阿比特龙行为机制的预期情况一致。“众所周知,这些不良反应是治疗去势抵抗性疾病患者的常见表现。”
 
阿比特龙组与安慰剂组的3~4级不良事件发生率分别为:高血压(20.3%对比10.0%)、低钾血症(10.4%对比1.3%)、ALT升高(5.5%对比1.3%)或AST升高(4.4%对比1.5%)。“对于有心脏病风险升高的患者,包括糖尿病患者,应用阿比特龙时需要谨慎。”
 
 研究影响:
 
 “Based on the LATITUDE data, it is likely that abiraterone will become the new standard of care in men with castration-sensitive disease.”
 
阿比特龙已经是去势抵抗性前列腺癌(CRPC)男性患者的标准治疗。我们已经在常规地使用这一药物。Fizazi教授认为,基于LATITUDE数据,阿比特龙可能将成为激素敏感型疾病男性患者的治疗新标准。换言之,我们将提早给这些男性患者阿比特龙治疗。
 
 下一步计划:
 
 “In the future, we will try to learn what the role is for these agents who have failed abiraterone and castration when used upfront.”
 
如果阿比特龙不奏效,这些患者甚至会进展至CRPC。Fizazi教授指出,未来我们将探究这些患者出现去势抵抗时的最佳治疗方案。令人欣慰的是,目前对于这些患者,我们有其他选择,包括多西他赛化疗、卡巴他赛化疗、镭-233和恩杂鲁胺,“未来,我们将尝试了解这些药物对于阿比特龙失败且提前使用去势治疗患者的疗效。”
 
2015年多西他赛化疗证明可以提高生存期,现在2017年阿比特龙也会帮助患者活得更长,“下一步研究计划是观察在多西他赛之前添加阿比特龙是否会提供进一步获益” ,目前相关研究正在欧洲开展。
 
英文原文:
 
Prof. Fizazi: LATITUDE is a phase III trial testing the role of abiraterone and prednisone in men with de novo metastatic prostate cancer. These men were originally treated with standard of care androgen deprivation therapy and were randomized in a one-to-one fashion to receive abiraterone and prednisone or placebos for these two drugs. It was a global trial with about 1200 men being randomized.
 
Our primary endpoints were radiographic progression-free survival and overall survival. The findings support significant improvement for both primary endpoints. For overall survival, we saw a 48% reduction in the risk of death, which is unprecedented. For radiographic progression-free survival, we observed a 53% reduction in the risk of progression or death. 
 
In terms of safety, this was associated with a higher incidence of hypertension and hypokalemia, which was expected based on the mechanism of action of abiraterone. Those are side effects that are very well known in patients with resistant disease.
 
Prof. Fizazi: Abiraterone is already standard of care for men with castration-resistant prostate cancer. We have been using it routinely. Based on the LATITUDE data, it is likely that abiraterone will become the new standard of care in men with castration-sensitive disease. In other words, we will be using abiraterone upfront in these men. 
 
Abiraterone is not curative and these patients will eventually develop castration-resistant disease and we will know in the future what the optimal management will be when these men indeed develop a resistance to castration. The good news, of course, is that we have other options for these men including docetaxel chemotherapy, cabazitaxel chemotherapy, radium-233 and enzalutamide. In the future, we will try to learn what the role is for these agents who have failed abiraterone and castration when used upfront.

版面编辑:洪山  责任编辑:吉晓蓉


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