ESMO 2025 Delivers Breakthrough Bladder Cancer Results with Perioperative Immunotherapy Combinations
Key Insights
The phase 3 KEYNOTE-905 trial demonstrated that perioperative enfortumab vedotin plus pembrolizumab significantly improved outcomes in cisplatin-ineligible muscle-invasive bladder cancer (search) patients, achieving a 57.1% pathological complete response rate compared to 8.6% with surgery alone.
The POTOMAC study showed that adding durvalumab to BCG induction and maintenance reduced disease-free survival events by 32% in high-risk non-muscle invasive bladder cancer (search) patients, establishing a new potential standard of care.
Multiple kidney cancer trials presented promising results, including a triplet regimen of belzutifan, pembrolizumab, and lenvatinib achieving 31.8 months median progression-free survival in previously untreated advanced clear cell renal cell carcinoma (search).
The 2025 European Society for Medical Oncology (ESMO) Congress in Berlin delivered a series of practice-changing results in genitourinary oncology, with bladder cancer leading the charge in therapeutic advances. Multiple phase 3 trials demonstrated significant improvements in patient outcomes through innovative immunotherapy combinations and biomarker-guided treatment strategies.
Bladder Cancer Breakthroughs Lead ESMO 2025
Perioperative Immunotherapy Shows Dramatic Results
The phase 3 KEYNOTE-905 trial presented by Christof Vulsteke, MD, PhD, demonstrated that perioperative enfortumab vedotin (EV, Padcev) plus pembrolizumab (Keytruda), combined with radical cystectomy and pelvic lymph node dissection, significantly improved outcomes in patients with muscle-invasive bladder cancer (search) who are cisplatin-ineligible or decline cisplatin. The combination achieved a remarkable pathological complete response rate of 57.1% compared with 8.6% in controls, while event-free survival and overall survival were markedly better in the combination arm versus surgery alone.
The benefits were consistent across subgroups, and importantly, perioperative therapy did not compromise surgical feasibility. Although treatment-emergent adverse events were more frequent with EV plus pembrolizumab, the safety profile was considered manageable, positioning this regimen as a potential new standard for this high-risk population.
BCG Combination Therapy Advances
The phase 3 POTOMAC study, presented by Maria De Santis, MD, demonstrated that adding durvalumab (Imfinzi) to BCG induction and maintenance significantly improves disease-free survival in patients with BCG-naïve, high-risk non-muscle invasive bladder cancer (search). Among 1,018 randomly assigned patients, the combination therapy reduced the risk of a disease-free survival event by 32% compared with BCG alone (HR, 0.68, P = .0154) without negatively affecting overall survival or quality of life.
Notably, durvalumab plus BCG induction only did not show a statistically significant benefit, highlighting the critical importance of maintenance therapy. The regimen was generally tolerable with manageable adverse events, supporting durvalumab plus BCG induction and maintenance as a potential new standard for high-risk non-muscle invasive bladder cancer (search).
In contrast, the phase 3 ALBAN trial found that adding atezolizumab (Tecentriq) to BCG did not improve event-free survival compared with BCG alone in similar patients. Among 517 patients, event-free survival, high-grade recurrence-free survival, and interim overall survival were similar between the combination and BCG monotherapy arms (HR for EFS, 0.98; P = 0.91).
Biomarker-Guided Adjuvant Therapy
The phase 3 IMvigor011 trial, presented by Thomas B. Powles, MBBS, MRCP, MD, showed that adjuvant atezolizumab guided by circulating tumor DNA (ctDNA) significantly improves disease-free survival and overall survival in patients with muscle-invasive bladder cancer (search) who are ctDNA positive after radical cystectomy. Among 250 ctDNA-positive patients, median disease-free survival was 9.9 versus 4.8 months (HR, 0.64, P = .0047) and median overall survival was 32.8 versus 21.1 months (HR, 0.59, P = .0131) for atezolizumab versus placebo.
Patients who were persistently ctDNA negative had excellent outcomes without treatment, highlighting the utility of ctDNA for selecting patients likely to benefit from adjuvant immunotherapy. Treatment was well tolerated, with grade 3 to 4 adverse events occurring in 7.3% of atezolizumab-treated patients.
Prostate Cancer Advances
EMBARK Trial Demonstrates Survival Benefit
The phase 3 EMBARK trial, presented by Stephen J. Freedland, MD, demonstrated that enzalutamide (Xtandi) plus leuprolide significantly improves overall survival in patients with high-risk, biochemically recurrent prostate cancer (search) compared with leuprolide alone. At 8 years, the overall survival rate was 78.9% with combination therapy versus 69.5% with ADT alone, representing a 40.3% reduction in risk of death, with benefits observed across all predefined subgroups.
Combination therapy also improved time to first use of new antineoplastic therapy, progression-free survival on subsequent therapy, and time to first symptomatic skeletal event, while maintaining a manageable safety profile. Enzalutamide monotherapy showed trends toward benefit but did not reach statistical significance for overall survival, reinforcing the combination with ADT as the standard of care for this population.
Novel Combinations Show Promise
The phase 3 CAPItello-281 trial showed that adding capivasertib (Truqap) to abiraterone acetate (Zytiga), prednisone, and androgen deprivation therapy significantly prolonged radiographic progression-free survival in patients with PTEN (search)-deficient de novo metastatic hormone-sensitive prostate cancer (search). The median radiographic progression-free survival was 33.2 months with capivasertib versus 25.7 months with placebo (HR, 0.81; P = .034), with the greatest treatment effect seen in patients with complete PTEN loss.
Kidney Cancer Innovations
Triplet Therapy Shows Superior Efficacy
Results from the KEYMAKER-U03 substudy 3A, presented by Cristina Suarez Rodriguez, MD, PhD, showed that the triplet regimen of belzutifan (Welireg) plus pembrolizumab (Keytruda) and lenvatinib (Lenvima) demonstrated improved efficacy versus other regimens in patients with previously untreated advanced clear cell renal cell carcinoma (search). The triplet achieved a duration of response of 33 months and a median progression-free survival of 31.8 months, outperforming the pembrolizumab/lenvatinib reference arm (duration of response, 26 months; progression-free survival, 20.8 months).
Safety was manageable, with grade 3 or higher adverse events reported in 70% of patients. Rodriguez concluded that this triplet may offer prolonged responses and a progression-free survival benefit compared with current standard therapy.
Post-Immunotherapy Treatment Sequencing
The phase 2 LenCabo trial, presented by Andrew W. Hahn, MD, showed that lenvatinib (Lenvima) plus everolimus (Afinitor) significantly improved progression-free survival compared with cabozantinib (Cabometyx) in patients with metastatic clear cell renal cell carcinoma (search) previously treated with a PD-1 (search) inhibitor. The combination reduced the risk of disease progression or death by 49% (median progression-free survival, 15.7 versus 10.2 months; HR, 0.51; P = .02) and achieved an objective response rate of 52.6%.
Implications for Clinical Practice
These results from ESMO 2025 represent significant advances in genitourinary oncology, particularly in bladder cancer where multiple combination strategies have demonstrated meaningful clinical benefits. The success of biomarker-guided approaches, such as ctDNA-directed adjuvant therapy and PTEN (search)-deficient patient selection, signals a move toward more personalized treatment strategies.
The consistent theme across these trials is the importance of combination therapy and appropriate patient selection, whether through biomarker identification or clinical characteristics. As these regimens move toward regulatory approval and clinical implementation, they promise to substantially improve outcomes for patients with genitourinary malignancies.