🚨⭐🟠 #ESMO26 | GU Oncology — Invited Discussion
KEYNOTE-866 • ENERGIZE • TROPHY-U-01
🎤 Prof. Robert Jones 🇬🇧
@OncoAlert @urologysummit
🔬 Why do apparently similar trials produce different outcomes?
An excellent critical appraisal of perioperative immunotherapy in #MIBC and emerging triplet strategies in metastatic #UrothelialCancer.
📊 1️⃣ PERIOPERATIVE IMMUNOTHERAPY
✅ NIAGARA: EFS HR 0.68
❌ KEYNOTE-866: EFS HR 0.88
❌ ENERGIZE: EFS HR 0.94

But are these trials directly comparable?

📌 Important baseline differences:
• T2 disease: 40% vs 15% vs 76%
• 24-month control-arm EFS: 59.8% vs 70% vs 71.6%

Different populations, endpoints and statistical designs complicate cross-trial interpretation.

🧬 2️⃣ ctDNA: PROGNOSTIC ≠ PREDICTIVE
Pretreatment ctDNA positivity was associated with shorter EFS and OS.
⚠️ In ENERGIZE, baseline ctDNA positivity differed between arms (59% vs 51%), potentially introducing prognostic imbalance.

🔬 ctDNA clearance before cystectomy identified patients with more favorable outcomes.

But can ctDNA clearance identify candidates for bladder preservation?
Not yet! Prospective validation is essential before considering omission of radical cystectomy.
💊 3️⃣ DUAL ADC + IMMUNOTHERAPY: THE NEXT FRONTIER?

TROPHY-U-01 Cohort 7:
✅ ORR 81%
✅ Median PFS 19.3 months
✅ Median DoR 16.7 months

⚠️ Grade ≥3 treatment-related AEs: 52%
⚠️ Treatment-related discontinuation of ≥1 agent: 33%

Promising efficacy, but only 21 patients and no randomized comparator.

⭐ MY POINT OF VIEW CLINICAL PEARLS

🔹 A positive trial does not prove the superiority of one checkpoint inhibitor over another.
🔹 ctDNA may redefine risk stratification, but molecular clearance is not yet a license to omit surgery.
🔹 Dual ADC intensification is scientifically exciting, but added efficacy must justify added toxicity.

💡 The future of GU oncology is not about treating everyone more aggressively. It is about treating the right patient with the right strategy, at the right time.

📌 PRACTICE IMPLICATION
These new results do not independently establish a new standard of care. Individual trials must be interpreted on their own merits.
Access also matters: perioperative gemcitabine/cisplatin + durvalumab remains an important option where EV + pembrolizumab is unavailable.
🌍 GU Oncology Community
@gbanna74 @ravikanesvaran @urologysummit
@tompowles1 @PGrivasMDPhD @apolo_andrea @sonpavde @DrYukselUrun @yekeduz_emre @drenriquegrande @TiansterZhang

@ecancer @UrologyTimes @urotoday @wearemedsir @OpenMedicineHQ @UCSFCancer
#BladderCancer #GUOncology #ctDNA #OncoAlert