Andrea Necchi, MD, Vita-Salute San Raffaele University, Milan, Italy, discusses results from the phase 2 SR-4 trial evaluating neoadjuvant TAR-200 plus cetrelimab compared with cetrelimab alone in patients with muscle-invasive bladder cancer who were ineligible for or declined platinum-based chemotherapy.

The study showed that TAR-200 plus cetrelimab achieved higher pathologic complete and overall response rates, along with improved 1-year recurrence-free survival, supporting the combination’s potential role in neoadjuvant treatment for muscle-invasive bladder cancer. Exploratory analyses also identified urinary and ctDNA as promising biomarkers for minimal residual disease detection.

These findings were presented at the 2025 European Society for Medical Oncology (ESMO) Congress.

Transcript: 

I’m Andrea Necchi, I'm an associate professor of oncology at Vita-Salute San Raffaele University in Milan, Italy and director of GU medical oncology at San Raffaele Hospital in Milan, Italy. Pleased to be here today at ESMO 2025 presenting the results of the SunRise-4 study, primary results and biomarker results of the SunRise-4 study. 

The results have been presented in interim analysis last year at the ESMO meeting and published a few months ago in Lancet Oncology. The SunRise-4 study is a phase 2, randomized study for patients with clinical T2 to T4a, N0, M0 muscle-invasive bladder cancer who are ineligible for or refuse cisplatin-based chemotherapy. The study randomized patients to receive 4 cycles of intravesical gemcitabine and TAR-200 in combination with the checkpoint inhibitor cetrelimab or cetrelimab monotherapy for 4 courses before radical cystectomy and before the follow-up period. The primary end point of the study was the pathologic complete response (pCR) and there were secondary end points like relapse-free survival and exploratory end points like biomarkers. We focused on 2 biomarkers: urinary tumor DNA (utDNA) and circulating tumor DNA (ctDNA). 

The findings that we have presented are the findings of the final analysis of the study confirming the pathologic response end point the initial findings. Pathologic response rate, complete response rate, was 38% in the combination therapy arm and it was higher than 50% in the TAR-200 and cetrelimab combination. These results were reported in a proportion of 24% and 44% in the cetrelimab monotherapy arm—so an increment of at least 10% in the pCR rate and pathologic downstaging rate with the combination of an intravesical therapy. The safety profile was pretty much in line with the initial findings. No new safety signals have been reported, and the vast majority of grade 3/4 side effects were related to local irritation, symptoms of local irritation, they were well manageable by the investigators. We reported the initial findings of relapse-free survival outcomes. Survival outcomes showed that at the cutoff for 1 year, 1-year relapse-free survival was 77% with the combination therapy as compared to less than 65% to 66% in the cetrelimab monotherapy arm. Again here, a 10% improvement with TAR-200 in relapse-free survival at the 1-year cut off point. 

This is what is reported in summary regarding the clinical end points, but there is an ongoing story that is quite compelling– this is related to biomarkers, in particular utDNA which was measured at baseline and post–neoadjuvant treatment at week 12 before cystectomy. utDNA at week 12 post–neoadjuvant therapy was clearly associated with pathologic complete response; it was able to predict complete response in most patients. The same for utDNA clearance in patients who had positivity at baseline and had negativization of the test post-treatment. Similarly, this was predictive for pathologic complete response. utDNA was positive in a proportion as high as 82% in patients who were judged to have received a complete resection of the tumor at baseline so it’s intriguing to see that despite visibly resected tumors, 82% of this patient population presented with positivity at the end of testing. For the ctDNA, the results confirmed those already reported from other studies – ctDNA at baseline or at week 12 was associated with relapse-free survival. Interestingly, this biomarker was not associated with pathologic complete response, so it reflected more the systemic disease rather than what is happening in the bladder. 

Altogether, these data indicate that there could be an opportunity from a treatment standpoint with the combination of intravesical therapy and immune checkpoint inhibitor. Second, from the biomarker standpoint, we could easily integrate utDNA and ctDNA as tools for predicting the possibility of bladder sparing and patient outcomes. It’s a nice story that is being built by the combination of clinical and biomarker data from this study.

Source: 

Necchi A, Guerrero-Ramos F, Crispen PL, et al. Neoadjuvant gemcitabine intravesical system (TAR-200) + cetrelimab (CET) or CET alone in patients (pts) with muscle-invasive bladder cancer (MIBC): SunRISe-4 (SR-4) primary analysis and biomarker results. Presented at the 2025 ESMO Congress. October 17-21, 2025; Berlin, Germany. LBA112