编者按：同源重组修复（HRR）基因在前列腺癌患者中的广泛存在，为研究前列腺癌靶向治疗提供了重要的生物标志物：大约12%的转移性去势抵抗性前列腺癌（mCRPC）患者携带BRCA1/2基因突变；大约25%的mCRPC患者携带HRR基因突变。在近日举办的2023年欧洲肿瘤内科学会（ESMO）年会上，BC癌症首席医疗官、温哥华前列腺中心的高级研究科学家Kim Nguyen N.Chi教授带来了题为“尼拉帕利（5-Niraparib，NIRA）联合醋酸阿比特龙加泼尼松（AAP）作为mCRPC和HRR基因改变患者的一线治疗：MAGNITUDE三年更新和最终分析”的精彩报告。《肿瘤瞭望》在会议现场有幸采访到Chi教授，就此进行深入解读，并就领域内其他重磅研究进行介绍。

 

专家简介

 

Kim Nguyen N.Chi教授

医学肿瘤学家，BC癌症首席医疗官，温哥华前列腺中心的高级研究科学家，不列颠哥伦比亚大学（UBC）医学系教授。

Chi博士的研究领域是泌尿生殖系统癌症，重点是前列腺癌和试验性新药，包括生物标志物、结果、I～III期临床试验、新辅助研究和治疗耐药性机制。Chi博士是加拿大癌症试验小组泌尿生殖疾病现场委员会的前任主席，曾获得加拿大卫生研究院（CIHR）、加拿大国家癌症研究所（NCIC）/加拿大癌症协会（CCS）、美国国防部、Movember、前列腺癌症基金会（美国）和加拿大癌症协会的同行评审资助。Chi博士在著名的同行评审期刊上发表了大量文章，包括最近的《临床肿瘤学杂志》、《肿瘤学年鉴》、《新英格兰医学杂志》和《柳叶刀肿瘤学》。

 

 

Thank you so much for the interview.Our first question is，can you describe the role of germline testing and tumor testing in the context of prostate cancer?

 

Chi教授：我认为我们现在所知道的是，HRR或同源重组修复基因突变在前列腺癌中非常常见，生殖系和体细胞的发生率均为25%～30%。因此，目前大多数机构对许多躯体疾病患者建议进行生殖细胞和体细胞检测。在我的临床实践中，所有躯体疾病患者都会进行生殖系检测以及肿瘤组织检测。我们还有循环肿瘤DNA（ctDNA）检测。这样做有三个原因：（1）HRR基因改变的前列腺癌患者预后不良；（2）这些基因改变可能起源于生殖系，因此我们需要了解是否是种系而进行遗传检测、遗传级联检测；（3）我们现在有了针对同源重组修复、基因改变患者的治疗方法，特别是治疗BRCA2突变的PARP抑制剂，如卢卡帕利（Rucaparib）、奥拉帕利（Olaparib）、他拉唑帕利（Talazoparib）。

 

I think what we now know understand is that the incidence of hrr or homologous recombination repair gene mutations can be quite common in prostate cancer，25 to 30%both germ line and somatic.So most bodies now recommend the testing of patients with many static disease for both germ line and somatic testing.In my clinical practice，all patients with many static disease will have a germ line test，as well as tumor tissue testing.And we also have ctdna testing available.There’s three reasons to do it.One is a prognostic patients with hrr gene alterations at poor outcomes.Number two half，these gene alterations can be germ line and origin.Therefore，we need to understand whether it is germ line to do hereditary testing，hereditary cascade testing.And thirdly，we now have treatments，patients that have homologous recombination repair，gene alterations，particularly bracket two in the form of park inhibitors，such as narrow probe，elaborate and tell us opera.

 

 

At this conference，you shared the research results of MAGNITUDE.Could you please introduce them to us again?

 

Chi教授：今天在ESMO上，我介绍了MAGNITUDE研究。它是一项3期、随机、双盲、安慰剂对照试验，探讨了尼拉帕利联合AAP作为mCRPC和HRR基因改变患者的一线治疗。特别是，这是最终分析。我们关注的是BRCA突变的基因改变患者。在第一次分析中取得积极结果，给重组修复基因突变患者带来影像学无进展生存获益。特别是，BRCA突变患者的HR为0.53，这意味着在延长影像学无进展生存方面几乎提高了50%。在最终分析中，我们介绍了次要终点，包括总生存、至症状进展时间以及至毒性化疗时间。多因素分析显示，尼拉帕利具有生存获益（HR 0.6；P=0.02）。此外，我们还发现，在至毒性化疗时间和至症状进展时间方面，尼拉帕利作为BRCA突变mCRPC患者的一线治疗是安全的。没有新的安全性问题，治疗耐受性良好，而且毒性可控，主要是血液学毒性，可通过减少和中断剂量进行控制。

 

So today at asthma，I presented on the magnitude study，the magnitude studies，a phase，three randomized double blind placebo controlled trial，had looked at the efficacy of narratives plus abrid on acetate and prentisone as first line therapy for patients with many static crpc and patients that had homologous recombination repair gene mutations.And particularly，this was the final analysis.We focused on patients with bracket to gene alterations.The first analysis，the study was positive.There was a radio graphic progression，Free survival benefit，were for patients that had among us recombination repair gene mutations.In particular，patients with bracket two had a hazard ratio of 0.53，meaning almost a 50%improvement in delaying radio graphic progression，Free survival.In this final analysis，we presented the results from the secondary in points，overall survival，time to symptomatic progression，and time decide to talk to chemotherapy for overall survival.Using a multivariate analysis，we saw that there was a survival benefit with narrativ，hazard ratio 0.6 p value 0.02.In addition，we saw continued benefit in terms of time to cytotoxic chemotherapy and time to symptomatic progression，with naraprobe，for the patients，with bracket mutations as first line mcrpc treatment，safe，there was no new safety concerns，and the treatment was well tolerated and toxicity manageable，mostly haematological，toxicity and manageable with dose reductions and dose interruptions.

 

 

How do you see the treatment landscape of mCRPC evolving with therapies like Niraparib?And what other research or new discoveries left a deep impression on you at this conference?

 

Chi教授：目前对于BRCA2和BRCA1突变的患者而言，尼拉帕利联合AAP是标准治疗，也是一线治疗。目前尼拉帕利已在美国、加拿大和欧洲获批。

 

我专注于前列腺癌和生殖泌尿癌症。我认为有两个改变实践的介绍。其中一个是在前列腺癌中围绕前列腺特异性膜抗原（PSMA）进行的试验，该试验评估了早期使用Lu-PSMA-617的疗效，结果显示了强大的影像学无进展生存。另一个是在尿路癌症中与化疗相比，ADC药物（EV）显示出总体生存的显著改善。这也是今天的主席专场（presidential presentation）。因此，我认为这是两个改变实践的试验。

 

For patients with bracket two and bracket one alterations?This is now a standard of care for Nairobi plus apparatus.And it’s a first line therapy.For patient，these patients.And it’s approved in the us Canada and Europe.

 

I’m focused on prostate cancer as well as genital urinary cancer.So I I think the two practice changing presentations are one are in prostate cancers around the psma for trial，which evaluated earlier use of luteation psma 617.It’s showing a robust radio graphic progression，Free survival.And then the other one is in for chemotherapy versus ev and urothereal cancer showing as a substantial improvement in overall survival.A that’s a presidential presentation today as well.So I think those are two practice changing trials.