The year 2025 marked a turning point in the management of advanced urothelial carcinoma (UC). Antibody–drug conjugates (ADCs) combined with immune checkpoint inhibitors (ICIs) demonstrated overwhelming advantages in the first-line setting, fundamentally challenging the long-standing dominance of platinum-based chemotherapy.Oncology Frontier – Urology Stream invited Prof. Jun Guo and Prof. Juan Li from Peking University Cancer Hospital to provide an in-depth review of the most influential 2025 data, including HER2-targeted therapy (RC48), Nectin-4–targeted therapy (enfortumab vedotin), and TROP-2–targeted therapy (sacituzumab govitecan), with the aim of offering evidence-based guidance for clinical practice.
First-Line Advanced Disease
From “Chemotherapy-Centered” to “ADC + Immunotherapy” Dual Leadership
1️⃣ Disitamab Vedotin (RC48) + Toripalimab: China’s Breakthrough Strategy
At ESMO 2025 (LBA7), results from the phase III RC48-C016 trial demonstrated that disitamab vedotin (DV) combined with toripalimab in HER2-expressing (IHC 1+/2+/3+) locally advanced or metastatic UC (la/mUC) achieved a dramatic improvement over standard chemotherapy:
- Median PFS: 13.1 vs 6.5 months (HR 0.36; P<0.0001)
- Median OS: 31.5 vs 16.9 months (HR 0.54; P<0.0001)
- ORR: 76.1% vs 50.2%
Importantly, the safety profile favored the combination:
- Grade ≥3 TRAEs: 55.1% vs 86.9% (chemotherapy)
Subgroup analyses showed consistent PFS benefit across HER2 expression levels:
- IHC 1+: HR 0.59
- IHC 2+: HR 0.47
- IHC 3+: HR 0.25 (greatest benefit)
Benefits were also consistent across PD-L1 status, visceral metastases, age, and sex.
Earlier phase Ib/II data from RC48-C014 (published in Annals of Oncology), led by Prof. Guo, had already demonstrated:
- ORR: 73.2%
- Median OS: 33.1 months
- Median PFS: 9.3 months
- Activity across HER2 levels (IHC 3+ to 0), with ORR 80% in IHC 3+
These data laid the groundwork for the successful phase III program.
Neoadjuvant Expansion: RC48-C017
The phase II RC48-C017 study extended DV + immunotherapy into the neoadjuvant setting for muscle-invasive bladder cancer (MIBC)—the first prospective trial globally evaluating ADC + ICI in this context.
Results were striking:
- pCR rate: 63.6%
- Pathologic response rate (pPR): 75.8%
- T2N0 subgroup pCR: 85.7%
- 12-month EFS: 92.5%
- 18-month EFS: 85.9%
Grade ≥3 TEAEs occurred in only 27.7%, lower than traditional chemotherapy (40–50%), without delaying surgery.
The RC48 program, led by Prof. Guo and collaborators including Prof. Xinan Sheng, firmly established HER2-targeted ADC + PD-1 inhibition as a transformative strategy for HER2-expressing UC—including IHC 1+ patients—marking the global rise of a “China-developed solution.”
2️⃣ Enfortumab Vedotin + Pembrolizumab (EV/P): Global Standard Consolidated
Updated analyses from ASCO 2025 further strengthened EV/P as the global first-line standard for all-comer advanced UC.
- cCR rate: 30.4% (vs 14.5% chemotherapy)
- 2-year PFS (cCR patients): 78.2%
- 2-year OS (cCR patients): 95.4%
- 2-year sustained cCR: 74.3% (vs 43.2%)
Long-term EV-302/KEYNOTE-A39 data confirmed durable and deep responses, reinforcing its position as the standard backbone for first-line treatment worldwide.
Second-Line Therapy
New Targets and Resistance Strategies
1️⃣ Sacituzumab Govitecan (SG): Phase III Setback
The phase III TROPiCS-04 trial (NCT04527991) evaluating sacituzumab govitecan (TROP-2–targeted ADC) failed to meet its primary OS endpoint:
- Median OS: 10.3 vs 9.0 months (HR 0.86; P=0.087)
Although ORR favored SG (23% vs 14%), this did not translate into survival benefit.
Notably:
- Grade 3/4 neutropenia: 56%
- G-CSF prophylaxis was not mandated
Following these results, the U.S. FDA withdrew accelerated approval for SG in UC.
This experience highlights the importance of supportive care optimization and precise patient selection in ADC development.
2️⃣ LOXO-435: Addressing FGFR Resistance
The phase I FORAGER-1 study, published in JCO 2025, evaluated LOXO-435, a highly selective FGFR3 inhibitor.
In patients previously treated with erdafitinib or other FGFR inhibitors:
- ORR exceeded 40%
- Activity observed in FGFR3 resistance mutations (e.g., V555M, G697C)
As erdafitinib use expands, resistance is increasingly encountered. Next-generation selective inhibitors such as LOXO-435 may address this unmet need.
Summary and Outlook
The 2025 data fundamentally reshaped advanced UC management.
First-Line Landscape
- ADC + ICI is now a foundational strategy.
- RC48 + toripalimab provides a highly effective chemotherapy-free option for HER2-expressing patients.
- EV + pembrolizumab remains the gold standard for the overall population.
Later-Line Innovations
- LOXO-435 offers hope in FGFR-resistant disease.
- TROP-2 targeting requires more refined biomarker strategies.
Future Directions
Treatment selection will increasingly rely on biomarker-driven strategies:
- HER2
- Nectin-4
- TROP-2
- FGFR3
Key priorities moving into 2026 include:
- Extending first-line success into neoadjuvant/adjuvant settings
- Optimizing ADC sequencing strategies
- Managing ADC-associated toxicities (neuropathy, dermatologic events, myelosuppression)
- Continuing global collaboration led increasingly by Chinese investigators
The shift from chemotherapy to biologically guided combination therapy is no longer theoretical—it is clinical reality.
Prof. Jun Guo
Prof. Juan Li
