ESMO 2025 recap: Top 13 trials in genitourinary oncology

The 2025 European Society for Medical Oncology (ESMO) Congress, held October 17-21, 2025 in Berlin, Germany, continued the recent pattern in urology of an onslaught of bladder cancer advancements. Notable bladder cancer research presented at ESMO 2025 included the phase 3 KEYNOTE-905 trial evaluating perioperative enfortumab vedotin-ejfv (EV, Padcev) plus pembrolizumab (Keytruda) combined with radical cystectomy and pelvic lymph node dissection, the phase 3 POTOMAC study looking at durvalumab (Imfinzi) plus BCG induction and maintenance, as well as the phase 3 IMvigor011 trial evaluating adjuvant atezolizumab (Tecentriq) guided by circulating tumor DNA.

Prostate cancer grabbed a share of the spotlight, however, especially with the presentation of the phase 3 EMBARK trial evaluating enzalutamide (Xtandi) in patients with high-risk, biochemically recurrent prostate cancer. There were also several notable trials in kidney cancer, including the KEYMAKER-U03 substudy 3A looking at the triplet regimen of belzutifan (Welireg) plus pembrolizumab (Keytruda) and lenvatinib (Lenvima) for previously untreated advanced clear cell renal cell carcinoma (ccRCC) and the phase 2 LenCabo trial comparing lenvatinib (Lenvima) plus everolimus (Afinitor) with cabozantinib (Cabometyx) in patients with metastatic ccRCC previously treated with a PD-1 inhibitor.

In this recap, we summarize these and other noteworthy genitourinary oncology research from ESMO 2025.

Bladder Cancer

Trial: KEYNOTE-905 (NCT03924895)

Presenter: Christof Vulsteke, MD, PhD

Key takeaways: The phase 3 KEYNOTE-905 trial demonstrated that perioperative EV plus pembrolizumab, combined with radical cystectomy and pelvic lymph node dissection, significantly improved outcomes in patients with muscle-invasive bladder cancer who are cisplatin-ineligible or decline cisplatin. Event-free survival and overall survival were markedly better in the EV plus pembrolizumab arm vs surgery alone, with a pathological complete response rate of 57.1% compared with 8.6% in controls. Benefits were consistent across subgroups, and 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.^1,2

Trial: POTOMAC (NCT03528694)

Presenter: Maria De Santis, MD

Key takeaways: The phase 3 POTOMAC study demonstrated that adding durvalumab to BCG induction and maintenance significantly improves disease-free survival (DFS) in patients with BCG-naïve, high-risk non–muscle invasive bladder cancer (NMIBC). Among 1018 randomly assigned patients, the combination therapy reduced the risk of a DFS event by 32% compared with BCG alone (HR, 0.68, P = .0154) without negatively affecting overall survival or quality of life. Durvalumab plus BCG induction only did not show a statistically significant DFS benefit, highlighting the 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 NMIBC.^3,4

Trial: ALBAN (NCT03799835)

Presenter: Morgan Rouprêt, MD, PhD

Key takeaways: The phase 3 ALBAN trial found that adding atezolizumab to BCG did not improve event-free survival (EFS) compared with BCG alone in patients with BCG-naïve, high-risk non–muscle invasive bladder cancer (NMIBC). Among 517 patients, EFS, 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). Although the safety profile was consistent with known effects of each agent, grade 3 or higher treatment-related adverse events were more frequent in the combination arm (22.7% vs 8.8%). Investigators highlighted that biomarker-driven patient selection may be needed to optimize the use of checkpoint inhibitors in this setting.⁵

Trial: BladderPath

Presenter: Nicholas D. James, MD, PhD

Key takeaways: The phase 2/3 BladderPath trial demonstrated that incorporating multiparametric MRI (mpMRI) prior to transurethral resection of the bladder tumor (TURBT) improves bladder cancer–specific survival in patients with suspected muscle-invasive bladder cancer (MIBC). Patients randomized to the mpMRI pathway showed a statistically significant reduction in bladder cancer–specific mortality (HR, 0.36, P = .046) and trends toward improved progression-free and overall survival. The study also indicated that mpMRI did not compromise diagnostic accuracy or lead to mismanagement compared with standard TURBT. Investigators concluded that an MRI-guided diagnostic pathway may accelerate treatment decision-making and meaningfully improve outcomes in MIBC.⁶

Trial: IMvigor011 (NCT04660344)

Presenter: Thomas B. Powles, MBBS, MRCP, MD

Key takeaways: The phase 3 IMvigor011 trial showed that adjuvant atezolizumab guided by circulating tumor DNA (ctDNA) significantly improves disease-free survival (DFS) and overall survival (OS) in patients with muscle-invasive bladder cancer (MIBC) who are ctDNA positive after radical cystectomy. Among 250 ctDNA-positive patients, median DFS was 9.9 vs 4.8 months (HR, 0.64, P = .0047) and median OS was 32.8 vs 21.1 months (HR, 0.59, P = .0131) for atezolizumab vs 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.^7,8

Trial: DISCUS (NCT06892860)

Presenter: Enrique Grande, MD

Key Takeaways: Data from the phase 2 DISCUS trial point to the feasibility of de-escalating systemic therapy in patients with metastatic urothelial carcinoma. Overall, the trial met its primary end point, showing that 3 cycles of platinum-based chemotherapy improved patient-reported outcomes compared with 6 cycles, without compromising efficacy. Although the trial was not designed to detect non-inferiority, 6 cycles of chemotherapy was not found to be superior to 3 cycles in terms of overall survival. Notably, more patients who received 3 cycles of chemotherapy went on to receive avelumab, which Grande noted may yield long-term efficacy.⁹

Prostate Cancer

Trial: EMBARK (NCT02319837)

Presenter: Stephen J. Freedland, MD

Key takeaways: The phase 3 EMBARK trial demonstrated that enzalutamide (Xtandi) plus leuprolide significantly improves overall survival (OS) in patients with high-risk, biochemically recurrent prostate cancer compared with leuprolide alone. At 8 years, the OS 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 OS, reinforcing the combination with ADT as the standard of care for this population.^10,11

Trial: CAPItello-281 (NCT04493853)

Presenter: Karim Fizazi, MD, PhD

Key takeaways: The phase 3 CAPItello-281 trial showed that adding capivasertib (Truqap) to abiraterone acetate (Zytiga), prednisone, and androgen deprivation therapy (ADT) significantly prolonged radiographic progression-free survival (rPFS) in patients with PTEN-deficient de novo metastatic hormone-sensitive prostate cancer (mHSPC). The median rPFS was 33.2 months with capivasertib vs 25.7 months with placebo (HR, 0.81; P = .034), with consistent benefits across secondary end points. The greatest treatment effect was seen in patients with complete PTEN loss. Grade 3 or higher AEs occurred in 67% of patients on capivasertib compared with 40% on placebo, reflecting a manageable but higher toxicity profile.¹²

Trial: PSMAddition (NCT04720157)

Presenter: Scott T. Tagawa, MD, MS, FACP, FASCO

Key takeaways: Data from the phase 3 PSMAddition study suggest a potential role for ¹⁷⁷Lu-PSMA-617 in an earlier disease setting. Specifically, results showed that the addition of ¹⁷⁷Lu-PSMA-617 to ADT plus an androgen receptor pathway inhibitor (ARPI) significantly extended radiographic progression-free survival (rPFS) in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (mHSPC). The benefit in rPFS was consistent across subgroups. Although adverse events were more frequent in the ¹⁷⁷Lu-PSMA-617 arm, the safety data were consistent with the known safety profile for the agent.¹³

Kidney Cancer

Trial: KEYMAKER-U03 substudy 3A (NCT04626479)

Presenter: Cristina Suarez Rodriguez, MD, PhD

Key takeaways: Results from the KEYMAKER-U03 substudy 3A showed that the triplet regimen of belzutifan (Welireg) plus pembrolizumab (Keytruda) and lenvatinib (Lenvima) demonstrated improved efficacy vs other regimens in patients with previously untreated advanced clear cell renal cell carcinoma (ccRCC). The triplet achieved a duration of response (DOR) of 33 months and a median progression-free survival (PFS) of 31.8 months, outperforming the pembrolizumab/lenvatinib reference arm (DOR, 26 months; PFS, 20.8 months). Safety was manageable, with grade 3 or higher adverse events reported in 70% of patients. Overall, Rodriguez concluded that this triplet may offer prolonged responses and a PFS benefit compared with current standard therapy.¹⁴

Trial: LenCabo (NCT05012371)

Presenter: Andrew W. Hahn, MD

Key takeaways: The phase 2 LenCabo trial showed that lenvatinib (Lenvima) plus everolimus (Afinitor) significantly improved PFS compared with cabozantinib (Cabometyx) in patients with metastatic ccRCC previously treated with a PD-1 inhibitor. Specifically, the combination reduced the risk of disease progression or death by 49% (median PFS, 15.7 vs 10.2 months; HR, 0.51; P = .02) and achieved an objective response rate of 52.6%. Safety was consistent with known profiles, with grade 3/4 adverse events (AEs) reported in 67.5% of patients. Hahn noted that these data may help inform optimal treatment sequencing in the post–immune checkpoint inhibitor setting.¹⁵

Trial: RAMPART (NCT03288532)

Presenter: James Larkin, PhD, FRCP

Key takeaways: James Larkin, PhD, FRCP, shared initial results from the phase 3 RAMPART trial, showing that adjuvant durvalumab (Imfinzi) plus tremelimumab (Imjudo) for resected primary renal cell carcinoma (RCC) improved disease-free survival vs active monitoring. The findings also indicated that this improvement was largely driven by patients at higher risk of relapse. The study is ongoing to assess durvalumab monotherapy vs active monitoring, with results expected in 2026.¹⁶

Penile Cancer

Trial: ALPACA (NCT03391479)

Presenter: Srikala S. Sridhar, MD, MSc, FRCPC

Key takeaways: The phase 2 ALPACA trial evaluated avelumab (Bavencio) in 23 evaluable patients with advanced penile cancer who were refractory to or unfit for platinum-based chemotherapy. Avelumab achieved an objective response rate of 17% and a median duration of response of 15.9 months, indicating benefit in a small subset of patients, although median progression-free and overall survival remained limited at 1.7 and 3.9 months, respectively. The treatment was well tolerated, with no new safety signals or grade 5 adverse events, but biomarkers to identify likely responders remain lacking. Sridhar emphasized that although avelumab shows promise for select patients, further studies—potentially in earlier disease settings or in combination therapies—are needed to improve outcomes.¹⁷

REFERENCES

1. Perioperative (periop) enfortumab vedotin (EV) plus pembrolizumab (pembro) in participants (pts) with muscle-invasive bladder cancer (MIBC) who are cisplatin-ineligible: The phase III KEYNOTE-905 study. Presented at: 2025 European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA2. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA2.html.pdf

2. PADCEV plus KEYTRUDA, given before and after surgery, cuts the risk of recurrence, progression or death by 60% and the risk of death by 50% for certain patients with bladder cancer. News release. Astellas Pharma. https://www.prnewswire.com/news-releases/padcev-plus-keytruda-given-before-and-after-surgery-cuts-the-risk-of-recurrence-progression-or-death-by-60-and-the-risk-of-death-by-50-for-certain-patients-with-bladder-cancer-302587853.html

3. De Santis M, Palou J, Nishiyama H, et al. Durvalumab (D) in combination with Bacillus Calmette-Guérin (BCG) for BCG-naïve, high-risk non-muscle-invasive bladder cancer (NMIBC): Final analysis of the phase III, open-label, randomised POTOMAC trial. Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA108. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA108.html.pdf

4. De Santis M, Redorta JP, Nishiyama H, et al. Durvalumab in combination with BCG for BCG-naive, high-risk, non-muscle-invasive bladder cancer (POTOMAC): final analysis of a randomised, open-label, phase 3 trial. Lancet. Published online October 17, 2025. Accessed October 18, 2025. https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(25)01897-5/abstract

5. Roupret M, Bertaut A, Pignot G, et al. ALBAN: A phase III, randomized, open-label international study of intravenous (iv) atezolizumab and intravesical Bacillus Calmette-Guérin (BCG) vs BCG alone in BCG-naïve high-risk, non-muscle-invasive bladder cancer (NMIBC). Presented at: 2025 European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. LBA110. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA107.html.pdf

6. James ND, Pirrie S, Liu W, et al. Randomized comparison of upfront magnetic resonance imaging versus transurethral resection for staging new bladder cancers: Final survival analysis from the BladderPath trial. Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA111. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA111.html.pdf

7. Powles T, Kann AG, Castellano D, et al. IMvigor011: A phase III trial of circulating tumour (ct)DNA-guided adjuvant atezolizumab vs placebo in muscle-invasive bladder cancer. Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. LBA8

8. Powles T, Kann AG, Castellano D, et al. ctDNA-guided adjuvant atezolizumab in muscle-invasive bladder cancer. N Engl J Med. Published online October 20, 2025. Accessed October 20, 2025. doi:10.1056/NEJMoa2511885

9. Grande E, Hussain SA, Duran MAC, et al. DISCUS: A phase II study comparing 3 vs 6 cycles of platinum-based chemotherapy prior to maintenance avelumab in advanced urothelial cancer. Presented at: 2025 European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. LBA109. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA109.html.pdf

10. Shore ND, de Almeida Luz M, De Giorgi U, et al. Overall survival with enzalutamide in biochemically recurrent prostate cancer. Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. LBA87.

11. Shore ND, de Almeida Luz M, De Giorgi U, et al. Improved survival with enzalutamide in biochemically recurrent prostate cancer. N Engl J Med. Published online October 19, 2025. Accessed October 19, 2025. doi:10.1056/NEJMoa2510310

12. Fizazi K, Clarke NW, De Santis M, et al. A phase III study of capivasertib (capi) + abiraterone (abi) vs placebo (pbo) + abi in patients (pts) with PTEN deficient de novo metastatic hormone-sensitive prostate cancer (mHSPC): CAPItello-281. Presented at: 2025 ESMO Congress; October 17-21, 2025; Berlin, Germany. Abstract 2383O. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/2383O.html.pdf

13. Tagawa ST, Sartor O, Piulats JM, et al. Phase III trial of [177Lu]Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition). Presented at: 2025 European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. LBA6. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA6.html.pdf

14. Suarez Rodriguez C, Rojas CI, Shin SJ, et al. First-line pembrolizumab-based regimens for advanced clear cell renal cell carcinoma: KEYMAKER-U03 substudy 03A. Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. Abstract LBA96. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA96.html.pdf

15. Hahn AW, Chahoud J, Skelton W, et al. LenCabo: A randomized phase II multicenter trial of lenvatinib plus everolimus (len/eve) versus (vs) cabozantinib (cabo) in patients (pts) with metastatic clear cell RCC (ccRCC) that progressed on PD-1 immune checkpoint inhibition (ICI). Presented at: 2025 European Society for Medical Oncology Congress; October 17-21, 2025; Berlin, Germany. Abstract LBA94. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA94.html.pdf

16. Larkin J, Powles TB, Frangou E, et al. First results from RAMPART: An international phase III randomised-controlled trial of adjuvant durvalumab monotherapy or combined with tremelimumab for resected primary renal cell carcinoma (RCC) led by MRC CTU at UCL. Presented at: 2025 European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. LBA93. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA93.html.pdf

17. Sridhar SS, Stecca CE, Fernandes R, et al. A phase II study of avelumab in locally advanced or metastatic penile cancer patients unfit for platinum-based chemotherapy or progressed on or after platinum-based chemotherapy (ALPACA). Presented at: European Society for Medical Oncology Congress. October 17-21, 2025. Berlin, Germany. LBA37. https://s3.eu-central-1.amazonaws.com/m-anage.com.storage.esmo/static/esmo2025_abstracts/LBA37.html.pdf