2025 ASCO Bladder Cancer Highlights

The potential impact of neoadjuvant therapy and the role of circulating tumor DNA (ctDNA) analysis were key discussion points at the 2025 ASCO Annual Meeting. Updated results from the phase 3 EV-302 trial were also presented with impressive outcomes among patients who experienced a complete response to enfortumab vedotin plus pembrolizumab (EV + P).Dr. Shilpa Gupta presented an exploratory analysis from the EV-302/KEYNOTE-A39 phase 3 trial, evaluating EV + P versus chemotherapy (CT) in treatment-naïve patients with locally advanced or metastatic urothelial carcinoma [1]. This analysis, with a median follow-up of 29.1 months, focused on efficacy and safety among patients achieving confirmed complete responses (cCR). The study randomized 886 patients 1:1 to EV + P or CT (gemcitabine with cisplatin/carboplatin). The primary endpoints were progression-free survival and overall survival (OS). Secondary endpoints included objective response rate, duration of response (DoR), and safety. EV + P demonstrated superior efficacy: confirmed objective response rate was 67.5% vs. 44.2% (EV + P vs. chemo), and cCRs were 30.4% vs. 14.5%. Among those with cCR, 66.2% (EV + P) and 59.4% (chemo) had initially achieved partial response before converting to CR. Response durability was notable; the 2-year CR maintenance probability was 74.3% with EV + P. Median DoR among CR patients was not reached in the EV + P arm versus 15.2 months with chemo. Among partial responders, median DoR was 10.6 months (EV + P) versus 5.4 months (chemo). OS among all responders favored EV + P (HR 0.59), with 76.3% alive at 2 years. Among CRs, OS was markedly better with EV + P (HR 0.37), with 95.4% 2-year survival. EV + P was administered for a median of 12 cycles (overall), 19 cycles (responders), and 30 cycles (CRs), without increased safety concerns. Dose modifications were common but manageable. The safety profiles of EV and P among responders were consistent with the overall population.EV + P significantly improves survival outcomes in patients achieving CR or PR versus CT, with durable responses and an acceptable safety profile. These data affirm EV + P as the standard first-line treatment for advanced urothelial carcinoma, including cisplatin-eligible and -ineligible patients.An exploratory ctDNA analysis from the phase 3 NIAGARA trial (NCT03732677) [2] underscores the clinical and molecular advantages of adding perioperative durvalumab to neoadjuvant chemotherapy (NAC) in cisplatin-eligible muscle-invasive bladder cancer (MIBC). NIAGARA demonstrated that durvalumab combined with NAC significantly improved event-free survival (EFS; HR 0.68), OS (HR 0.75), and pathologic complete response (pCR) by 10% over NAC alone, supporting FDA approval in March 2025. Patients received either NAC plus durvalumab followed by radical cystectomy (RC) and adjuvant durvalumab, or NAC and RC alone. ctDNA was assessed using the Signatera MRD assay at baseline, pre-RC, and post-RC. Among 462 biomarker-evaluable patients, baseline characteristics mirrored the full cohort. At baseline, 57% of patients were ctDNA-positive. This declined to 22% pre-RC, with ctDNA clearance rates of 41% in the durvalumab arm versus 31% in the control arm, suggesting enhanced molecular response with immunotherapy. Persistent ctDNA positivity prior to surgery was associated with poor pathologic outcomes; 97% of ctDNA+ patients pre-RC failed to achieve pCR. Post-RC, ctDNA positivity dropped to 9%, reflecting effective tumor eradication. EFS and disease-free survival (DFS) benefits from durvalumab were seen across ctDNA-positive and -negative subgroups. Notably, post-RC ctDNA+ patients still experienced DFS improvement with durvalumab (HR 0.49), highlighting its impact even in minimal residual disease.Perioperative durvalumab enhances both clinical and molecular outcomes in MIBC. ctDNA clearance correlates with improved pCR, EFS, and DFS, reinforcing ctDNA as a valuable biomarker for early response prediction and relapse risk stratification. These results support incorporating ctDNA monitoring into personalized treatment algorithms and establish perioperative durvalumab as a new standard for cisplatin-eligible MIBC patients.The phase 2 SURE-02 trial evaluated neoadjuvant sacituzumab govitecan (SG), a TROP2-targeting antibody-drug conjugate, combined with pembrolizumab (Pembro) in patients with MIBC who were ineligible for or declined standard cisplatin-based CT and/or RC [3]. Led by Dr. Andrea Necchi, the study explored a response-adapted, bladder-sparing approach. A total of 49 patients received neoadjuvant SG + Pembro, followed by either bladder-sparing restage transurethral resection of bladder tumor (reTURBT) or RC. Post-surgical patients received adjuvant Pembro. Among the 36 patients evaluable for efficacy, 16 (44.4%) achieved clinical complete response (cCR), and 23 underwent bladder-sparing reTURBT. Two patients relapsed intravesically after cCR. The treatment was well tolerated: 98% experienced treatment-related adverse events, predominantly grade 1 (86%). Only 6% discontinued neoadjuvant therapy due to treatment-related adverse events. With a median follow-up of 10 months, 12-month EFS was 71.3%, and metastasis-free survival was 84.2%. All cCR patients remained event-free and bladder-intact at 12 months. The 12-month bladder-intact EFS rate in the reTURBT group was 74%. Biomarker analysis showed higher cCR rates in patients with luminal subtypes and elevated tumor mutation burden (median TMB 12 vs. 6.6 mutations/Mb). Improved EFS correlated with higher TROP2 expression and mismatch repair signatures.SG + Pembro shows promise as a bladder-preserving strategy in MIBC patients unfit for or unwilling to undergo standard therapy. High cCR rates, favorable survival, and manageable toxicity support further investigation of this approach in future trials.The author has no conflicts of interest to declare.This report was not supported by any sponsor or funder.The author confirms sole responsibility for the following: manuscript preparation, including drafting the original work and critically revising it for important intellectual content.