ESMO 2025 was the year of the presentation of the primary analysis and biomarker analysis from SunRISe-4. SunRISe-4 was a randomised phase II study including patients with T2-T4, N0, M0 muscle-invasive bladder cancer who are ineligible for or refuse to receive the standard radical cystectomy. The initial findings, the interim results, have been already presented at last year’s meeting and published in Lancet Oncology recently. So we presented at this year’s meeting the primary analysis, the final results, for the clinical standpoint and also the first circulating biomarker data.
Regarding the clinical data, the primary endpoint of the study was pathological complete response after either four cycles of gemcitabine intravesical system and cetrelimab every three weeks or cetrelimab monotherapy. This was the randomisation of the study. A pathCR rate was achieved in 38% of the patients with the combination therapy, with a pathological downstaging higher than 50%, basically confirming the initial findings from the interim analysis. With cetrelimab monotherapy 28% and 44% were the two proportions for pathCR [??] downstaging to non-muscle invasive disease.
We initially presented the preliminary and first relapse-free survival data, showing that at one year the relapse free survival proportion, the relapse free survival rate, was 77% with TAR200 and cetrilumab versus 66% with cetrilumab monotherapy. So there was a 10% increase in survival with the addition of intravesical therapy.
Importantly, we have the first biomarker data, as I have said, focussing on two particular biomarkers, so utDNA, urinary tumour DNA, and circulating tumour DNA, ctDNA. They were both assessed at baseline and at week 12 post-treatment, post-systemic therapy, just before radical cystectomy. Let’s start from utDNA: utDNA, first of all, was seen to be positive in a proportion as high as 80% of the patients, regardless of the completeness of prior TURBT. This is an important point. utDNA at week 12, post neoadjuvant therapy, was a strong predictor of pathological complete response. Also in the 30-patient population for which we had the comparison of pre and post matched samples, we could assess the clearance of the utDNA. In this case we also saw that the clearance of the utDNA was clearly associated with pathological complete response.
With regards to ctDNA, both baseline test and post-treatment test, they were significantly associated with relapse-free survival. Interestingly, and for the first time to my knowledge, we did not report a significant association between ctDNA and pathological response. So with the interim endpoint of pathological response to the bladder, ctDNA did not perform the same as the utDNA test.
In conclusion, globally we have a strong, or very promising, combined intravesical and systemic therapy combination possibility for these patients that spares most of the toxicity of old combinations of systemic therapies. We can use utDNA and ctDNA both in the same patients to either predict the fate of the tumour in the bladder and maybe the destiny of the bladder, in the bladder-saving approaches, in the future bladder-sparing approaches, and ctDNA when it comes to the prediction of the outcome of the patients. So they are pretty well interchangeable and could be used potentially as a combined assessment to predict the future of the bladder or to shape newer strategies for bladder preservation in patients who are deep responders to a kind of neoadjuvant therapy.
