编者按：2025年美国临床肿瘤学会泌尿男生殖系肿瘤分会（ASCO GU 2025）年会已经于美国旧金山举行，这场全球瞩目的学术盛会汇聚了顶尖肿瘤学者，共同探索泌尿肿瘤领域的前沿突破与未来方向。在ASCO GU大会现场，肿瘤瞭望-泌尿时讯特邀邱雪峰教授和Darren Poon教授就转移性前列腺癌的精准治疗进展展开了精彩讨论，包括PARP抑制剂及其联合治疗的疗效，雄激素受体通路抑制剂（ARPI）经治后的选择，以及放射配体治疗等方面。

 

邱雪峰教授：这是一个非常重要的问题。正如您提到的，在中国，新确诊的前列腺癌患者中，有超过50%已经发展到局部晚期或晚期。这一比例相较于美国等西方国家要高得多，主要原因是中国尚未建立全国性的PSA筛查计划。

 

在临床实践中，我们面临两大挑战。首先是如何向老年男性推荐PSA检测，尤其是那些已经出现明显症状的患者，由于缺乏筛查意识，许多人并未接受常规检查。其次，即便是在经济发达的城市，如上海和北京，PSA筛查的推广仍处于探索阶段。如果能在这些城市进一步评估筛查的有效性，并逐步扩大覆盖范围，将有助于提高前列腺癌的早期发现率和干预效果。

 

That’s a very good question.As you mentioned，more than 50%of newly diagnosed prostate cancer patients in China present with locally advanced or advanced disease.This is actually quite high compared to Western countries like the United States.The main reason for this is the lack of a nationwide PSA screening program in China.

 

In clinical practice，we face two major challenges.The first is recommending PSA testing for older men who exhibit significant symptoms，as many are not routinely screened.The second challenge is implementing PSA screening programs in economically developed cities like Shanghai and Beijing，where we can assess its effectiveness.Expanding such initiatives could help improve early detection and intervention strategies.

 

Darren Poon教授：我认为精准医学在前列腺癌管理中发挥着至关重要的作用。目前，我们已经了解到，部分患者携带可靶向治疗的突变，例如BRCA1、BRCA2等HRR基因突变，这使得他们有机会从PARP抑制剂治疗中获益。此外，尽管比例较低（<5%），仍有部分患者表现出微卫星不稳定性（MSI），这可能使他们受益于免疫检查点抑制剂。

 

在香港，我们开展了组织活检和液体活检研究，数据显示约36%的患者携带HRR突变，其中9.9%的患者携带BRCA1或BRCA2突变。我们已在东亚地区发表相关研究，并证明这一亚型患者可从PARP抑制剂治疗中获得显著获益。

 

此外，基因检测不仅影响治疗决策，也具有重要的家族遗传学意义。部分患者不仅存在体细胞突变，还可能携带胚系突变，这对其家属的癌症风险评估具有重要影响。因此，我们在临床上会向这些患者提供遗传咨询，以帮助其家人进行癌症风险评估，并采取必要的预防措施。

 

Thank you.I appreciate your questions.I believe precision medicine plays a crucial role in managing prostate cancer patients.We now understand that a significant proportion of patients may harbor actionable mutations，such as BRCA1，BRCA2，or HRR(homologous recombination repair)mutations，which can make them eligible for PARP inhibitors.Additionally，although they represent a smaller subset—likely less than 5%of cases—some patients exhibit microsatellite instability(MSI)，which may allow them to benefit from immune checkpoint inhibitors.

 

From our experience in Hong Kong，we have conducted biopsy and liquid biopsy studies，revealing that approximately 36%of patients harbor HRR mutations，with 9.9%of them carrying BRCA1 or BRCA2 mutations.We have published and presented our data across East Asia，demonstrating that this subgroup of patients experiences a significant impact on treatment decisions and benefits from the use of PARP inhibitors.

 

Beyond the therapeutic implications，one aspect that is often overlooked is the familial impact of these genetic findings.Some patients not only exhibit somatic mutations but may also have germline mutations，which carry significant implications for their families.Identifying germline mutations allows us to offer genetic counseling，which is crucial，as it helps assess potential cancer risks among their offspring and relatives.This highlights the second key implication of genetic analysis:the importance of genetic counseling for prostate cancer patients and their families，ensuring appropriate risk assessment and preventive strategies.

 

邱雪峰教授：PROact研究是一项非常有价值的研究。我们入组了携带HRR突变的mHSPC患者，并采用PARP抑制剂奥拉帕利联合AR通路抑制剂阿比特龙进行治疗，以评估其安全性和疗效。

 

目前，我们的初步数据（基于30例患者）显示，客观缓解率（ORR）约为84%。然而，要全面评估其长期临床获益，仍需要更长期的随访数据。此外，该研究为单臂II期临床试验，尚未与单药治疗（如阿比特龙或恩扎卢胺）进行对照。因此，未来仍需开展III期临床试验，以确定该联合方案是否能显著优于单药治疗。

 

Thank you for this question.The PROact study is indeed a very interesting trial.We enrolled patients with metastatic hormone-sensitive prostate cancer(mHSPC)who had HRR mutations and treated them with a combination of the PARP inhibitor olaparib and the androgen receptor(AR)pathway inhibitor abiraterone to evaluate the safety and efficacy of this combination therapy.

 

Our current data，based on 30 patients，indicate an objective response rate(ORR)of approximately 84%.However，it is important to note that we still need to wait for long-term oncological outcomes to fully understand the clinical benefits of this approach.Another key point to highlight is that this is a single-arm Phase II clinical trial，meaning that we do not yet have comparative data against monotherapies such as abiraterone or enzalutamide.Moving forward，Phase III clinical trials will be necessary to establish whether the combination offers a significant advantage over standard monotherapies in treating mHSPC patients with HRR mutations.

 

邱雪峰教授：昨天的TALAPRO-2试验公布了最终的总生存期（OS）数据，其结果似乎与PROpel试验的数据存在一定差异。基于这些数据，您认为HRR阴性的mCRPC患者是否能从PARP抑制剂+恩扎卢胺的联合治疗中获益？

 

I have a question for Dr.Poon.In yesterday’s presentation，the TALAPRO-2 trial released its final overall survival(OS)data，which appears to differ from the OS data in the PROpel trial.Based on these findings，do you think patients without HRR mutations in the mCRPC population could benefit from the combination of PARP inhibitors and enzalutamide?

 

Darren Poon教授：是的，TALAPRO-2试验在ASCO GU大会上公布了最新数据，显示在意向治疗（ITT）人群中观察到一定的OS获益。然而，我仍然认为ARPI+PARP抑制剂联合治疗主要适用于HRR或BRCA1/2突变患者。

 

具体来看，HRR突变亚组的OS获益更显著，而在整体人群（ITT）中，该联合方案的获益较小。此外，该试验中40%的患者出现3级贫血，部分患者需要输血，这显著影响了生活质量。因此，在决定是否使用联合治疗时，我们需要仔细权衡疗效与不良反应。

 

对于存在BRCA1、BRCA2或HRR突变时，联合方案治疗mCRPC的获益更加明显，使这些患者成为联合治疗方案的优选人群。这就是为什么我总是推荐mCRPC患者进行基因检测。如果他们的HRR或BRCA1/2突变检测呈阳性，我会与他们讨论联合治疗的潜在获益，以指导最佳治疗决策。

 

Yes，the TALAPRO-2 study，which was presented on Day 1 of ASCO GU，provided updated data showing an overall survival(OS)benefit in the all-comer population.However，I still consider the combination of AR pathway inhibitors(ARPIs)with PARP inhibitors primarily for patients with HRR or BRCA1/2 mutations.

 

If we look at the subgroup analysis，the OS benefit was significantly more pronounced in patients with BRCA1，BRCA2，or HRR mutations，whereas the benefit in the all-comer or intention-to-treat(ITT)population was less substantial.This is an important distinction because combination therapy，particularly in the TALAPRO-2 trial，was associated with grade 3 anemia in some patients，requiring blood transfusions，which can significantly impact quality of life.

 

Therefore，we need to carefully balance the risks and benefits when considering combination therapy，especially in the overall ITT population.If the OS benefit is not highly significant，but the patients experience severe side effects，then the trade-off must be weighed carefully.

 

For patients with BRCA1，BRCA2，or HRR mutations，the benefit of combination treatment in the mCRPC setting is much clearer，making them the ideal candidates for this approach.This is why I would always conduct genetic testing for my mCRPC patients.If they test positive for HRR or BRCA1/2 mutations，I would discuss with them the potential benefits of combination therapy to guide the best treatment decision.

 

Darren Poon教授：新一代雄激素受体抑制剂，如阿比特龙和恩扎卢胺，已成为mCRPC的标准治疗方案。然而，随着这些ARPI疗法逐步前移至mHSPC阶段，许多mCRPC患者在疾病早期已接受过这些药物。因此，我们需要针对不同患者群体采取个性化策略。

 

近年来，联合治疗策略逐渐受到关注。今年ASCO-GU会议上，至少两项随机对照试验探讨了联合治疗的优势：TALAPRO-2研究评估了恩扎卢胺联合他拉唑帕利的获益情况，而ENZA-p研究则探索了177Lu-PSMA联合恩扎卢胺的疗效。这两项研究均表明，联合治疗较单药治疗具有OS优势，但副作用（如贫血）需慎重考虑。因此，在选择治疗方案时，我们应综合考量疗效、毒性及患者生活质量，为mCRPC患者提供个体化精准治疗。

 

Thank you for the question.Next-generation hormonal agents，such as abiraterone and enzalutamide，have been the standard of care for mCRPC patients for more than a decade.Over time，these AR pathway inhibitors(ARPIs)have been increasingly used earlier in the treatment pathway，particularly in the mHSPC setting.As a result，many mCRPC patients have already been exposed to or have experience with these agents.

 

However，there remains a subset of mCRPC patients who have not received prior ARPIs，particularly those who received upfront chemotherapy instead.In such cases，my approach is to introduce an ARPI at some point in their disease course，whether in the mHSPC or mCRPC setting.

 

In the mCRPC setting，both abiraterone and enzalutamide have long been established as key treatment options.However，we are now witnessing a growing shift toward combination therapies.At ASCO-GU this year，at least two randomized controlled trials were presented that evaluated combination approaches.The TALAPRO-2 study assessed the combination of enzalutamide and talazoparib，while the ENZA-p trial investigated the combination of lutetium-177 PSMA with enzalutamide.Both studies demonstrated overall survival benefits compared to enzalutamide monotherapy alone，highlighting the growing importance of combination strategies not only in mHSPC but also in mCRPC treatment paradigms.

 

That said，we must carefully balance efficacy with toxicity and quality of life considerations.As previously discussed，in the TALAPRO-2 trial，the combination of talazoparib and enzalutamide resulted in 40%of patients requiring blood transfusions，which can significantly impair quality of life.Therefore，we need to carefully weigh the benefits of combination therapy against the potential risks.

 

When comparing different combination strategies，such as those in the PROpel trial，we observe that the rate of anemia with olaparib plus abiraterone appears lower compared to talazoparib plus enzalutamide.This suggests that treatment selection should consider not only efficacy but also toxicity profiles to optimize both survival outcomes and quality of life for mCRPC patients.

 

邱雪峰教授：对于在mHSPC阶段已经接受过阿比特龙或恩扎卢胺治疗的mCRPC患者，当他们进展到mCRPC时，您会推荐哪种治疗方案？

 

For mCRPC patients who have previously been treated with abiraterone or enzalutamide in the mHSPC setting，what treatment approach would you recommend when they progress to mCRPC?

 

Darren Poon教授：这是一个很好的问题。我们知道，阿比特龙、恩扎卢胺以及其他雄激素受体通路抑制剂（ARPIs）如今已广泛应用于mHSPC阶段。当这些患者进展为mCRPC时，继续使用相同的ARPI可能不是最佳选择，因此我通常会考虑其他替代方案。

 

首先需要检查基因突变情况。如果患者携带BRCA1、BRCA2或HRR突变等可靶向治疗的基因突变，我会优先推荐PARP抑制剂，如奥拉帕利。如果未发现可靶向的突变，则需要考虑其他治疗策略。

 

一种主要的选择是化疗，如多西他赛（Docetaxel）或卡巴他赛（Cabazitaxel），它们仍然是mCRPC患者的标准治疗方案。另一种重要的方法是进行PSMA PET-CT扫描，以评估患者是否适合177Lu PSMA放射配体治疗。根据VISION试验数据，相较于单纯更换ARPI，177Lu PSMA治疗可带来更好的生存获益。此外，PSMAfore试验的最新数据显示，对于未接受过化疗的患者，177Lu治疗可进一步改善生存结局。基于这些研究结果，我认为177Lu PSMA治疗正在成为mCRPC患者的重要选择，尤其是对于已经用尽ARPI治疗方案、寻求有效替代方案的患者。

 

That is a very good question.As we know，abiraterone，enzalutamide，and other AR pathway inhibitors(ARPIs)are now commonly used earlier in the mHSPC setting.When these patients progress to mCRPC，continuing the same ARPIs may not be the best frontline option，so I usually consider alternative approaches.

 

The first step is to check for genomic alterations.If the patient has actionable mutations，such as BRCA1，BRCA2，or HRR mutations，I would definitely recommend PARP inhibitors like olaparib.If there are no actionable mutations，other treatment options need to be considered.

 

One of the primary options is chemotherapy，such as docetaxel or cabazitaxel，which remains a standard treatment choice for mCRPC patients.Another important approach is to perform a PSMA PET-CT scan to evaluate whether the patient is eligible for lutetium-177 PSMA radioligand therapy.Based on the VISION trial，we know that lutetium-177 PSMA therapy provides a survival benefit compared to simply switching to another ARPI.Additionally，recent data from the PSMAfore trial have shown that lutetium-177 treatment leads to better survival outcomes in patients who have not received prior chemotherapy.Given these findings，I believe that lutetium-177 PSMA therapy is becoming an increasingly important treatment option for mCRPC patients，particularly those who have exhausted ARPIs and are looking for effective alternatives.

 

邱雪峰教授：我还有一个关于同一类患者的问题。如果基因检测发现患者携带HRR突变，如BRCA突变，我们应该为他们提供PARP抑制剂单药治疗，还是联合AR通路抑制剂的联合方案会更有益？

 

I have another question regarding the same patient group.If we conduct genetic testing and find that they have an HRR mutation，such as a BRCA mutation，should we offer them PARP inhibitor monotherapy，or would it be more beneficial to combine it with an AR pathway inhibitor?

 

Darren Poon教授：这主要取决于患者是否在mHSPC阶段已接受过ARPI治疗。

 

如果他们在mHSPC阶段已接受ARPI，情况就变得复杂了。目前针对mCRPC阶段PARP抑制剂联合ARPI的三项主要随机对照试验——PROpel、TALAPRO-2和MAGNITUDE，都开展于ARPI尚未广泛用于mHSPC阶段的时期。例如，在TALAPRO-2试验中，仅有约10%的患者在mHSPC阶段使用过ARPI。这就引发了一个核心问题：对于已在mHSPC阶段接受ARPI治疗的mCRPC患者，PARP抑制剂联合ARPI是否仍然能够带来显著的生存获益？目前我们尚无确切证据。

 

挑战在于，对于ARPI耐药的患者，如果换用另一种ARPI，ORR或PSA缓解比例仅约5%~10%，这表明如果患者已对ARPI耐药，简单更换另一种ARPI可能无效。真正的问题是：添加PARP抑制剂是否能增强ARPI在已耐药患者中的疗效？遗憾的是，我们目前没有确凿的数据支持这种治疗策略。因此，如果患者已经对ARPI进展，我不会推荐PARP抑制剂联合ARPI的治疗方案。

 

此外，疾病进展的时间点也至关重要。如果患者在ARPI治疗后短期内即进展，我绝对不会推荐PARP抑制剂联合ARPI治疗，因为获益的可能性极低。

 

It really depends on whether the patient has previously received ARPIs in the mHSPC setting.

 

If they have already been treated with an ARPI during the mHSPC stage，the situation becomes more complex.The three major randomized controlled trials that assessed PARP inhibitor combinations in mCRPC—PROpel，TALAPRO-2，and MAGNITUDE—were conducted in earlier years when most patients had not yet received ARPIs in the mHSPC setting.In TALAPRO-2，for instance，only around 10%of patients had prior exposure to an ARPI in the mHSPC stage.This raises a key uncertainty.We still do not have definitive evidence on whether combining a PARP inhibitor with an ARPI in mCRPC patients who have previously received ARPIs in mHSPC truly provides a meaningful survival benefit.The challenge is that when ARPI-refractory patients are switched to another ARPI，the objective response rate(ORR)or PSA response rate is only around 5-10%.This suggests that if a patient has already failed ARPI therapy，switching to another ARPI may not be helpful.

 

The real question is whether adding a PARP inhibitor could enhance ARPI response in patients who have already progressed on a prior ARPI.Unfortunately，we do not have conclusive data to support this approach.Personally，if a patient has already progressed on an ARPI，I would not offer combination treatment with a PARP inhibitor.

 

Additionally，the timing of disease progression matters.If the patient progresses very soon after the last ARPI exposure，I would definitely not recommend combining an ARPI with a PARP inhibitor，as the likelihood of benefit is low.

 

 

邱雪峰教授和Darren Poon教授就转移性前列腺癌的精准医学进行了深入探讨。他们强调了PSA筛查、HRR和BRCA基因检测在精准治疗中的重要性，并探讨了联合治疗的潜在价值。尽管靶向治疗正在不断发展，但在优化患者预后时，疗效与毒性之间的平衡仍然至关重要。感谢两位专家的宝贵时间和专业见解，并期待未来关于前列腺癌治疗的进一步讨论和进展。