Editor's Note: The 2025 Genitourinary Cancers Symposium of the American Society of Clinical Oncology (ASCO GU 2025) has already taken place in San Francisco, USA. This globally renowned academic event brought together top oncology scholars to jointly explore the cutting-edge breakthroughs and future directions in the field of genitourinary oncology.In this insightful exchange, Dr. Xuefeng Qiu from the Nanjing Drum Tower Hospital and Dr. Darren Poon from the Hong Kong Sanatorium and Hospital Comprehensive Cancer Center,China discuss key advances in mCRPC treatment, focusing on PARP inhibitors, ARPIs, and radioligand therapy. While genomic testing is shaping precision medicine, uncertainties remain regarding the benefit of PARP-ARPI combinations in ARPI-refractory patients. Dr. Poon highlights the potential of lutetium-177 PSMA therapy, especially for patients without prior chemotherapy.As precision oncology evolves, balancing efficacy, toxicity, and quality of life remains crucial. We appreciate our experts' insights and look forward to continued progress in prostate cancer treatment.

Urology Frontier: Welcome, Professor Qiu and Dr. Poon. Thank you for joining us. Let’s begin with our first question to Professor Qiu.More than half of newly diagnosed prostate cancer patients in China are already at an advanced stage. Based on your clinical experience, what are the urgent diagnostic and treatment challenges that you believe need to be addressed?

Dr. Xuefeng Qiu: 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.

Urology Frontier: Precision therapy has now entered the field of prostate cancer. Based on relevant data and clinical experience, how do you select precision treatment for Chinese patients with metastatic hormone-sensitive prostate cancer (mHSPC)?

Dr. Darren Poon: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.

Urology Frontier: Professor Qiu, you presented the PROACT study at this year’s ASCO GU conference. What are the clinical implications of this study for mHSPC patients with HRR mutations?

Dr. Xuefeng Qiu: 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. I have a question for Dr. Poon. In yesterday’s presentation, the PALOALTO-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?

Dr. Darren Poon: 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.

Urology Frontier: Now, Dr. Poon, regarding patients who progress to metastatic castration-resistant prostate cancer (mCRPC), what value does non-hormonal antiandrogen (NHA) therapy hold? How do you balance patient survival and quality of life in clinical practice?

Dr. Darren Poon: Thank you for the question. Next-generation hormonal agents (NGHAs), 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 ENZOP 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.

Expert Discussion

Dr. Xuefeng Qiu: I have a question for Dr. Poon. 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?

Dr. Darren Poon: 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 PSMA-4 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.

Dr. Xuefeng Qiu: 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?

Dr. Darren Poon: 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.

Conclusion

The interview with Dr. Xuefeng Qiu and Dr. Darren Poon provided valuable insights into precision medicine in metastatic prostate cancer. The discussion highlighted the importance of early PSA screening, HRR and BRCA testing, and the emerging role of combination therapies. While targeted treatments continue to evolve, the balance between efficacy and toxicity remains critical for optimizing patient outcomes and quality of life.

We extend our gratitude to both experts for their time and expertise, and we look forward to further discussions on prostate cancer advancements in the future.