🚨 DAY 3 | #GUARDSymposium2026 🇪🇸 🌌 When does “advanced” urothelial cancer really begin? 🎙️ Dr. @tompowles1 🇬🇧 | Barts Cancer Institute 📡 @OncoAlert × @GuardConsortium A fascinating way to start the advanced bladder cancer session. Powles used Andromeda to challenge a very simple assumption: What we can see is not necessarily all the disease that is already there. Radiology defines visible disease. But micrometastatic disease may already exist below the threshold of imaging — and ctDNA may allow us to detect that biology earlier. This raises a provocative question: 👉 Does “advanced disease” begin when metastases become radiologically visible — or when molecular evidence tells us the disease has already escaped? Post-surgery ctDNA levels clearly stratify prognosis, and dynamic changes can be informative very early: 🔹 clearance → better outcomes 🔹 falling ctDNA → intermediate risk 🔹 persistent or rising ctDNA → substantially worse prognosis So perhaps the boundary between localized and advanced disease is becoming less anatomical and more biological. And then came the historical perspective. A few years ago, first-line trials were still asking whether adding checkpoint inhibition to platinum chemotherapy could meaningfully move the needle. Now, EV-302/KEYNOTE-A39 has completely changed the first-line landscape. At ~3.5 years of follow-up, EV + pembrolizumab continues to show durable benefit, but one detail is particularly striking: complete responses can deepen over time. Among patients achieving CR with EV + pembrolizumab, many did not start with CR. They first achieved a partial response — and then converted to CR later. And importantly, patients whose response deepened from PR → CR had similar 3.5-year survival to the overall CR population: 82.4% vs 83.6%. That changes how we think about response assessment. 🎯 My takeaway: We may need to rethink two traditional boundaries in urothelial cancer: 1️⃣ When does advanced disease really begin? Perhaps before radiology can see it. 2️⃣ When is the final depth of response really known? Perhaps much later than the first scan suggests. From ctDNA-detected molecular disease to delayed conversion from PR to CR, the common theme is the same: biology evolves continuously — our clinical categories are the ones that are discrete. And that may be one of the most important lessons as treatment becomes more effective. @OncoAlert @GuardConsortium @cdanicas @tompowles1 @DrRosenbergMSK @AndreaNecchi @urbano_anido @drenriquegrande @mjuanfi81 @tonivilaseca @MarioHArroyo @DrJaVallejo @dralvaropinto @Ecastromarcos @OncBrothers #BladderCancer #UrothelialCancer #ctDNA #GUOncology