编者按：PARP抑制剂（PARPi）开启了前列腺癌的精准治疗时代，已有多项研究证实携带同源重组修复缺陷突变（HRRm）的转移性去势抵抗性前列腺癌（mCRPC）患者可获益于该治疗方案。在近日举行的2025年欧洲泌尿外科学会年会（EAU25）上，报道了一项南京大学医学院附属鼓楼医院开展的单臂II期PROact研究显示，奥拉帕利＋阿比特龙＋泼尼松用于转移性去势敏感性前列腺癌（mHSPC）患者治疗，也展现了积极的初步疗效和安全性。《肿瘤瞭望》有幸邀请南京大学医学院附属鼓楼医院庄君龙教授与我国香港威尔士亲王医院的Samson Chan教授展开对话，分享前列腺癌精准治疗的前沿进展和临床实践经验。

01

《肿瘤瞭望-泌尿时讯》

感谢两位接受我们的采访，我们这次的采访主要聚焦在前列腺癌。在这次EAU大会上，庄君龙教授团队汇报了II期PROact研究，首次将PARPi＋ARPi拓展至mHSPC阶段。能否与我们分享一下该研究？

庄君龙教授：感谢《肿瘤瞭望-泌尿时讯》的邀请，也很荣幸能与陈教授一起参与这次讨论。PROact研究将在明天的EAU会议上正式报告，这是一项II期、单臂的临床研究，我们共纳入了30例携带同源重组修复（HRR）基因突变的初诊mHSPC患者，使用奥拉帕利＋阿比特龙＋泼尼松治疗。入组患者最常见的HRR突变是BRCA2，约占40%。研究的主要终点是1年影像学无进展生存率（rPFS）。虽然在提交摘要时尚未达到主要终点，但目前我们已经获得了更新数据：1年rPFS约为78%。

在次要终点方面，30名患者的客观缓解率（ORR）为84%。中位随访时间为14个月，所有患者（100%）均达到PSA下降50%（PSA50）的治疗反应，其中29名患者（96.7%）更达到了PSA90治疗反应。安全性方面，未观察到5级不良事件，最常见的任意级别不良事件是贫血，发生率为43%。总体来看，治疗耐受性良好，安全性是可以接受的。这项单臂II期研究的初步结果表明，奥拉帕利＋阿比特龙＋泼尼松用于治疗mHPSC具有良好的抗肿瘤活性和安全性，未来值得进行扩大样本研究的进一步验证。

Prof. Zhuang: Thank you for the interview. It’s a pleasure to be here with Oncology Frontier, and it’s a great honor to join Prof. Chan. The PROact clinical trial will be presented at tomorrow’s EAU conference. It was designed as a phase II, single-arm clinical trial. We enrolled 30 patients with de novo mHSPC who had homologous recombination repair (HRR) mutations,and were administered olaparib 3 plus abiraterone and prednisone.The most common HRR mutation was BRCA2, present in 40% of cases. The primary endpoint was the 1-year radiographic progression-free survival (rPFS) rate. At the time of abstract submission, the primary endpoint had not been reached. But now, we have data showing a 1-year rPFS of approximately 78%.

As for secondary endpoints, the overall response rate (ORR) was 84% among the 30 patients. With a median follow-up of 14 months, all patients achieved PSA50 response, and 29 out of 30 reached PSA90 response.In terms of safety, we observed no grade 5 adverse events. The most common adverse event of any grade was anemia, with an incidence rate of 43%. Overall, the safety profile is tolerable and acceptable.These results of this single-arm Phase II study indicate that the combination of olaparib, abiraterone, and prednisone has good anti-tumor activity and safety in the treatment of mHSPC. It is worth further validation through expanded sample studies in the future.

02

《肿瘤瞭望-泌尿时讯》

接下来想请教Chan教授，这次EAU大会有没有您比较感兴趣的研究？尤其是PARPi精准治疗，目前仍需基于基因检测（包括基于组织的检测，或者ctDNA液体活检），这次EAU大会是否也有此类检测相关的研究报道？

Samson Chan教授：确实有一项非常值得关注的研究，明天将由首都医科大学附属北京友谊医院研究团队报告。该研究聚焦于ctDNA液体活检，在阿比特龙或恩扎卢胺治疗一线治疗后发生进展的转移性去势抵抗性前列腺癌患者中的应用。

这项研究与PROfound研究中的个案分析非常类似，研究人员利用新一代测序（NGS）技术分析ctDNA，发现了广泛的体细胞与胚系突变谱。更重要的是，接受ctDNA检测的患者，其总生存显著改善（30 vs 20个月，P=0.035）。实际上，有超过90%的患者在ctDNA检测后获得了更有针对性的后续治疗方案。检测到胚系突变的发生率为54.55%，其中BRCA1/2和ATM突变的发生率高达23.3%，意味着这类患者可以从奥拉帕利等PARPi精准治疗中获益。这个结果强有力地支持了液体活检在mCRPC中的临床应用，正如庄教授提到的，这种技术也可能在更早期的mHSPC阶段发挥作用。

Prof. Chan: There is indeed a very noteworthy study that will be reported by the research team from Beijing Friendship Hospital, Capital Medical University, tomorrow. This study focuses on the application of ctDNA liquid biopsy in patients with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after first-line treatment with abiraterone or enzalutamide.

This study is highly similar to the case analysis in the PROfound study. Researchers utilized next-generation sequencing (NGS) technology to analyze ctDNA and identified a broad spectrum of somatic and germline mutations. More importantly, patients who underwent ctDNA testing had a significant improvement in overall survival (30 months vs. 20 months, P=0.035). In fact, over 90% of patients received more targeted subsequent treatment plans after ctDNA testing. The detection rate of germline mutations was 54.55%, with the incidence of BRCA1/2 and ATM mutations as high as 23.3%. This indicates that these patients could benefit from precision treatments like olaparib and other PARP inhibitors. This result strongly supports the clinical application of liquid biopsy in mCRPC. As Professor Zhuang mentioned, this technology may also play a role in the earlier metastatic hormone-sensitive prostate cancer (mHSPC) stage.

03

《肿瘤瞭望-泌尿时讯》

我们知道基于PROpel研究，奥拉帕利已经被应用于mCRPC一线治疗。两位能否结合你们的临床实践经验，分享一下你们对PARPi治疗价值的看法，以及相关基因检测时机、方法的思考？

庄君龙教授：我认为PARP抑制剂在治疗转移性前列腺癌方面具有非常大的潜力。在mCRPC阶段，已有多个关键临床试验，包括PROfound、PROpel、MAGNITUDE和TALAPRO-2，都显示了PARPi联合ARPi一线治疗在HRR突变和非突变患者中，可改善rPFS乃至OS。

从临床角度出发，我倾向于更早启动基因检测与PARP靶向治疗，尤其在以下具有不良预后因素的患者中：有BRCA突变家族史，Gleason≥5分的肿瘤，患者年龄较轻，转移病灶肿瘤负荷高等。目前也有多项研究正在评估PARPi在mHSPC中HRR突变患者中的应用前景，我对此持积极乐观态度。

Samson Chan教授：在香港，我们目前主要在mCRPC阶段开展HRR基因检测，特别是在一线ARPi治疗失败后。这一阶段患者PSA水平升高，有利于ctDNA检测中突变的检出率。我们的本地共识指南——由香港泌尿外科学会与香港临床肿瘤学会联合制定——建议在一线治疗失败后进行ctDNA检测，这也与EAU与NCCN指南保持一致。但相信随着PROpel等研究的影响深入，会有越来越多的患者在mCRPC乃至mHSPC初治时就进行HRR基因检测。

此外，ctDNA检测结果与组织活检结果的一致性超过80%。ctDNA还可以帮助我们发现胚系突变，对于患者个体化治疗方案制定以及BRCA突变相关的家族遗传咨询都具有重要意义。

Prof. Zhuang: I believe that PARP inhibitors have great potential in the treatment of metastatic prostate cancer. In the mCRPC stage, several key clinical trials, including PROfound, PROpel, MAGNITUDE, and TALAPRO-2, have shown that the combination of PARPi and ARPi in first-line treatment can improve rPFS and even OS in patients with both HRR mutations and non-mutations.

From a clinical perspective, I am inclined to initiate genetic testing and PARP-targeted therapy earlier, especially in patients with the following poor prognostic factors: family history of BRCA mutations, Gleason grade 5 histological type, younger age, and high tumor burden of metastatic lesions. Currently, several studies are also evaluating the potential application of PARPi in patients with HRR mutations in mHSPC, and I am very optimistic about this.

Prof. Chan: In Hong Kong, we currently mainly conduct HRR gene testing in the mCRPC stage, especially after failure of first-line ARPi treatment. At this stage, patients have elevated PSA levels, which is conducive to the detection rate of mutations in ctDNA testing. Our local consensus guidelines—jointly formulated by the Hong Kong Urological Society and the Hong Kong Society of Clinical Oncology—recommend ctDNA testing after failure of first-line treatment, which is also consistent with the EAU and NCCN guidelines. However, with the increasing influence of studies like PROpel, we believe that more and more patients will undergo HRR gene testing at the initial treatment of mCRPC and even mHSPC.

In addition, the concordance rate between ctDNA testing results and tissue biopsy results is over 80%. CtDNA can also help us identify germline mutations, which is of great significance for the formulation of individualized treatment plans for patients and for genetic counseling related to BRCA mutations in families.

04

《肿瘤瞭望-泌尿时讯》

除了PARPi以外，近年来也有新的前列腺癌治疗策略正在探索中，包括PSMA核素治疗、免疫检查点抑制剂（ICIs）、抗体偶联药物（ADC）等，两位认为未来前列腺癌治疗领域最有前景的方向是什么？

庄君龙教授：坦率来说，我对免疫检查点抑制剂在前列腺癌中的应用并不乐观。目前大部分III期临床试验，不论是单药或联合方案，均未显示出显著疗效。我个人更看好抗体药物偶联物（ADCs）——这类药物本质上是靶向化疗，目前在前列腺癌领域仍处于发展中阶段，但前景可期。不过，我认为最具前景的仍然是靶向PSMA的放射性配体治疗。像VISION、PSMAfore等研究已经证明，Lu-177 PSMA治疗在mCRPC患者中显示了改善生存的疗效。目前有多个相关新药与研究正在推进中，我对这一治疗路径充满信心。

Samson Chan教授：我完全同意庄教授的看法。遗憾的是，ICIs在前列腺癌中的疗效整体较差，目前只有在微卫星不稳定性高（MSI-H）的患者中，帕博利珠单抗在mCRPC阶段展现出一定疗效。除此之外，大多数临床试验结果都不理想。但PSMA放射性配体治疗确实非常值得关注。我们中心也尝试对PSMA阳性的患者进行Lu-177 PSMA放疗，疗效显著。尽管有部分患者出现了严重骨髓抑制，需定期输血支持，但从治疗反应来看，值得继续探索。未来，也许可以尝试将ICIs与PSMA靶向治疗联用，或许能带来更佳疗效。

Prof. Zhuang: To be honest, I am not optimistic about the application of immune checkpoint inhibitors in prostate cancer. Currently, most Phase III clinical trials, whether monotherapy or combination regimens, have not shown significant efficacy. Personally, I am more optimistic about antibody–drug conjugates (ADCs). These drugs are essentially targeted chemotherapy and are still in the developmental stage in the field of prostate cancer, but they hold promise. However, I believe the most promising treatment remains radioligand therapy targeting PSMA. Studies such as VISION and PSMAfore have demonstrated that Lu-177 PSMA therapy shows efficacy in improving survival in patients with mCRPC. Several new drugs and studies in this area are currently in progress, and I am very confident in this therapeutic pathway.

Prof. Chan: I agree with Professor Zhuang's view. Regrettably, the overall efficacy of ICIs in prostate cancer is rather poor. Currently, only in patients with high microsatellite instability (MSI-H), has pembrolizumab shown some efficacy in the mCRPC stage. Beyond that, the results of most clinical trials have been less than satisfactory. However, PSMA radioligand therapy is indeed very noteworthy. Our center has also attempted Lu-177 PSMA radiotherapy for PSMA-positive patients, with significant therapeutic effects. Although some patients have experienced severe bone marrow suppression, requiring regular blood transfusion support, the therapeutic response is promising and warrants further exploration. In the future, perhaps we could consider combining ICIs with PSMA-targeted therapy, which might lead to better outcomes.

▌参考文献：

[1]Guo X., Zhang F. The role of plasma ctDNA detection for CRPC patients with failure of first-line abiraterone/enzalutamide treatment.EAU25; Abstract P009

[2]Zhuang J., et al.Update efficacy results of PROact: A prospective phase II study to evaluate olaparib plus abiraterone and prednisone combination therapy in metastatic hormone sensitive prostate cancer patients with HRR gene mutation.EAU25; Abstract P191

庄君龙 教授

副主任医师

南京鼓楼医院泌尿外科科室助理、副主任医师

南京大学、南京医科大学副教授、硕士生导师

南京鼓楼医院泌尿外科前列腺癌亚专业组长

江苏省泌尿外科学分会青年委员会委员

江苏省医师协会泌尿外科医师分会委员

江苏省“333高层次人才培养工程”培养对象

江苏省自然科学基金优秀青年

主持各类科研项目共15项，国家级课题3项；第一/通讯作者发表SCI论文20篇

主攻方向为泌尿肿瘤特别是前列腺癌的精准化诊疗。

Samson Chan 教授

香港中文大學何善衡泌尿中心临床副教授

香港医院管理局泌尿外科顾问医生；

香港外科医学教育与培训计划指导委员会（SOMIP）泌尿外科专业小组成员；

2018年获香港外科医学院和爱丁堡皇家外科学院院士资格，因出色表现被授予C.H. LEONG勋章；

擅长泌尿外科微创手术，复杂泌尿外科重建手术等，发表了多篇同行评议论著

（来源：《肿瘤瞭望-泌尿时讯》编辑部）

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