Neoadjuvant sacituzumab govitecan in patients with muscle-invasive bladder cancer: Final results and biomarker analyses of the SURE-01 trial.

4619 Background: To evaluate neoadjuvant sacituzumab govitecan (SG), followed by radical cystectomy (RC), in patients with muscle-invasive bladder cancer (MIBC) who are ineligible for/refuse neoadjuvant chemotherapy (NAC). We report the results of the primary analysis and final biomarker analyses of the open-label, phase 2 SURE-01 trial (NCT05226117). Methods: Patients aged ≥18 years, ECOG PS 0-1, with histologically confirmed cT2-T4aN0M0 MIBC, ineligible/refusing NAC, and scheduled for RC received 4 cycles of SG 10 mg/Kg on D1 and D8, every three weeks (Q3W), followed by RC. The primary outcome measure was the pathological complete response (pCR) rate. Transcriptome-wide analyses and comprehensive genomic profiling assays were performed on baseline tumor samples. Results: From 03/22 to 07/25, 44 patients were treated and efficacy evaluable. After the initial 8 patients enrolled, the protocol was amended with a SG dose of 7.5 mg/Kg, with primary prophylaxis for neutropenia, due to the occurrence of two deaths (one treatment-related). Subsequent Grade 3-4 treatment-related adverse-events (TRAE) occurred in 5 pts (13.9%). Twenty-six patients (59.1%) had a cT3-4 stage, 20 (45.5%) had a variant histology. Fourteen patients (31.8%) refused to undergo RC and underwent a repeated transurethral resection of the bladder tumor. The median follow-up was 22 months (interquartile range: 15-26). In the intention-to-treat population: the ypT0N0-x rate was 29.5% (95% confidence interval CI: 16.7-45.2). We observed an enrichment of ypT0 responses in non-Luminal subtypes (46% vs 14% of Luminal), with the Infiltrated Luminal subtype having the highest proportion of ypT0 (62%). Variance by subtype revealed that TOP1 had the lowest scores in the Infiltrated Luminal subtype. A few signatures involving metabolism and tumor microenvironment were statistically significantly associated with a lower odds ratio of ypT0, whereas TROP2 expression (p=0.72) was not. The 24-month event-free survival (EFS) rate was 71.4% (95%CI: 58-87.8) and the 24-month overall survival (OS) rate was 80.2% (95%CI: 67.7-95). Longer EFS was observed for participants with lower TOP1-expressing tumors (p=0.04). Conclusions: To our knowledge, SURE-01 is the first to report results of an antibody-drug conjugate monotherapy targeting TROP2 in the neoadjuvant setting for patients with MIBC. Neoadjuvant SG at the reduced dose of 7.5mg/kg demonstrated compelling activity and survival estimates, with a manageable safety profile, corroborating TROP2 as a suitable target for MIBC. Molecular biomarkers pointing to the payload were associated with neoadjuvant SG activity. Clinical trial information: NCT05226117 .