2025 Pujiang Uro-Oncology Academic Conference
Editor’s Note: At the 2025 Pujiang Uro-Oncology Academic Conference, leading experts from China and abroad gathered to discuss the latest progress and breakthroughs in prostate cancer treatment. Professors Guowen Lin and Junlong Wu from Fudan University Shanghai Cancer Center delivered a keynote lecture titled “Breaking Barriers in mCRPC Treatment — A New Era of Precision Targeting.” Their presentation provided a systematic overview of the current treatment landscape, major challenges, and future directions in metastatic castration-resistant prostate cancer (mCRPC). 01. The Grim Reality of mCRPC Treatment
Professor Junlong Wu noted that once prostate cancer progresses to the mCRPC stage, it is like entering the endgame of a chess match — signaling rapid disease progression and a shrinking survival window. He emphasized that disease evolution in this stage is not linear but often exponential.
At present, first-line treatments, including novel hormonal agents (NHAs) and chemotherapy, offer limited efficacy. Several prospective clinical trials have reported a median overall survival (OS) of around three years, but real-world data suggest that the actual median OS may barely exceed two years.
Facing this sobering reality, clinicians and researchers are actively seeking ways to break the impasse — exploring sequential therapies, combination regimens to overcome cross-resistance, and precision strategies targeting specific gene mutations. According to Professor Wu, these innovative approaches may hold the key to turning the tide in the battle against mCRPC.
02. Re-exploring the AR Pathway: PROTAC Technology Emerges
The androgen receptor (AR) signaling pathway remains the central driver of prostate cancer progression. Even in mCRPC, more than 70% of patients exhibit abnormal activation of this pathway. Targeting this crucial node, the rise of PROTAC (Proteolysis Targeting Chimera) technology offers an entirely new therapeutic concept.
As explained by Professor Junlong Wu, PROTAC molecules harness the cell’s own ubiquitin–proteasome system to label and degrade mutated AR proteins — effectively “marking” them for destruction.
At the 2022 ASCO Genitourinary Cancers Symposium (ASCO GU), the first oral AR-PROTAC agent, ARV-110, showed promising early results in heavily pretreated mCRPC patients. Notably, in those harboring AR T878A or H875Y mutations, the PSA response rate (≥50% decline) exceeded 50%, and the median radiographic progression-free survival (rPFS) reached 11.1 months. These findings suggest that PROTAC-based therapies may offer a new path forward in overcoming resistance to traditional AR inhibitors.
03. Maturing Precision Targeting: PARP Inhibitors Lead the Way in Combination Therapy
Targeted therapy, particularly with PARP inhibitors, has become one of the most mature and successful strategies in mCRPC management. Professor Wu systematically reviewed three pivotal phase III clinical trials: the PROpel study (olaparib plus abiraterone), the TALAPRO-2 study (talazoparib plus enzalutamide), and the MAGNITUDE study (niraparib plus abiraterone).
He highlighted that all three studies demonstrated clear and significant benefits for patients harboring BRCA mutations, establishing the efficacy of PARP inhibitor combinations as a new clinical standard. Beyond BRCA, the results also extended to broader homologous recombination repair (HRR) gene mutations, confirming substantial benefit within this subgroup.
Although the findings for HRR–wild-type populations remain heterogeneous, both PROpel and TALAPRO-2 observed signals of benefit even in the all-comer populations.
Particularly noteworthy are the latest data from TALAPRO-2, which reported a median OS of 45.8 months in the combination arm — an 8.8-month improvement over control — marking the longest OS ever reported for first-line mCRPC therapy to date. This result provides compelling evidence supporting the expansion of PARP inhibitor combinations to a wider patient population.
04. New Frontiers in Combination Therapy: Radioligand Drugs and Emerging Targets
Radioligand therapy has shown powerful potential in mCRPC management. Professor Wu presented two key studies:
The PEACE-III trial investigated Radium-223 combined with enzalutamide as first-line therapy. The results demonstrated a significant improvement in rPFS, meeting the primary endpoint, with interim analyses also showing encouraging trends toward improved OS — indicating promising future potential.
The ENZA-p phase II trial evaluated Lutetium-177 (Lu-177)-PSMA in combination with enzalutamide. The findings were equally encouraging: the combination significantly prolonged PSA-PFS and rPFS, with a median OS of 34 months compared to 26 months for enzalutamide monotherapy. These outcomes suggest that Lu-177–based radioligand therapy may soon shine not only in advanced stages but possibly in earlier disease settings as well.
However, not all combination strategies have proven successful. For example, the CYCLONE-2 study combining abemaciclib (a CDK4/6 inhibitor) with abiraterone failed to meet its primary endpoint, underscoring that not every combination yields synergistic efficacy.
05. Immunotherapy and ADC Drugs: Seeking Opportunities Amid Challenges
Prostate cancer has long been regarded as an “immune desert,” and monotherapy with immune checkpoint inhibitors has repeatedly failed to demonstrate meaningful benefit in mCRPC. However, Professor Wu emphasized that this does not mean immunotherapy is irrelevant.
For patients with high tumor mutational burden (TMB-high) or microsatellite instability-high (MSI-H), immune checkpoint blockade may still offer significant benefit. In Chinese populations, such biomarkers are estimated to be present in approximately 3%–5% of patients, highlighting the importance of precise molecular screening.
In terms of new drug development, several novel targets are attracting global attention:
EZH2 inhibitors — As a “star molecule” in recent years, EZH2 inhibition combined with enzalutamide has shown encouraging preliminary results, improving median rPFS by 8.1 months in early studies, warranting further investigation in larger trials.
Antibody–Drug Conjugates (ADCs) — Targeting B7-H3, a protein expressed in nearly 100% of prostate cancers, ADC drugs have demonstrated tremendous potential. Professor Wu referenced the DB-1311 ADC presented at the 2025 ASCO Annual Meeting, which showed strong efficacy signals in heavily pretreated mCRPC patients, with a 6-month rPFS rate exceeding 60% and manageable safety.
06. Future Perspectives
Professor Junlong Wu concluded that the “endgame” of mCRPC is becoming increasingly dynamic thanks to ongoing innovation in drug development. Beyond AR-PROTACs, PARP inhibitors, radioligand therapies, and ADCs, multiple novel targets — including CXCR2, adenosine A2A receptor, BET, and Trop-2 — are currently under clinical investigation, with new data expected within the next one to two years.
With the continuous advancement of precision medicine, and the emergence of next-generation immunotherapies and cell-based treatments, mCRPC therapy is evolving toward greater diversification and personalization.
Breakthrough therapies first validated in the mCRPC setting may soon be moved to earlier disease stages, transforming the full continuum of prostate cancer care. The progress showcased at this year’s conference underscores the fusion of global innovation and Chinese clinical expertise, injecting powerful momentum into overcoming one of oncology’s most formidable challenges.
Professor Guowen Lin Fudan University Shanghai Cancer Center
Professor Junlong Wu Fudan University Shanghai Cancer Center
