编者按：近年来，在雄激素剥夺治疗（ADT）的基础上，AR通路抑制剂等新型内分泌治疗已经成为转移性激素敏感性前列腺癌（mHSPC）患者的标准治疗，而且临床正在探索更多强化治疗策略，包括联合化疗、放疗，乃至免疫和靶向治疗。在近日举行的2024年EAU大会上，比利时布鲁塞尔天主教大学圣吕克大学医院Bertrand Tombal教授报告了ARASENS研究欧洲患者的最新数据。《肿瘤瞭望》特邀南京大学医学院附属鼓楼医院庄君龙教授远程连线Bertrand Tombal教授，共同探讨更多mHSPC强化治疗和安全性管理的热点问题。

 

 

Oncology Frontier:Good morning，Dr.Tombal.The ARASENS study has demonstrated that the combination of ADT+docetaxel+darolutamide can improve overall survival in patients with mHSPC.How do you think patients should be screened for this treatment?

 

Bertrand Tombal教授：反思试验的起源很重要。早在2014年，我们就将ADT加多西他赛作为侵袭性疾病患者的治疗标准，并得到了三项试验的支持。随后，阿比特龙和恩扎卢胺出现，引发了关于多西他赛和这些新方案之间选择的争论。2015年，我们试图回答在ADT加多西他赛的基础上添加AR通路抑制剂是否有益于侵袭性疾病患者。

 

阿帕鲁胺和恩扎卢胺的挑战是它们的药物相互作用（DDI）较多，使它们难以与多西他赛联合。因此，我们选择了达罗他胺。我们的研究结果表明，如果患者因侵袭性疾病（包括多发性骨转移）需要化疗，同时使用AR途径抑制剂是有利的。选择达罗他胺不会增加与多西他赛相关的毒性，这对我们来说是一个关键因素。按照和以前相同毒性的剂量给药，然后继续使用达罗他胺直到进展。简单来说，单用多西他赛是不够的；应该在这个方案中联合AR通路抑制剂。

 

Dr.Tombal:It’s important to reflect on the genesis of the trial.Back in 2014，we had established ADT plus docetaxel as the standard of care for patients with aggressive disease，supported by three trials.Subsequently，abiraterone and enzalutamide emerged，prompting debates over the choice between docetaxel and these newer options.In 2015，we sought to answer whether adding an AR pathway inhibitor to ADT plus docetaxel，for patients with aggressive disease，would be beneficial.

 

The challenge with apalutamide and enzalutamide was their significant drug-drug interactions，making them difficult to combine with docetaxel.Hence，we chose darolutamide.Our findings revealed that if a patient requires chemotherapy for aggressive disease，including multiple bone metastases，it is advantageous to administer an AR pathway inhibitor concurrently.Choosing darolutamide does not increase the toxicity associated with docetaxel，which was a critical factor for us.The ability to administer it with the same toxicity as before and then continue with darolutamide until progression is the main takeaway.Simply put，docetaxel alone is not adequate;an AR pathway inhibitor must be included in the regimen.

 

Oncology Frontier:Dr.Zhuang，if the efficacy of mHSPC patients fails to reach the target during combined ADT treatment，will you consider intensive treatment such as surgery or radiotherapy?

 

庄君龙教授：是的，我会考虑使用强化治疗策略。回顾性研究已经证明，在全身治疗基础上联合手术或放疗等局部疗法可以改善OS，尤其是对于低负荷（寡转移）的转移性激素敏感性前列腺癌。在真实世界的临床实践中，对于低负荷或寡转移的mHSPC，我们建议患者可考虑局部治疗。

 

Dr.Zhuang:Yes，absolutely.Retrospective studies have proven that systematic therapy plus local therapies like surgery or radiotherapy are more beneficial for overall survival，especially for low-volume metastatic hormone-sensitive cancers.In the real world，for low-volume or local metastatic hormone-sensitive breast cancer，we recommend local therapy for patients.

 

 

Oncology Frontier:Dr.Tombal，intensive treatment has been a hot topic in the field of mHSPC in recent years.What do you think of new intensive treatment strategies such as"quadruple therapy"(NHT+ADT+chemotherapy+radiotherapy)and NHT+immunotherapy?

 

Bertrand Tombal教授：我在这个领域已经有了大约25到30年的实践经验。人们往往会忘记，没有一项试验表明，在没有局部治疗的情况下，单独使用雄激素剥夺疗法可以提高总生存率。因此，添加NHT提高总生存率并不奇怪。在许多国家，我们建议最大限度地阻断雄激素，但以前使用的药物不是很有效。现在，我们的EMBARK试验表明，单独的AR途径抑制剂比ADT更有效。当人们决定单独服用ADT时，他们需要明白他们使用的药物不会提高总生存率。如果他们想让患者活得更长，就必须增加一些东西。

 

目前，最简单、最有效的方法是添加AR抑制剂，如阿比特龙、阿帕他胺、达罗他胺或恩扎卢胺。未来，我们还将讨论在特定的病例中进行强化治疗，比如MSI-H的患者选择免疫治疗，BRCA突变的患者选择PARP抑制剂。重要的是要承认，仅用ADT治疗转移性患者的时代已经结束。20年后，我们甚至可能会质疑ADT本身的必要性。过去的十年最重要的发现是，转移性前列腺癌需要AR通路抑制剂，我们应该从那里开始构建新的治疗格局。

 

Dr.Tombal:You need to have a bit of history in the field，like I do，having been involved for about 25 to 30 years.People tend to forget that there hasn’t been a single trial that showed androgen deprivation therapy alone increases overall survival without local treatment.Thus，it’s not surprising that adding an NHT increases overall survival.In many countries，we had recommended maximal androgen blockade，but the drugs previously used were not very effective.Now，we have the EMBARK trial showing that an AR pathway inhibitor alone is more effective than ADT.When people decide to administer ADT alone，they need to understand that they are using a drug that does not increase overall survival.If they want their patient to live longer，they must add something more.

 

At this moment，the simplest and most efficient approach is to add an AR inhibitor，such as abiraterone，apalutamide，darolutamide，or enzalutamide.In the future，we will also discuss adding immunotherapy in selected cases，like patients with MSI mutation POP inhibitor and those with BRCA mutation.It’s important to acknowledge that the era of treating metastatic patients with ADT alone is over.In 20 years，we might even question the need for ADT alone.The last decade has importantly shown that the necessary drug for a patient with metastasis is an AR inhibitor，and we should start building from there.

 

 

Oncology Frontier:Dr.Zhuang，how do you think complications from treatment should be managed to improve survival and quality of life for prostate cancer patients?

 

庄君龙教授：首先，我们将Tombal教授在EAU提供的数据与我们1月份收到的中国患者的数据进行比较。ARASENS研究结果的分析表明，达罗他胺联合ADT和多西他赛显著延长了中国和欧洲mHSPC患者的总生存期，两组患者都证明了达罗他胺的良好安全性。我们还观察到，不同组的不良事件相似，其中许多已知与脱发、中性粒细胞减少、疲劳和贫血等治疗有关。不同治疗组的大多数不良事件发生率相似，与ARASENS研究的总体人群一致。真实世界的经验也非常相似，达罗他胺与多西他赛或常用药物之间的潜在相互作用非常少。这表明，将达罗他胺与不同治疗方法联合，如多西他赛和ADT，可以为患者带来获益。

 

Dr.Zhuang:First，we need to compare to the data provided by Professor Tombal in the EAU and the data we received in January for Chinese patients.The analysis of results from the ARASENS study shows that darolutamide plus ADT and docetaxel significantly prolonged overall survival in both Chinese and European mHSPC patients，with a good safety profile for darolutamide demonstrated in both groups.We also observed that adverse events were similar across groups，many of which are known to be associated with treatments such as alopecia，neutropenia，fatigue，and anemia.Most adverse event rates were similar between the different treatment groups and consistent with the overall population studied in the RSS study.Similar to real-world experience，the potential interactions between darolutamide and docetaxel or commonly used drugs are very low.This suggests that our approach to combining different treatments，like docetaxel and ADT，is beneficial for patients.

 

 

Oncology Frontier:For this year’s EAU 24 conference，do you have any other interesting topics or research outcomes you would like to share?

 

Bertrand Tombal教授：如果要我为读者们推荐EAU后的重要探索方向，我会推荐由Nick James安排的《柳叶刀》前列腺癌委员会的相关项目。这是一项重要的工作，旨在预测癌症治疗在未来十年将如何发展。我赞赏这项倡议的全球视角，认识到癌症在亚洲，包括中国、日本和韩国的发病率正在上升。其中也展示了EAU上发表科学文献的大部分内容，我鼓励大家阅读它。

 

Dr.Tombal:Honestly，if I have to recommend something for our listeners to explore post-EAU，it would be The Lancet Commission on Prostate Cancer，arranged by Nick James.It’s a substantial piece of work that projects how prostate cancer treatment will evolve over the next decade.I appreciate this initiative for its global perspective，recognizing the emerging prevalence of prostate cancer in Asia，including China，Japan，and Korea.This represents a significant portion of the scientific literature presented at EAU，and I encourage everyone to read it.

 

庄君龙教授：由于时间冲突，我无法参加在巴黎举行的会议，但我一直在密切关注mHSPC领域关于强化治疗的讨论。虽然三联或四联治疗现在是一个焦点，但关键的考虑因素不仅是生存获益，还要考虑如何管理副作用。在我看来，不良反应是医生在决定强化治疗是否适合患者时考虑的最关键因素，这也是我特别关注的领域。

 

Dr.Zhuang:Unfortunately，I couldn’t attend the conference in Paris due to a time conflict，but I’ve been closely following the discussions on intensive treatment in the field of mHSPC.While triple or quadruple therapy is now a focus，the key consideration is not just the benefits but also how patients manage the side effects.Adverse reactions are，in my view，the most critical factor for doctors to consider when deciding whether intensive treatment is appropriate for their patients.This is the area I’m particularly focused on.