The phase II SURE-01 trial (NCT05226117) has reported primary results for neoadjuvant sacituzumab govitecan (SG) followed by radical cystectomy (RC) in patients with muscle-invasive bladder cancer (MIBC) who were ineligible for or refused cisplatin-based neoadjuvant chemotherapy. Conducted at IRCCS San Raffaele Hospital in Milan, Italy, the trial provides the first prospective data on a TROP2-targeting antibody-drug conjugate (ADC) monotherapy in the neoadjuvant MIBC setting, alongside exploratory biomarker analyses identifying lower TOP1 expression and nonluminal molecular subtypes as putative biomarkers of activity.

Clinical Takeaway

Neoadjuvant sacituzumab govitecan at the amended dose of 7.5 mg/kg demonstrated activity and a manageable safety profile in cisplatin-ineligible or cisplatin-refusing patients with MIBC. Although the trial did not meet its protocol-defined primary endpoint, a post hoc ypT0N0-x rate of 29.5% and a 24-month event-free survival (EFS) rate of 71.4% were observed. Responses were enriched among nonluminal tumor subtypes, while lower TOP1 expression was associated with longer EFS.

Drug Profile & Mechanism

  • Drug: Sacituzumab govitecan (SG), an anti-TROP2 ADC conjugated to the topoisomerase I inhibitor payload SN-38 (the active metabolite of irinotecan)
  • Regulatory context: SG received accelerated FDA approval in 2021 for advanced urothelial carcinoma after platinum and immune checkpoint inhibitor (ICI) therapy; this approval was voluntarily withdrawn in 2024 after the confirmatory TROPICS-04 trial failed to demonstrate an overall survival (OS) benefit versus investigator-choice chemotherapy
  • Mechanism: SG binds TROP2, a cell-surface glycoprotein overexpressed in urothelial carcinoma, delivering SN-38 intracellularly to induce DNA damage via TOP1 inhibition
  • Dose in SURE-01: Initially 10 mg/kg IV on days 1 and 8 every 3 weeks; amended to 7.5 mg/kg following unacceptable toxicity in the first 8 patients

Target Population

  • Age ≥18 years with histologically confirmed MIBC (cT2–T4aN0M0)
  • ECOG performance status 0–1
  • Ineligible for or refusing cisplatin-based neoadjuvant chemotherapy (NAC)
  • Scheduled for radical cystectomy
  • Variant histology (VH) subtypes allowed if predominant urothelial carcinoma component (≥50% of biopsy sample)
  • Key baseline characteristics (N = 44):
    • Median age: 72 years (IQR 63–75)
    • Female: 22.7%
    • cT3–4 stage: 59.1% (including cT4: 20.5%)
    • Variant histology component: 45.5%
    • Cisplatin refusal (rather than ineligibility): 45.4%

Study Design

  • Design: Single-center, single-arm phase II trial; A’Hern single-stage design
  • Setting: IRCCS San Raffaele Hospital, Milan, Italy
  • Enrollment period: March 2022 – July 2025; clinical cutoff: November 10, 2025
  • Treatment regimen: SG (amended to 7.5 mg/kg IV, days 1 and 8) every 3 weeks for 4 cycles, followed by RC
  • Protocol amendment: After 2 deaths in the initial 10 mg/kg cohort (n = 8), including 1 treatment-related death, the dose was reduced to 7.5 mg/kg; pegylated G-CSF was added as primary neutropenia prophylaxis from cycle 1, day 9; patients with ≥3 febrile neutropenia risk factors were excluded
  • Sample size: 44 patients (80% power; one-sided significance at 10%); ≥13 ypT0N0 responses required to support further investigation
  • Biomarker analyses: Comprehensive genomic profiling (CGP; Foundation Medicine) and transcriptome-wide analyses (Decipher Bladder Genomic Subtyping Classifier, Veracyte) performed on baseline TURBT samples

Endpoints

  • Primary endpoint: Pathologic complete response rate (ypT0N0) — no residual viable disease in the RC specimen
  • Secondary endpoints:
    • Overall pathologic response (downstaging to ypT≤1N0)
    • Event-free survival (EFS): defined as disease relapse or progression (RECIST v1.1), initiation of off-protocol treatment, or death from any cause
    • Overall survival (OS)
    • Safety (CTCAE v5.0)
  • Exploratory endpoints: Tumor biomarker associations with ypT0 and EFS, including molecular subtypes and gene expression signatures

Efficacy Outcomes

  • Protocol-defined primary endpoint (ypT0N0 by RC): Achieved in 4 patients (9.1%) (95% CI, 2.5–21.7) — did not meet the prespecified threshold of ≥13 responders
  • Overall ypT0N0-x rate (post hoc; RC + reTURBT populations): 29.5% (95% CI, 16.7–45.2; n = 13 patients)
  • Pathologic downstaging to ypT≤1N0-x: 34.1% (n = 15)
  • RC refusal post-neoadjuvant therapy: 14 patients (31.8%) — 12 underwent re-TURBT and 2 had imaging assessments of complete response without biopsy because they declined biopsy
  • 24-month EFS rate: 71.4% (95% CI, 58–87.8)
  • 24-month OS rate: 80.2% (95% CI, 67.7–95)
  • EFS by pathologic response (post hoc):
    • ypT0 population: 100% 24-month EFS
    • Non-ypT0 population: 61.3% (95% CI, 42.6–88.2) 24-month EFS
  • Disease progression: 1 patient (2.3%) experienced progression and initiated second-line platinum-based chemotherapy
  • Relapses and deaths: 9 total relapses and 7 deaths at median follow-up of 22 months (IQR, 15–26); all relapses were distant metastases — no intravesical recurrences in bladder-preservation patients

Biomarker Findings

  • Molecular subtype and ypT0: ypT0 responses were enriched in nonluminal subtypes (46%) versus luminal subtypes (14%); the infiltrated luminal subtype had the highest proportion of ypT0 responses among the assessed subtypes
  • TOP1 expression and ypT0: Higher TOP1 expression trended toward lower odds of ypT0 response (P = .07); lower TOP1 expression was significantly associated with longer EFS (P = .04)
    • Patients in the lowest TOP1 tertile (n = 11): 100% EFS at 24 months
    • Patients with below-median TOP1 expression (n = 16): 92.3% (95% CI, 77.2–100) 24-month EFS
  • TROP2 expression: Not significantly associated with ypT0 (P = .72) or EFS (P = .77)
  • FGFR3 activity signature: Lower FGFR3 scores were also associated with longer EFS
  • Tumor mutational burden (TMB): Median 8 mut/Mb in both ypT0 and non-ypT0 subgroups; no significant enrichment of genomic alterations in responders
  • UGT1A1 polymorphism: Homozygous patients experienced higher rates of any-grade neutropenia and diarrhea, though no significant difference in grade 3–4 TRAEs was observed versus wild-type patients

Safety

  • Initial cohort (10 mg/kg; n = 8):
    • Any TRAE: 100%
    • Grade 3–4 neutropenia: 75%
    • Grade 3–4 diarrhea: 50%
    • 2 deaths: 1 treatment-related (septic shock); 1 attributed to progressive cognitive impairment following recovery from grade 4 neutropenia and sepsis
    • All severe TRAEs occurred after cycle 1, day 8
  • Amended cohort (7.5 mg/kg + G-CSF prophylaxis; n = 36):
    • Grade 3–4 neutropenia: 5.6% (2 patients)
    • Grade 3–4 diarrhea: 2.8% (1 patient)
    • SG discontinuation due to TRAE: 5.6% (2 patients)
    • Dose reduction to 5 mg/kg required: 1 patient
    • Overall grade 3–4 TRAEs in amended cohort: 13.9% (5 patients)

Key Clinical Implications

✔ The amended 7.5 mg/kg dose of sacituzumab govitecan with G-CSF prophylaxis was associated with substantially fewer grade 3–4 toxicities compared with the initial 10 mg/kg regimen.

✔ The post hoc ypT0N0-x rate of 29.5%, incorporating both RC and reTURBT assessments, was within the range reported in neoadjuvant ICI studies and supports further investigation of TROP2-targeting ADCs in MIBC.

✔ Nonluminal molecular subtypes appeared enriched for ypT0 response, offering a hypothesis-generating framework for future biomarker-driven patient selection.

✔ Lower baseline TOP1 expression emerged as a putative biomarker of activity, showing a trend toward association with ypT0 response and a significant association with longer EFS; these exploratory findings warrant prospective validation.

✔ A 24-month EFS of 71.4% across the ITT population is encouraging, particularly given that 59.1% had cT3–4 disease; longer follow-up is needed to establish durability of these outcomes.

✔ The approximately 32% rate of RC refusal observed in this trial reflects a growing trend across neoadjuvant MIBC studies and highlights the need for validated bladder-preservation pathways as novel therapies improve response rates and patient confidence in organ-sparing strategies.

✔ The positioning of anti-TROP2 ADCs in the evolving MIBC treatment landscape will need to be contextualized against the recently FDA-approved perioperative enfortumab vedotin plus pembrolizumab (EVP) regimen (Keynote-905/EV-303), which achieved a 57% pCR rate; SG and related ADCs may find a role in patients with poor response to EVP or as biomarker-selected alternatives.

Bottom Line

SURE-01 is the first prospective trial to evaluate an anti-TROP2 ADC monotherapy in the neoadjuvant MIBC setting. While the trial did not meet its protocol-defined primary endpoint, with ypT0N0 achieved in 4 patients (9.1%) versus the prespecified requirement of at least 13 responders, the amended 7.5 mg/kg SG regimen demonstrated activity, with a post hoc ypT0N0-x rate of 29.5% and a 24-month EFS of 71.4%, alongside a substantially improved safety profile after protocol amendment. Nonluminal tumor subtypes and lower TOP1 expression emerged as exploratory, hypothesis-generating biomarkers of activity that warrant prospective validation. These findings, alongside data from the parallel SURE-02 trial (neoadjuvant SG plus perioperative pembrolizumab), support continued investigation of anti-TROP2–based strategies in MIBC.

Sources:

  • Necchi A, de Jong JJ, Maiorano BA, et al. Neoadjuvant sacituzumab govitecan in patients with muscle-invasive bladder cancer: primary results of the SURE-01 trial. J Clin Oncol. 2026;44(21):2017-2028. doi:10.1200/JCO-26-00142.