Editor's Note: The 2025 American Society of Clinical Oncology Genitourinary Cancers Symposium  (ASCO GU 2025) is currently taking place in San Francisco, USA. This globally renowned academic conference brings together top oncology experts to explore cutting-edge breakthroughs and future directions in the field of genitourinary cancers. On-site at ASCO GU, Urology Frontier invited Dr. Jianming Guo from Zhongshan Hospital, Fudan University, to engage in a discussion with Dr. Philip Kwong from The University of Hong Kong. Together, they analyzed key advancements in metastatic castration-resistant prostate cancer (mCRPC), covering treatment strategies, novel ADC drugs, precision medicine, and radioligand therapy.

Urology Frontier: Several significant research findings have been presented at this year’s ASCO GU conference. In the field of mCRPC, which studies have intrigued you the most?

Dr. Jianming Guo: In recent years, with the growing maturity of research and development in oncology, various new therapeutic approaches—such as PSMA-targeted radioligand therapy, PARP inhibitors, FGFR inhibitors, immune checkpoint inhibitors (ICIs), and ADC drugs—have been actively explored to improve the prognosis of mCRPC patients. At this ASCO GU conference, several noteworthy studies in the mCRPC field were unveiled, and the following stand out:

1. PSMA-Targeted Radioligand Therapy

The ENZA-p (ANZUP 1901) trial compared 177Lu-PSMA-617 plus enzalutamide versus enzalutamide monotherapy in high-risk, metastatic castration-resistant prostate cancer (mCRPC) patients. The results revealed a median overall survival (OS) of 34 months, highlighting the clinical significance of combining radioligand therapy with novel hormonal agents. This study demonstrated that enzalutamide combined with Lu-PSMA-617 improves overall survival, reduces pain and fatigue scores, and extends progression-free survival in terms of physical function and health-related quality of life (HRQoL) for high-risk mCRPC patients. These findings offer a more effective treatment approach while advancing the broader application of radioligand therapy in mCRPC treatment.

Additionally, the PSMAfore study presented a ctDNA subgroup analysis comparing 177Lu-PSMA-617 monotherapy versus switching androgen receptor pathway inhibitors (ARPI). As a liquid biopsy technology, ctDNA dynamically reflects tumor molecular characteristics and therapeutic responses. By analyzing the relationship between ctDNA and the efficacy of 177Lu-PSMA-617, this study provides insights into patient stratification, treatment efficacy prediction, and individualized therapy, further optimizing the clinical application of radioligand therapy.

2. PARP Inhibitors

The phase III TALAPRO-2 trial released final OS analyses for talazoparib plus enzalutamide as first-line treatment in HRRm+ and intent-to-treat (ITT) populations. Meanwhile, the PROpel trial of olaparib plus abiraterone also reported updates, though median OS has not yet been reached, showing a trend toward clinical benefit. These findings expand precision treatment options for mCRPC patients and have the potential to reshape the current treatment landscape.

3. ICI Therapy

Prostate cancer is traditionally considered a “cold tumor”, and past attempts with ICIs have largely been unsuccessful. However, at this year’s ASCO GU, the COSMIC-021 trial investigating atezolizumab plus cabozantinib in mCRPC challenged this notion once again. The results showed that compared to cabozantinib monotherapy, the combination therapy did not significantly improve PFS (5.5 months vs. 6.7 months), and OS benefits were also limited (15.6 months vs. 13.8 months).

4. Emerging Therapies

One notable ongoing study presented at the conference focuses on FGFR inhibitors. Previous research suggests that JAK1 and FGFR activation can mediate ARPI resistance, and preclinical studies have shown that inhibiting JAK1 and FGFR can restore ARPI sensitivity. Tinengotinib, a tyrosine kinase inhibitor (TKI) that simultaneously inhibits JAK1 and FGFR, is currently being investigated in a multicenter phase Ib/II trial evaluating its combination with abiraterone/prednisone or enzalutamide for patients with mCRPC who have progressed after ARPI therapy. The phase Ib study focuses on safety, while the phase II study evaluates efficacy, with the trial expected to launch in 2025. The hypothesis is that combination therapy could restore ARPI sensitivity, though the research remains in its early stages.

The randomized dose-expansion study of mevrometostat plus enzalutamide also warrants attention. Mevrometostat is a novel EZH2 inhibitor, designed to suppress tumor growth via epigenetic regulation. Combining an EZH2 inhibitor with hormonal therapy could produce synergistic effects. The study found that mevrometostat plus enzalutamide demonstrated superior efficacy compared to enzalutamide monotherapy, with manageable adverse events, offering a novel treatment approach for mCRPC patients.

The phase I/II study of Nezastomig (PSMA × CD28 bispecific antibody) monotherapy for mCRPC and clear cell renal cell carcinoma (ccRCC) is another key highlight. Nezastomig is a bispecific antibody that binds PSMA and CD28 receptors to activate an anti-tumor immune response. Preliminary results indicated clinical activity in mCRPC, making it the first therapy to validate CD28 co-stimulation in solid tumors. Further studies are required to confirm its safety and efficacy.

Moreover, an early-phase study of LuPSMA plus carboplatin in mCRPC treatment is particularly innovative. This study evaluates the safety and efficacy of combining LuPSMA with carboplatin, with carboplatin acting as a radiation sensitizer to potentially enhance LuPSMA’s anti-tumor effects. The phase Ia study has determined a safe dosage, while the phase Ib study further evaluates efficacy and biomarker responses. The trial aims for a ≥50% decline in PSA levels in at least 15 patients as an efficacy benchmark. So far, six patients have been enrolled, and the study remains in its early stages.

Dr. Philip Kwong: I completely agree with Professor Guo’s comments. Additionally, I am particularly interested in the mature data from the TALAPRO-2 study and the ENZA-p study, as both have now released their final OS results. These findings will provide a clearer definition of the efficacy of these two treatment strategies, helping us determine the optimal sequencing or combination of therapies for mCRPC patients.

Moreover, the development of new drugs is also highly intriguing and exciting. I hope that in the coming years, we will see more available new drugs and phase III studies exploring novel targeted combination therapies. This will enable us to improve treatment strategies for both mCRPC and even mHSPC patients. We eagerly anticipate further advancements that can bring greater benefits to patients.

Urology Frontier:mCRPC represents the terminal stage of prostate cancer, and NHT + ADT has become the foundation of comprehensive treatment at this stage. How do you view drug selection and combination therapy for mCRPC?

Dr. Philip Kwong:Based on previous research findings, ADT combined with ARPI, NHT, or chemotherapy has become the standard treatment regimen for mCRPC patients. However, with advancements in technology and research, we are now also using ADT combined with ARPI or chemotherapy in mHSPC patients. When patients progress to mCRPC, switching ARPI often yields poor results. In this scenario, we must improve patient outcomes and explore alternative treatment combinations.

Therefore, for patients who have received ADT + ARPI in the mHSPC stage, if they become eligible for chemotherapy at the mCRPC stage, we would consider chemotherapy. Additionally, based on new findings, if an mCRPC patient has an HHR mutation, I believe PARP inhibitors should be used. The strategy of ARPI + PARP inhibitors holds promise, but currently, there is no data confirming the efficacy of using ARPI + PARP inhibitors in patients who previously received ARPI for mHSPC and later progressed to mCRPC. This area requires further investigation.

Furthermore, we can consider other drugs or treatment approaches, such as Lutetium-177. If a patient’s PSMA PET/CT is positive, this treatment strategy may achieve good efficacy. We also look forward to the emergence of new targets and novel research.

In my view, the future of mCRPC treatment lies in adopting more precise, targeted approaches for patients with different mutations or at different disease stages, allowing us to deliver personalized treatment regimens.

Urology Frontier: In recent years, various ADC drugs targeting Trop-2, HER3, PSMA, and other markers have been explored in prostate cancer. You and your team have also shared relevant research progress at this conference. Could you briefly introduce these new ADC drugs and their efficacy in mCRPC?

Dr. Jianming Guo: Antibody-drug conjugates (ADCs) have gained significant attention in recent years as a systemic treatment strategy. ADCs consist of three key components: an antibody targeting a tumor-specific antigen, a cleavable or non-cleavable linker connecting the antibody and the payload, and a highly potent cytotoxic payload, which is delivered to tumor cells. The antibody binds to tumor-specific antigens, and the ADC is internalized by the cancer cell, where the cytotoxic payload is released, leading to tumor cell apoptosis or death by targeting DNA or microtubules.

Globally, ADCs have been widely used in lymphomas, breast cancer, and urothelial carcinoma, but no ADC has yet been approved for prostate cancer. However, in recent years, ADC development for mCRPC has progressed rapidly, with targeted therapies focused on Trop-2, HER3, and PSMA, offering new treatment directions for this hard-to-treat disease.

Trop-2-Targeted ADC

Trop-2 is a transmembrane glycoprotein that is highly expressed in many solid tumors, including prostate cancer. Sacituzumab Govitecan (SG), a Trop-2-targeted ADC, delivers the topoisomerase I inhibitor SN-38 to tumor cells. While SG research has mainly focused on bladder cancer, such as in the PRISMA-1 trial, which studied SG combined with immune checkpoint inhibitors in muscle-invasive bladder cancer, its mechanism suggests potential efficacy in prostate cancer by inhibiting DNA repair and enhancing anti-tumor activity.

HER Family-Targeted ADC

HER3, a member of the EGFR family, is overexpressed in prostate cancer and is associated with treatment resistance. Although no HER3-targeted ADCs were featured at ASCO GU, similar drugs, such as Disitamab Vedotin, a HER2-targeting ADC, have demonstrated high pathological complete response (pCR) rates of 63.6% in bladder cancer. Since Disitamab Vedotin binds to HER2 and releases the microtubule inhibitor MMAE, this mechanism could provide insights into the development of HER3-targeted ADCs for prostate cancer.

PSMA-Targeted Radioligand Therapy

Prostate-specific membrane antigen (PSMA) remains a key target in mCRPC. Lu177-PSMA-vipivotide tetraxetan (Lu177-PVT) is a radiopharmaceutical conjugate that delivers radiation directly to PSMA-expressing cancer cells. Studies presented at this conference showed that Lu177-PVT induces PSA responses across different metastatic sites, including bone, lymph nodes, liver, and lungs. However, patients with liver metastases had shorter overall survival (OS) of 15 months compared to 18 months in other subgroups, indicating the need for optimized treatment strategies in this patient population.

CBP-1018: A Dual-Ligand Conjugate Targeting PSMA and FRα

CBP-1018 is the first Bi-XDC dual-ligand conjugate targeting both PSMA and folate receptor alpha (FRα). The Bi-XDC platform efficiently delivers small-molecule drugs to specific cells by targeting two complementary receptors, improving tumor selectivity and therapeutic efficacy.

At this year’s ASCO GU, our team presented an updated analysis from a phase I/II study on CBP-1018. Previously, at ASCO 2024 and ESMO 2024, we reported the safety and preliminary efficacy results in 112 mCRPC patients who had progressed after ARPI therapy, confirming a recommended phase 2 dose (RP2D) of 0.14 mg/kg. At ASCO GU, we presented new data on 120 patients, focusing on safety and efficacy at doses equal to or greater than 0.14 mg/kg, supporting the initiation of a phase III study.

Safety Findings

Among all patients, 8.3% required dose reductions due to treatment-related adverse events (TRAEs), while 4.2% discontinued treatment due to TRAEs. The most common grade 3 or higher TRAEs were hematologic toxicities, which were transient and manageable. ADC-related adverse events were rare, with only one case of vision impairment observed. Peripheral neuropathy occurred in 11.7% of patients, but all cases were grade 1.

Efficacy Analysis

Among 76 patients treated at doses equal to or greater than 0.14 mg/kg, 68.4% had ECOG 1 performance status, 17.1% had liver metastases, and 15.8% had lung metastases. Additionally, 67.1% had prior exposure to both taxane chemotherapy and at least one second-generation ARPI, 53.9% had received at least two second-generation ARPIs, and 21.1% had received prior PARP inhibitor therapy.

Among 25 patients with measurable target lesions at doses equal to or greater than 0.14 mg/kg, the objective response rate (ORR) was 20%, the disease control rate (DCR) was 88%, and 60% of patients experienced a reduction in target lesion size. Among 15 patients who had previously received taxane chemotherapy and second-generation ARPIs, the ORR was 20% and the DCR was 80%.

In 69 patients treated at 0.14 mg/kg, the median radiographic progression-free survival (rPFS) had not yet been reached. The seven-month rPFS rate was approximately 70%, while the 12-month rPFS rate was around 60%. Among 48 patients who had previously received taxane chemotherapy and second-generation ARPIs, the seven-month rPFS rate was about 66%.

Our study confirms that CBP-1018 demonstrated good tolerability and durable anti-tumor activity in 120 mCRPC patients, particularly in those receiving doses equal to or greater than 0.14 mg/kg, where the ORR reached 20% and the DCR was as high as 88%. The main adverse events were hematologic toxicity and peripheral neuropathy.

Overall, the key advantage of ADCs lies in their precise delivery, which reduces systemic toxicity while enhancing therapeutic efficacy. However, challenges remain, including resistance mechanisms, safety concerns, and biomarker selection. Further clinical validation is needed to assess long-term survival benefits and optimize combination strategies.

Urology Frontier: With the development of ADC drugs, PARP inhibitors, and other targeted therapies, mCRPC has entered the era of precision medicine. Based on clinical research and experience, what aspects should we focus on to further improve precision diagnosis and treatment for mCRPC?

Dr. Philip Kwong: Indeed, with advancements in treatment, we are now entering the era of precision medicine in prostate cancer. I believe one of the most important diagnostic tools that should be more widely used is next-generation sequencing (NGS). In Hong Kong, we recommend that patients undergo NGS testing at the mCRPC stage, as this helps us consider treatment strategies that include PARP inhibitors and other targeted therapies. Before determining the next treatment approach, it is crucial to understand the patient’s mutation profile, particularly in patients with metastatic disease, especially those with high-volume disease, where a precise diagnosis is necessary. I strongly advocate for performing NGS testing at the time of diagnosis, as this allows us to develop an early and comprehensive treatment plan for patients.

Although targeted therapy is not yet a core component of mHSPC treatment strategies, I believe that with emerging research, it will eventually be integrated into early treatment approaches. We are now studying these targets earlier in the disease course, and we may consider adding PTEN-targeted therapies for certain patients. New research suggests that adding PTEN-related targeted treatments to ADT plus ARPI could provide survival benefits, particularly for patients who may progress to mCRPC relatively early. If we can identify mutation status earlier, we can design mutation-specific treatment strategies and gain a better understanding of a patient’s disease progression risk at an earlier stage.

Therefore, I believe that NGS testing should be more widely adopted, and for patients with high-volume metastatic disease, we should strongly consider performing NGS at the time of diagnosis to guide treatment planning effectively.

Urology Frontier: Radium-223 and Lutetium-177 radioligand therapies are increasingly demonstrating their therapeutic value in mCRPC. How do you think these treatments will impact future clinical practice?

Dr. Jianming Guo: Cancer diagnosis and treatment are gradually shifting toward a multidisciplinary team (MDT) model, and the emergence of novel “cross-disciplinary” therapies such as Radium-223 (Ra-223) and Lutetium-177 (Lu-177) radioligand therapy has become an important addition to mCRPC treatment. These therapies selectively target tumor cells, delivering radiation directly to cancerous tissue while minimizing damage to normal tissue.

Clinical Research on 177Lu-PSMA-617

177Lu-PSMA-617 radioligand therapy exemplifies this approach by precisely identifying PSMA-positive prostate cancer cells. Upon binding to these cells, it emits beta radiation, breaking DNA strands and leading to tumor cell death. This ensures a highly targeted treatment approach with minimal impact on surrounding healthy tissue, offering high precision, reliable efficacy, and limited toxicity.

The phase III VISION trial analyzed mCRPC patients who had previously received at least one ARPI and one to two taxane-based chemotherapy regimens. Compared to standard therapy, the addition of 177Lu-PSMA-617 significantly extended overall survival (OS) (15.3 months vs. 11.3 months, P<0.001) and radiographic progression-free survival (rPFS) (8.7 months vs. 3.4 months, P<0.001).

The PSMAfore study evaluated 177Lu-PSMA-617 versus switching ARPI therapy in chemotherapy-naïve mCRPC patients. Previous reports showed that patients in the 177Lu-PSMA-617 group had a higher PSA50 response rate (57.6% vs. 20.4%) and longer rPFS (12.02 months vs. 5.59 months) compared to those who switched ARPI therapy. At this year’s ASCO GU, an updated ctDNA subgroup analysis was presented to explore the correlation between baseline and Cycle 2 Day 1 (C2D1) ctDNA levels, PSA kinetics, rPFS, and OS.

A Cox regression model adjusted for clinical characteristics in the 177Lu-PSMA-617 group indicated that higher ctDNA levels were associated with shorter rPFS and OS, with a stronger correlation observed at C2D1 than at baseline. A random forest model incorporating clinical characteristics and C2D1 ctDNA levels showed that adding baseline ctDNA did not improve predictive accuracy (rPFS AUC = 0.87; OS AUC = 0.86).

In the overall study population, reductions in ctDNA (P=0.0015) and PSA (P<0.0001) between baseline and C2D1 were strongly correlated with longer rPFS, although they were only weakly correlated with each other (correlation coefficient = 0.26). In the 177Lu-PSMA-617 group, ctDNA reduction (P=0.002) was more strongly correlated with OS than PSA reduction (P=0.12). This subgroup analysis confirmed that C2D1 ctDNA levels provided stronger prognostic value for rPFS and OS than baseline ctDNA levels, suggesting that early ctDNA changes may serve as a better predictor of long-term treatment outcomes compared to PSA alone.

Future Clinical Implications

From the perspective of urologists and oncologists in China, radioligand therapy is expected to profoundly impact future clinical practice.

First, radioligand therapy provides new treatment options for mCRPC patients. While traditional treatments such as chemotherapy and androgen deprivation therapy (ADT) are effective, some patients develop resistance or experience significant side effects. Ra-223 and Lu-177 selectively target bone metastases and tumor cells, improving overall survival and quality of life. This is particularly valuable for patients with advanced prostate cancer, especially those with bone metastases.

Second, the use of radioligand therapy will further promote the multidisciplinary team (MDT) model. The implementation of these therapies requires collaboration among urologists, nuclear medicine specialists, oncologists, and radiologists. Enhanced multidisciplinary coordination will not only optimize treatment plans but also improve diagnostic efficiency, ensuring that patients receive personalized and comprehensive care.

Furthermore, the growing adoption of radioligand therapy will drive research and technological innovation. The development of improved radiopharmaceuticals, optimization of targeting ligands, and advancements in post-treatment efficacy assessment will continue to enhance treatment precision. These efforts will fuel progress in nuclear medicine and cancer therapy, broadening the therapeutic landscape for other malignancies.

Challenges in Clinical Adoption

Despite the promise of radioligand therapy, its widespread adoption in China still faces several challenges. High treatment costs, limited availability of radionuclide supply, and infrastructure constraints in some hospitals remain barriers to routine clinical implementation. Moving forward, it will be essential to strengthen policy support, expand technical training, and optimize resource allocation to ensure that these therapies become more accessible and standardized across clinical settings.

Conclusion

Ra-223 and Lu-177 radioligand therapies have introduced new hope for mCRPC treatment, offering targeted and effective therapeutic options. In the future, these therapies will play a crucial role in clinical practice, while also driving further advancements in oncology and nuclear medicine.

Dr. Jianming Guo

• Chair, Professor, and Doctoral Supervisor at the Department of Urology, Zhongshan Hospital, Fudan University
• Standing Committee Member of the Urology Branch, Chinese Medical Doctor Association
• Member of the Oncology Group, Urology Branch, Chinese Medical Association
• Vice Chair of the Urology Branch, Shanghai Medical Association, and Head of the Oncology Group
• Vice Chair of the Urological Oncology Committee, Shanghai Anti-Cancer Association
• Vice Chair of the Urology and Andrology Committee, Shanghai Association of Integrative Medicine
• Standing Committee Member of the Urological Oncology Committee, Chinese Anti-Cancer Association
• Standing Committee Member of the Male Reproductive Oncology Committee, Chinese Anti-Cancer Association
• Standing Committee Member of the Prostate Cancer and Urothelial Cancer Committees, Chinese Society of Clinical Oncology (CSCO)
• Vice Chair of the Urological Surgery Branch, Chinese Sexology Association
• Standing Committee Member and Deputy Secretary-General of the World Chinese Urological Medical Association
• Vice Chair of the Urology Branch, Cross-Strait Medical Exchange Association
• Vice Chair of the Geriatric Urology and Andrology Committee, Chinese Association of Geriatric Healthcare

Dr. Philip Kwong

• Bachelor of Medicine and Surgery (MBBS), The University of Hong Kong
• Diploma in Therapeutic Radiology, United Kingdom
• Fellow of the Royal College of Radiologists (FRCR), United Kingdom
• Fellow of the Hong Kong College of Radiologists (FHKCR)
• Fellow of the Hong Kong Academy of Medicine (FHKAM) in Radiology