🚨⭐🟠 #ESMO26 | Abstract 4757RO | GDFATHER-NEO @OncoAlert @myESMO Final pathological and radiological outcomes and initial EFS from a blinded, exploratory phase 2 trial of nivolumab ± visugromab in MIBC (GDFATHER-NEO) 🎤 Presented by @AndreaNecchi 🇮🇹 @OncoAlert @myESMO 🔬 Can targeting GDF-15 overcome resistance to PD-1 blockade in muscle-invasive bladder cancer? Exciting updated results, simultaneously published in Nature Medicine! 📖 🧬 THE SCIENTIFIC RATIONALE GDF-15 is an immunosuppressive cytokine implicated in resistance to checkpoint inhibition. Visugromab, a GDF-15-neutralizing antibody, may help restore antitumor immune activity and enhance nivolumab efficacy. 📊 STUDY DESIGN Blinded, exploratory phase II | N=31 Patients with cisplatin-ineligible or cisplatin-refusing MIBC (cT2–T4aN0M0). 🟠 Nivolumab + visugromab 🔵 Nivolumab + placebo 28 patients evaluable for efficacy (15 vs 13). 📊 KEY RESULTS ✅ Pathological complete response (pCR) 33.3% vs 7.7% ✅ Major pathological response (MPR) 60.0% vs 23.1% ✅ Radiographic ORR 60.0% vs 15.4% 📌 Consistent improvements across pathological and radiological endpoints. 🧬 EVENT-FREE SURVIVAL & BLADDER PRESERVATION At a median follow-up of 15.7 months: ✅ No recurrences among the 6 patients achieving pCR (5 vs 1). ✅ Four of five patients with pCR in the combination arm retained their bladder following re-TURBT alone. 📈 Median EFS was not reached in either arm. ⚠️ Follow-up remains limited, and durable EFS or bladder-preservation benefit has not yet been established. 🛡️ SAFETY ✅ No new safety signals. ✅ No treatment-related discontinuations or delays to surgery in the combination arm. 🧬 BIOMARKER INSIGHTS Baseline proliferating CD8+ T-cell infiltration correlated with response to nivolumab + visugromab. A promising biological signal supporting further investigation of GDF-15-mediated immune resistance. ⭐ MY POINT OF VIEW | CLINICAL PEARL What makes GDFATHER-NEO particularly interesting is not simply the improvement in pCR, but the possibility of overcoming an immunosuppressive mechanism limiting PD-1 activity. However, recent perioperative MIBC trials remind us that higher pathological response rates do not automatically translate into better EFS or OS. 💡 Can GDF-15 blockade help identify a biologically selected population for effective, less invasive treatment? That is the question worth pursuing. 📌 For now, this is promising proof-of-concept—not a new standard of care or sufficient evidence to omit cystectomy. Larger prospective trials, validated biomarkers and longer follow-up are essential. 👏 Congratulations to @AndreaNecchi, Chiara Mercinelli, Felix S. Lichtenegger and all co-authors on the Nature Medicine publication! @urologysummit @gbanna74 @ravikanesvaran @Uromigos @LosUromigos @tompowles1 @PGrivasMDPhD @apolo_andrea @sonpavde @drenriquegrande @shilpaonc @MattGalsky @ecancer @UrologyTimes @urotoday @wearemedsir @OpenMedicineHQ #BladderCancer #MIBC #GDF15 #Immunotherapy #GUOncology #PrecisionOncology

🚨⭐🔵 #ESMO26 | Abstract 2215O | PEACE-1 Long-term overall survival with abiraterone acetate plus prednisone in the PEACE-1 phase 3 trial for de novo metastatic castration-sensitive prostate cancer (mCSPC) 🎤 Presented by Prof. Karim Fizazi 🇫🇷 @OncoAlert @myESMO 🔬 7.7 years of follow-up: Does upfront treatment intensification translate into durable survival? PEACE-1 provides a compelling answer! 📊 PHASE III | N=1,173 Randomized 2×2 factorial design evaluating abiraterone + prednisone and/or prostate radiotherapy added to standard of care (ADT ± docetaxel). Median follow-up: 7.7 years. 📈 1️⃣ OVERALL POPULATION ✅ OS HR 0.75 (95% CI 0.65–0.87) ✅ p=0.0001 Median OS: 🔹 With abiraterone: 6.1 years 🔹 Without abiraterone: 4.6 years ➡️ A sustained 25% relative reduction in the hazard of death. 💥 2️⃣ TRIPLET THERAPY | N=710 ADT + docetaxel + abiraterone vs ADT + docetaxel: ✅ Median OS: 6.2 vs 4.4 years ✅ HR 0.68 (95% CI 0.56–0.82) ⭐ 1.8 additional years in median survival! 📊 8-YEAR OVERALL SURVIVAL ✅ Triplet: 40.3% 🔹 Doublet: 27.1% ➡️ Absolute difference: +13.2 percentage points. These are clinically meaningful long-term outcomes, beyond early response rates or surrogate endpoints. 🔬 3️⃣ DOES METASTATIC VOLUME MATTER? 🔵 HIGH-VOLUME DISEASE ✅ Median OS: 4.6 vs 3.5 years ✅ HR approximately 0.68 A clear and durable survival advantage. 🔵 LOW-VOLUME DISEASE 📈 Median OS: 7.8 vs 6.2 years HR 0.74 (95% CI 0.52–1.05) Numerically favorable, although the subgroup CI crossed 1. 📌 No significant interaction by disease volume (p=0.56). ⚠️ This does not establish identical treatment benefit in both subgroups. ⭐ MY POINT OF VIEW | CLINICAL PEARL Long-term follow-up is where a treatment strategy proves its true value. Unlike early response signals, PEACE-1 provides mature evidence that upfront systemic intensification can translate into substantially longer survival. 💡 In appropriately selected patients with de novo mCSPC who are candidates for docetaxel, these findings strongly reinforce the role of upfront triplet therapy. The clinical question is increasingly not simply whether to intensify, but which patients should receive a triplet, how best to integrate local treatment, and how to preserve quality of life. 🎯 Precision matters—but so does acting early when a proven survival advantage is available. 👏 Congratulations to Prof. Karim Fizazi and the entire PEACE-1 team for this important long-term contribution to prostate cancer care! @urologysummit @gbanna74 @ravikanesvaran @Uromigos @LosUromigos @neerajaiims @Silke_Gillessen @EfstathiouEleni @AOmlin @declangmurphy @cdanicas @montypal @DrScottTagawa @ecancer @UrologyTimes @urotoday @wearemedsir @OpenMedicineHQ #ProstateCancer #mCSPC #mHSPC #GUOncology #PEACE1 #TripletTherapy

🚨⭐🟠 #ESMO26 | Day 2 | Abstract 4741RO | NIAGARA Exploratory Analysis of Molecular Subtypes and Association With Treatment Outcomes in Muscle-Invasive Bladder Cancer 🎤 Excellent presentation by @MattGalsky 🇺🇸 @OncoAlert @myESMO 🧬 Does tumor biology influence the benefit of perioperative durvalumab in MIBC? 🔬 STUDY DESIGN Phase III NIAGARA | N=1,063 Perioperative durvalumab + neoadjuvant gemcitabine/cisplatin vs chemotherapy alone, followed by radical cystectomy. Exploratory molecular analysis: ✅ Whole-exome sequencing: n=407 ✅ RNA sequencing: n=402 📊 KEY MOLECULAR FINDINGS 🔹 Broad EFS benefit: Durvalumab-containing treatment favored EFS across multiple mutation-defined subgroups. 🔹 Genomic alterations: Greater apparent benefit was observed in tumors harboring TP53 or FGFR3 mutations, cell-cycle or RTK/RAS/PI3K pathway alterations, and high tumor mutational burden. 🔹 Basal-squamous subtype: Showed one of the strongest exploratory signals of benefit, with increased immune-infiltration signatures. 🔹 Luminal-papillary subtype: The EFS benefit appeared less evident than in other transcriptomic subtypes. ⚠️ These findings are exploratory. No molecular subtype has been prospectively validated to predict differential benefit from perioperative durvalumab. ⭐ MY POINT OF VIEW | CLINICAL PEARL Molecular heterogeneity may influence the magnitude of benefit, but it should not yet determine who receives potentially curative perioperative immunotherapy. 🧬 The real opportunity is moving from molecular classification toward clinically validated predictive biomarkers. 💡 The future is not simply knowing the tumor subtype—it is knowing how to act on it without compromising cure. Congratulations to @MattGalsky and the NIAGARA investigators for this insightful translational analysis! @urologysummit @gbanna74 @ravikanesvaran @Uromigos @LosUromigos @tompowles1 @PGrivasMDPhD @apolo_andrea @AndreaNecchi @sonpavde @drenriquegrande @montypal @ecancer @UrologyTimes @urotoday @wearemedsir @OpenMedicineHQ #BladderCancer #MIBC #GUOncology #PrecisionOncology #Biomarkers

🚨⭐🟠 #ESMO26 | Day 2 | Abstract 4740RO | EV-103 / KEYNOTE-869 Long-Term Follow-up of Enfortumab Vedotin ± Pembrolizumab in Cisplatin-Ineligible Advanced or Metastatic Urothelial Cancer 🎤 Excellent presentation by @Maroto5Pablo 🇪🇸 @OncoAlert @myESMO 🔬 How durable is the benefit of first-line EV + pembrolizumab? Updated phase Ib/II EV-103 findings provide valuable long-term evidence in #UrothelialCancer. 📊 STUDY DESIGN • EV + pembrolizumab: n=121 (pooled DE/A/K cohorts) • EV monotherapy: n=73 (cohort K) • Cisplatin-ineligible, previously untreated la/mUC Median survival follow-up: 🔹 EV + pembro: 64.2 months 🔹 EV alone: 58.6 months 📈 KEY EFFICACY RESULTS | EV + PEMBROLIZUMAB ✅ Median duration of response: 29.6 months (95% CI 10.3–71.9) ✅ Median PFS: 10.4 months (95% CI 8.3–20.9) ✅ Median OS: 27.7 months (95% CI 20.9–39.6) ⭐ 5-YEAR SURVIVAL • Estimated OS: 33.0% • Estimated PFS: 24.3% At 7 years, estimated OS remained 28.2%. 📌 Sustained responses and long-term survival in a historically difficult-to-treat population. ⚠️ SAFETY & TOLERABILITY Grade ≥3 treatment-related AEs: • EV + pembro: 64.5% • EV alone: 47.9% No new safety signals were identified. However, peripheral neuropathy remains an important consideration, particularly with prolonged survivorship. ⚠️ No formal statistical comparisons between cohort K treatment arms were planned. These results should not be interpreted as a randomized demonstration of superiority. ⭐ MY POINT OF VIEW | CLINICAL PEARL Durability is what transforms an impressive initial response into meaningful long-term clinical benefit. EV-103 provides important mature follow-up supporting the sustained activity of EV + pembrolizumab, while EV-302 provides the randomized evidence underpinning its first-line standard-of-care role. 💡 As more patients achieve prolonged survival, managing cumulative toxicity becomes just as important as achieving tumor response. The next challenge is optimizing treatment duration, toxicity management and sequencing while preserving long-term benefit and quality of life. 👏 Congratulations to @Maroto5Pablo and all EV-103 investigators! @urologysummit @gbanna74 @ravikanesvaran @Uromigos @LosUromigos @tompowles1 @PGrivasMDPhD @apolo_andrea @AndreaNecchi @sonpavde @drenriquegrande @montypal @ecancer @UrologyTimes @urotoday @wearemedsir @OpenMedicineHQ #BladderCancer #GUOncology #ADC #EV103 #Immunotherapy

🚨⭐🔵 #ESMO26 | Abstract 2045O | STAMPEDE / Decipher Transcriptome Classifier Risk Stratification and Intensification With Androgen Receptor Pathway Inhibitors for Clinically Very High-Risk Prostate Cancer 🎤 Excellent presentation by Dr. Sarah Howlett 🇬🇧 @OncoAlert @myESMO 🧬 Can Decipher help identify who truly benefits from abiraterone intensification in high-risk M0 prostate cancer? An important step toward biologically guided treatment decisions! 📊 STUDY DESIGN Retrospective biomarker analysis of the randomized phase III STAMPEDE trial. 👥 N=401 patients: 🔹 ADT alone: n=208 🔹 ADT + abiraterone/prednisolone: n=193 Complemented by a large real-world genomic dataset. 🔬 KEY RESULTS 🧬 1️⃣ DECIPHER IS PROGNOSTIC Higher Decipher scores were associated with increased risk of distant metastasis and worse overall survival. In the STAMPEDE ADT-alone arm, each 0.1-point increase in Decipher score was associated with: 📈 Distant metastasis: aHR 1.44 (95% CI 1.19–1.76). 🎯 2️⃣ DECIPHER MAY PREDICT ABIRATERONE BENEFIT A significant treatment-by-biomarker interaction was observed for distant metastasis: ✅ Interaction p=0.03 📊 Absolute reduction in distant metastasis at 5 years: 🔹 Lower Decipher (<0.60): 2 percentage points ✅ High Decipher (0.60–0.85): 12 percentage points ✅ Very high Decipher (>0.85): 8 percentage points 📌 Patients with higher genomic risk appeared to derive greater absolute benefit from treatment intensification. 🔬 A particularly relevant predictive signal was observed in node-negative patients. ⚠️ No statistically significant treatment-by-Decipher interaction was established for OS. ⭐ MY POINT OF VIEW | CLINICAL PEARL Clinical high-risk disease is not necessarily biologically homogeneous. The key innovation is moving beyond Decipher as a prognostic classifier toward its potential use as a predictive biomarker for treatment intensification. 💡 The future is not simply identifying who is at greater risk, but identifying who gains the greatest absolute benefit from additional treatment. However, these retrospective findings do not yet justify withholding abiraterone solely because of a low Decipher score. 🎯 Precision intensification—and eventually evidence-based de-escalation—will require prospective validation. Congratulations to Sarah Howlett and the STAMPEDE investigators! 👏⭐ @urologysummit @gbanna74 @ravikanesvaran @Uromigos @LosUromigos @neerajaiims @Silke_Gillessen @EfstathiouEleni @AOmlin @declangmurphy @cdanicas @montypal @DrScottTagawa @ecancer @UrologyTimes @urotoday @wearemedsir @OpenMedicineHQ #ProstateCancer #STAMPEDE #Decipher #PrecisionOncology #GUOncology

🚨⭐🔵 #ESMO26 | Emerging Immune-Based Therapies in Prostate Cancer From Molecular Selection to Next-Generation Immunotherapy in mCRPC 🎤 Presented by Niven Mehra 🇳🇱 @OncoAlert 🔬 Is prostate cancer really an immunologically cold tumor—or have we simply not identified the right patients and therapeutic platforms? An outstanding overview of the evolving immunotherapy landscape in #ProstateCancer. 🧬 1️⃣ CHECKPOINT INHIBITION: BIOMARKERS MATTER dMMR/MSI-H (~3% of patients) remains the best-established subgroup for immune checkpoint inhibition in mCRPC. 📊 International multicenter real-world cohort (n=93): ✅ ORR: 46% ✅ PSA50 response: 60% ✅ Median PFS: 7.7 months ✅ Median OS: 27 months ✅ 3-year PFS: 26% 🔬 INSPIRE: nivolumab + ipilimumab In the dMMR subgroup: ✅ ORR: 75% ✅ PSA50: 86% ✅ Median PFS: 32.7 months ⚠️ Grade ≥3 treatment-related AEs occurred in 48% of the overall INSPIRE population. 📌 CDK12 and BRCA2 alterations alone are not sufficiently validated predictive biomarkers for checkpoint inhibition. TMB-high/MSS disease remains a more uncertain subgroup. 🎯 Clinical implication: Test for dMMR/MSI-H. Missing this biomarker can mean missing a meaningful therapeutic opportunity. 💥 2️⃣ T-CELL ENGAGERS: A NEW FRONTIER Among emerging immune strategies, T-cell engagers are one of the most clinically advanced approaches. 🔹 Xaluritamig (STEAP1 × CD3) Demonstrates early antitumor activity in mCRPC, with cytokine release syndrome remaining a major consideration. 🔹 Pasritamig (KLK2 × CD3) Phase I | N=174 ✅ PSA50: 42.4% at the recommended phase II dose (n=33) ✅ Median rPFS: 7.85 months in that cohort ✅ CRS: 8.9%, all grade 1, in the RP2D safety population 🔹 Conditionally activated PSMA engagers JANX007 and VIR-5500 illustrate how tumor-selective activation and masking technologies may improve the therapeutic window. 🔬 The challenge is no longer simply engaging T cells, but achieving sustained activity while limiting cytokine release, immunogenicity and on-target/off-tumor toxicity. 🧪 3️⃣ CAR-T THERAPY: PROOF OF CONCEPT Early phase I programs targeting PSCA, PSMA and other prostate-associated antigens demonstrate feasibility. However, important challenges remain: • T-cell persistence • Antigen heterogeneity • Immunosuppressive tumor microenvironment • On-target/off-tumor toxicity • Manufacturing complexity 📌 Promising biology, but not yet an established treatment in prostate cancer. 💉 4️⃣ PERSONALIZED VACCINES & IN-SITU IMMUNOTHERAPY Personalized neoantigen vaccines aim to generate immune responses against patient-specific tumor mutations. Manufacturing time, low neoantigen burden and limited immunogenicity remain important barriers. 🔬 SYNC-T SV-102: intratumoral immunotherapy Early phase I results (n=15): ✅ ORR: 87% ✅ Complete responses: 53% ⚠️ Highly encouraging, but preliminary findings from a very small, selected cohort requiring independent validation. 🦠 5️⃣ ONCOLYTIC VIROTHERAPY CAN-2409 + radiotherapy represents an important randomized phase III development in localized prostate cancer. 📊 N=745 ✅ Disease-free survival HR 0.70 ✅ 95% CI 0.52–0.94 ✅ p=0.016 An important proof of concept for immune-based therapeutic strategies, although these findings concern localized disease rather than mCRPC. 🧬 6️⃣ PATIENT SELECTION WILL BE EVERYTHING Future immune strategies may require different selection criteria: 🔹 dMMR/MSI-H → checkpoint inhibitors 🔹 Antigen expression (STEAP1, KLK2, PSMA) → T-cell engagers 🔹 Low disease burden and favorable immune contexture → possible opportunities for vaccines and in-situ immunotherapy Emerging biomarkers include genomic and transcriptomic profiles, antigen heterogeneity, ctDNA tumor fraction and PSMA-PET tumor volume. ⭐ MY POINT OF VIEW | CLINICAL PEARL Prostate cancer is not uniformly resistant to immunotherapy. Our challenge is identifying which immune strategy fits each biological context. Three important lessons: ✅ Molecular testing must be integrated into routine metastatic prostate cancer care. ✅ T-cell engagers may expand immunotherapy beyond the small dMMR/MSI-H population. ✅ CAR-T cells, vaccines and oncolytic approaches are exciting, but clinical adoption must follow robust evidence of meaningful patient benefit. 💡 The next breakthrough in prostate cancer immunotherapy may come not from activating the immune system more aggressively, but from activating it more precisely. From biomarker selection to engineered immune recognition: precision immunotherapy is beginning to reshape the field. @urologysummit @gbanna74 @ravikanesvaran @Uromigos @LosUromigos @neerajaiims @Silke_Gillessen @declangmurphy @EfstathiouEleni @AOmlin @scserendipity1 @cdanicas @montypal @DrJaVallejo @salvolarosa @ecancer @UrologyTimes @urotoday @wearemedsir @OpenMedicineHQ #ProstateCancer #mCRPC #GUOncology #Immunotherapy #PrecisionOncology #TCellEngagers

🚨⭐🔵 #ESMO26 | Optimising Radioligand Therapy in Advanced Prostate Cancer 🎤 Presented by @AzadOncology 🇦🇺 @OncoAlert 🔬 Beyond ¹⁷⁷Lu-PSMA: combinations, alpha emitters and the emerging promise of Auger electrons. An excellent overview of how radioligand therapy (RLT) is evolving in #mCRPC. 📊 1️⃣ EVOLUTION: RADIOLIGANDS + DUAL IMMUNOTHERAPY Phase II EVOLUTION (ANZUP2001): ¹⁷⁷Lu-PSMA-617 + nivolumab/ipilimumab vs ¹⁷⁷Lu-PSMA-617 alone. ✅ PSA-PFS at 12 months: 33% vs 17% ✅ rPFS at 12 months: 47% vs 23% 📈 Median rPFS: 12.0 vs 8.5 months ⚠️ However: • Grade 3–4 AEs: 75% vs 29% • Treatment-related myocarditis: 7% in the combination arm • Trial recruitment stopped early. ⭐ An important reminder: biological synergy must translate into meaningful benefit without unacceptable toxicity. 💊 2️⃣ Lu-PSMA COMBINATIONS: ENCOURAGING SIGNALS 📊 PSA50 | Median rPFS | Median OS 🔹 VISION (¹⁷⁷Lu-PSMA-617 + protocol-permitted standard care): 46% | 8.7 mo | 15.3 mo 🔹 PRINCE (+ pembrolizumab, n=37): 76% | 11.2 mo | 20.8 mo 🔹 LuPARP (+ olaparib, n=29): 69% | 12.8 mo | 33.5 mo 🔹 AlphaBet (+ radium-223, n=33): 55% | 10.0 mo | 13.5 mo 🔹 LuCAB (+ cabazitaxel, n=26): 73% | 10.9 mo | 16.5 mo ⚠️ These are cross-trial descriptive comparisons, not evidence that any combination is superior to VISION. Patient selection, prior therapies and trial designs differ. ☢️ 3️⃣ ALPHA EMITTERS: A NEW LEVEL OF PRECISION Unlike beta particles, alpha particles have shorter tissue penetration and high linear energy transfer, potentially improving tumor-cell killing. 🔬 PAnTHa: ²²⁵Ac-PSMA-Trillium Phase I dose escalation | N=50 ✅ PSA50: 58% overall ✅ PSA50: 83% at 125 kBq/kg ✅ PSA90: 58% at the expansion dose ✅ ORR: 46% ✅ Disease control: 83% ⚠️ Xerostomia: 76% ⚠️ Grade ≥3 treatment-emergent AEs: 38% ✅ No dose-limiting toxicities observed. These preliminary results support further investigation, not routine clinical adoption. ⚛️ 4️⃣ AUGER ELECTRONS: TARGETING MICROSCOPIC DISEASE An exciting emerging concept. Auger electrons deposit energy over extremely short distances, potentially targeting microscopic tumor deposits and individual cells. 🔬 Terbium-161 (¹⁶¹Tb) emits beta particles and Auger/conversion electrons. Could this improve radioligand effectiveness against micrometastatic disease? The biological rationale is compelling, but clinical benefit remains to be demonstrated. ⭐ MY POINT OF VIEW | CLINICAL PEARL The future of radioligand therapy will not be defined by the strongest radiation emitter, but by the right radiation strategy for the right patient. Three essential questions remain: 🔹 Which combinations truly improve survival? 🔹 Can we intensify antitumor activity without unacceptable toxicity? 🔹 How should PSMA expression, tumor heterogeneity and disease burden guide isotope selection? 💡 Precision radioligand therapy means more than targeting PSMA: it means optimizing the payload, the partner, the timing and the patient. From beta to alpha and Auger emitters, we are entering an exciting new era in #ProstateCancer. @urologysummit @gbanna74 @ravikanesvaran @Uromigos @LosUromigos @neerajaiims @Silke_Gillessen @EfstathiouEleni @AOmlin @declangmurphy @montypal @DrScottTagawa @ChrisSweens1 @brian_rini @ecancer @UrologyTimes @urotoday @wearemedsir @OpenMedicineHQ #GUOncology #mCRPC #PSMA #RadioligandTherapy #NuclearMedicine #PrecisionOncology

🚨⭐🔵 #ESMO26 | New Targets in Prostate Cancer: ADCs & Emerging Biologies 🎤 Presented by Ana Aparicio 🇺🇸 | MD Anderson Cancer Center @OncoAlert 🔬 ADCs in mCRPC: Is choosing the right target enough, or does the construct matter just as much? A fascinating overview of the next generation of antibody-drug conjugates in #ProstateCancer. 🧬 1️⃣ WHAT DETERMINES ADC ACTIVITY? ADC efficacy depends on much more than antigen expression: 🔹 Target density and inter/intratumoral heterogeneity 🔹 Antigen shedding and internalization 🔹 Intracellular trafficking 🔹 Antibody, linker, payload and drug-to-antibody ratio (DAR) 🔹 Bystander effect 🔹 Tumor microenvironment and resistance mechanisms 📌 Target expression is dynamic—not a fixed biological property. 🎯 2️⃣ PHASE III: B7-H3 ADCs MOVE FORWARD Two major randomized trials are evaluating B7-H3-directed ADCs against docetaxel in mCRPC: ✅ IDeate-Prostate01 NCT06925737 | N=1,440 • Ifinatamab deruxtecan (I-DXd) • B7-H3-directed ADC • Topoisomerase I inhibitor payload • DAR 4 ✅ BNT324-03 NCT07365995 | N=736 • BNT324 (DB-1311) • B7-H3-directed ADC • Topoisomerase I inhibitor payload • DAR 6 🔬 These studies will help determine whether ADCs can improve outcomes over taxane chemotherapy. 💥 3️⃣ ABBV-969: A BISPECIFIC ADC TARGETING PSMA + STEAP1 A particularly innovative approach designed to address heterogeneous target expression. Phase I | N=49 heavily pretreated patients with mCRPC. 📊 At doses ≥3 mg/kg: ✅ Confirmed PSA50 response: 67% ✅ Confirmed PSA90 response: 28% ✅ Confirmed ORR: 45% among 29 RECIST-evaluable patients ⚠️ Grade ≥3 treatment-emergent AEs: 63%, predominantly anemia. 📌 Encouraging antitumor activity, including in patients previously treated with taxanes and radioligand therapy, but still early-phase evidence. 🧬 4️⃣ EMERGING TARGETS: STEAP2 & CD46 🔹 STEAP2: Potentially favorable and relatively homogeneous expression across prostate cancer progression. 🔹 CD46: Broadly expressed membrane protein with internalization properties that may be exploited therapeutically. Both represent interesting opportunities for ADC development, although expression and biological rationale alone cannot establish clinical efficacy. 🔬 CONCLUSION The ADC landscape in prostate cancer is expanding beyond single-target approaches. Bispecific constructs, novel payloads and strategies addressing tumor heterogeneity may help overcome resistance. ⭐ MY POINT OF VIEW | CLINICAL PEARL The future of ADC therapy in prostate cancer will not be determined by identifying the most highly expressed antigen alone. What matters is the interaction between: 🎯 The right target 🧬 The right construct 💊 The right payload 👤 The right patient 💡 A highly expressed target does not guarantee an effective ADC—and heterogeneous expression does not necessarily preclude response. The challenge is to translate molecular targeting into durable survival benefit with an acceptable therapeutic index. 📌 For now, these agents remain investigational. Randomized efficacy, safety and biomarker data will determine their place in clinical practice. @urologysummit @gbanna74 @ravikanesvaran @Uromigos @LosUromigos @neerajaiims @Silke_Gillessen @EfstathiouEleni @AOmlin @declangmurphy @DrJaVallejo @cdanicas @montypal @apolo_andrea @ecancer @UrologyTimes @urotoday @wearemedsir @OpenMedicineHQ #ProstateCancer #mCRPC #ADC #PrecisionOncology #GUOncology

🚨⭐🔵 #ESMO26 Novel AR targeted therapies in mCRPC 🎤 Presented by Alice Bernard-Tessier @OncoAlert 🔬 Androgen receptor (AR) remains a central therapeutic target in mCRPC—but the field is clearly evolving beyond conventional ARPIs. 📌 KEY CONCEPTS 🧬 1. AR alterations are common AR alterations are enriched in mCRPC and may be found in up to 80% of patients, including: • AR amplification • AR mutations • AR splice variants • AR rearrangements These alterations are associated with worse prognosis, although their role as fully validated predictive biomarkers of ARPI resistance remains incomplete. 💊 2. The next generation of AR targeting is expanding The session reviewed several new strategies beyond standard AR pathway inhibition: • Next-generation AR inhibitors • AR degraders • CYP11A1 inhibition • RIPTACs, a novel concept exploiting AR presence, rather than classic AR dependence 🧪 3. AR degraders are gaining momentum Emerging compounds and trials suggest that AR degradation may overcome resistance mechanisms not fully addressed by current ARPIs. Examples discussed included: • Luxdegalutamide • BMS-986460 • Other AR degraders in clinical development 🧬 4. Genotype may increasingly guide drug choice A major practical message from this talk: “Genotype picks the drug.” Different novel strategies may be better suited for different AR alterations: • AR degraders and CYP11A1 inhibition may be particularly relevant when tumors harbor AR alterations • AR activating mutations may identify biologically distinct therapeutic vulnerabilities 💥 5. RIPTACs may shift the paradigm The RIPTAC concept is especially interesting because it moves the field: ➡️ from AR dependence to AR presence This could potentially expand AR-directed therapy even in tumors where canonical AR addiction is less clear. Early phase 1 data with JNJ-6143 showed PSA responses across doses and across heterogeneous molecular backgrounds. 📌 TAKE-HOME MESSAGES 1️⃣ AR is still the target. 2️⃣ AR alterations are frequent and drive resistance to ARPIs. 3️⃣ Genotype may increasingly determine therapeutic selection. 4️⃣ RIPTACs introduce a potentially new framework for AR-directed therapy. ⭐ MY POINT OF VIEW | CLINICAL PEARL This talk reinforces that mCRPC is entering a more biologically segmented era. The future is not simply “more AR blockade,” but smarter AR targeting, choosing the right mechanism for the right resistance biology. 💡 The real shift is from one-size-fits-all AR inhibition to precision AR-directed therapy. For daily practice, this means molecular characterization will become progressively more relevant—not only for prognosis, but for selecting the next therapeutic strategy after ARPI resistance emerges. @urologysummit @gbanna74 @ravikanesvaran @Uromigos @LosUromigos @nataliagandur @brian_rini @tompowles1 @montypal @declangmurphy @salvolarosa @RenuEapen @seanmcbride @DrJaVallejo @Silke_Gillessen @crisbergerot @DrDanielHeng @apolo_andrea @DrChoueiri @PGrivasMDPhD @TiansterZhang @HHammersMD @neerajaiims @amerseburger @sonpavde @drenriquegrande @scserendipity1 @EfstathiouEleni @BraunMDPhD @cdanicas @AOmlin @ecancer @UrologyTimes @urotoday @wearemedsir @OpenMedicineHQ @gu_onc #ProstateCancer #mCRPC #GUOncology #AR #PrecisionOncology #ESMO

🚨⭐🔵 #ESMO26 | Emerging immune-based therapies in mCRPC 🎤 Presented by Niven Mehra @OncoAlert 🔬 Immunotherapy in prostate cancer is finally becoming more nuanced: checkpoint blockade works in selected biologic subsets, while T-cell engagers are opening a new therapeutic frontier. 📌 KEY MESSAGES 🧬 1. Checkpoint inhibition has clear activity in dMMR / MSI-H mCRPC International real-world data presented for dMMR/MSI-H mCRPC showed: ✅ ORR: 46% ✅ PSA50 response: 60% ✅ Median PFS: 7.7 months ✅ Median OS: 27 months This is a critical reminder that prostate cancer is not uniformly immunologically “cold”—selected molecular subgroups can derive meaningful and durable benefit from anti–PD-(L)1 therapy. 📌 In contrast, the role of immunotherapy in TMB-high but microsatellite-stable mCRPC remains much less clear. 🧪 2. Beyond checkpoint blockade, four immune strategies are emerging The talk reviewed a broader immunotherapy landscape in prostate cancer: • T-cell engagers • In-situ vaccines • Oncolytic viruses • CAR-T cells Among these, CD3 T-cell engagers appear particularly advanced and clinically relevant. 🎯 3. T-cell engagers are showing encouraging early activity Two key examples were highlighted: Xaluritamig (STEAP1 × CD3) • Novel bispecific T-cell engager targeting STEAP1 • Early data support proof of concept • CRS occurred in 72%, but grade ≥3 CRS in only 2%, mostly confined to cycle 1 with step-up dosing Pasritamig (KLK2 × CD3) • First-in-class KLK2-directed engager • 174 patients treated • PSA50 at RP2D: 42.4% • KLK2 may provide a more prostate-restricted target and potentially widen the therapeutic window ⚙️ 4. Next-generation engager design aims to improve tolerability A key challenge for T-cell engagers remains cytokine release and off-tumor toxicity. Strategies under development include: • Masking / conditional activation • Costimulation (signal 2) • Alternative effectors These innovations may help preserve efficacy while improving safety and outpatient feasibility. ⭐ MY POINT OF VIEW | CLINICAL PEARL This talk highlights a very important shift: Immunotherapy in prostate cancer is no longer a yes-or-no question. It is becoming a biomarker- and platform-specific question. Checkpoint inhibitors are clearly relevant in dMMR/MSI-H disease, while T-cell engagers may expand immune-based treatment well beyond this small subset. 💡 The future of immune therapy in mCRPC will likely depend on matching the right immune strategy to the right tumor biology—and on engineering therapies that are not only active, but deliverable in practice. For now: ✅ Test for dMMR/MSI-H ✅ Watch the evolution of T-cell engagers ✅ Expect immune therapy in prostate cancer to become increasingly selective, modular and precision-driven @urologysummit @gbanna74 @ravikanesvaran @Uromigos @LosUromigos @nataliagandur @brian_rini @tompowles1 @montypal @declangmurphy @salvolarosa @RenuEapen @seanmcbride @DrJaVallejo @Silke_Gillessen @crisbergerot @DrDanielHeng @apolo_andrea @DrChoueiri @PGrivasMDPhD @TiansterZhang @HHammersMD @neerajaiims @amerseburger @sonpavde @drenriquegrande @scserendipity1 @EfstathiouEleni @BraunMDPhD @cdanicas @AOmlin @ecancer @UrologyTimes @urotoday @wearemedsir @OpenMedicineHQ @gu_onc #ProstateCancer #mCRPC #Immunotherapy #TCellEngagers #PrecisionOncology #GUOncology

🚨⭐🟠 #ESMO26 | Abstract 4733O | KEYNOTE-905 / EV-303 Perioperative Pembrolizumab or Enfortumab Vedotin + Pembrolizumab in Cisplatin-Ineligible Muscle-Invasive Bladder Cancer: Ad Hoc Analysis 🎤 Presented by Anders Ullén 🇸🇪 @OncoAlert 🔬 What is the contribution of each agent to the benefit of perioperative EV + pembrolizumab? 📊 STUDY DESIGN Exploratory 3-arm analysis | N=255 Patients with #MIBC ineligible for or declining cisplatin, concurrently randomized to: 🟢 EV + pembrolizumab (n=85) 🔵 Pembrolizumab alone (n=83) 🔴 Radical cystectomy + PLND alone (n=87) 📊 KEY RESULTS ✅ OVERALL SURVIVAL 🔹 EV + pembro vs control: HR 0.48 (95% CI 0.29–0.80) 🔹 Pembro vs control: HR 0.76 (95% CI 0.48–1.20) 📈 Median OS: • EV + pembro: NR • Pembro: 51.0 months • Control: 41.7 months ✅ PATHOLOGICAL COMPLETE RESPONSE 🟢 EV + pembro: 58.8% 🔵 Pembro: 25.3% 🔴 Control: 10.3% Absolute differences vs control: • EV + pembro: +48.6 percentage points • Pembro: +15.7 percentage points 📌 EFS and OS favored perioperative EV + pembro versus surgery alone, while pembrolizumab monotherapy showed numerically favorable outcomes. ⚠️ SAFETY Grade ≥3 AEs: • Neoadjuvant: 44.0% vs 20.7% (EV + pembro vs pembro) • Adjuvant: 60.0% vs 44.9% 🔬 INTERPRETATION The efficacy pattern supports a potential contribution of both EV and pembrolizumab. However, this was an ad hoc exploratory analysis, and comparisons should not be interpreted as confirmatory evidence of the independent contribution of each drug. ⭐ MY POINT OF VIEW | CLINICAL PEARL The question is evolving from whether perioperative EV + pembrolizumab works to understanding why the combination works—and which patients truly need both agents. The striking pCR difference and favorable OS signal reinforce the biological rationale for combining an ADC with immune checkpoint inhibition. 💡 But treatment intensification must always be balanced against toxicity, patient fitness and long-term benefit. 📌 EV + pembrolizumab is an established perioperative option for cisplatin-ineligible MIBC based on the parent KEYNOTE-905 trial. These exploratory findings add insight rather than establish a new treatment indication. 🌍 GU Oncology Community @gbanna74 @ravikanesvaran @urologysummit @tompowles1 @brian_rini @montypal @crisbergerot @DrDanielHeng @apolo_andrea @DrChoueiri @PGrivasMDPhD @TiansterZhang @HHammersMD @neerajaiims @amerseburger @sonpavde @drenriquegrande @scserendipity1 @Silke_Gillessen @EfstathiouEleni @BraunMDPhD @cdanicas @AOmlin @declangmurphy @salvolarosa @RenuEapen @seanmcbride @DrJaVallejo @ecancer @UrologyTimes @urotoday @wearemedsir @OpenMedicineHQ @UCSFCancer #BladderCancer #MIBC #GUOncology #ADC #ClinicalTrials

🚨⭐🟠 #ESMO26 | Abstract 4734O | KEYNOTE-B15 / EV-304 ctDNA Analysis of the Phase III KEYNOTE-B15 Trial: Neoadjuvant and Adjuvant Enfortumab Vedotin + Pembrolizumab in Cisplatin-Eligible Muscle-Invasive Bladder Cancer 🎤 Presented by Jonathan Chatzkel 🇺🇸 | Moffitt Cancer Center @OncoAlert @urologysummit 🧬 Can molecular response help redefine perioperative treatment in MIBC? 🔬 STUDY DESIGN Phase III KEYNOTE-B15/EV-304 | N=808 🟢 Perioperative EV + pembrolizumab (n=405) 🔴 Neoadjuvant gemcitabine/cisplatin followed by observation (n=403) All patients underwent planned radical cystectomy + PLND. Exploratory ctDNA analysis using the tumor-informed Signatera assay at baseline, presurgery, postsurgery and during adjuvant treatment. 📊 KEY RESULTS 🧬 1️⃣ Baseline ctDNA: a powerful prognostic marker ctDNA positivity was associated with worse EFS. EV + pembrolizumab vs chemotherapy: ✅ Baseline ctDNA-positive: HR 0.54 (95% CI 0.37–0.80) ✅ Baseline ctDNA-negative: HR 0.68 (95% CI 0.37–1.26) 📌 EFS estimates favored EV + pembrolizumab in both subgroups, although the CI crossed 1 in ctDNA-negative patients. 🧬 2️⃣ ctDNA CLEARANCE BEFORE SURGERY ✅ EV + pembrolizumab: 82.1% 🔴 Gemcitabine/cisplatin: 66.7% 📈 Absolute difference: +15.4 percentage points. Molecular clearance was associated with more favorable EFS and pathological response. 🔬 3️⃣ pCR BY PRESURGICAL ctDNA STATUS Among patients who were ctDNA-negative before surgery: ✅ EV + pembrolizumab: 72.4% 🔴 Gemcitabine/cisplatin: 43.7% Among those remaining ctDNA-positive: • EV + pembrolizumab: 3.7% • Chemotherapy: 2.2% 📌 Persistent ctDNA positivity identified patients with a very low probability of pCR. 🧬 4️⃣ POSTSURGICAL ctDNA AND EFS EV + pembrolizumab vs chemotherapy: ✅ ctDNA-negative: HR 0.48 (95% CI 0.29–0.81) 🔹 ctDNA-positive: HR 0.63 (95% CI 0.30–1.35) Postoperative ctDNA positivity was associated with particularly poor EFS. ⚠️ Interpretation requires caution: the postsurgical ctDNA-positive subgroup was small, and sample availability decreased over time. 🔬 CONCLUSIONS ✅ ctDNA positivity identifies patients with poorer prognosis. ✅ ctDNA clearance was higher with EV + pembrolizumab than with cisplatin-based chemotherapy. ✅ Molecular clearance correlated with improved pathological response and EFS. ✅ EFS estimates favored EV + pembrolizumab across ctDNA-defined groups. ⭐ MY POINT OF VIEW | CLINICAL PEARL We are moving beyond pathological response toward molecular assessment of treatment effectiveness. 🧬 ctDNA could become an essential tool for perioperative risk stratification in MIBC. But an important distinction remains: Prognostic ≠ Predictive. These findings do not yet establish ctDNA as a biomarker for selecting EV + pembrolizumab, omitting cystectomy or safely de-escalating adjuvant therapy. 💡 The next breakthrough may not be another treatment combination, but learning how to personalize treatment intensity according to molecular response. 📌 Prospective ctDNA-guided trials will be essential to translate molecular clearance into clinical decisions. 🌍⭐ GU ONCOLOGY COMMUNITY @brian_rini @tompowles1 @declangmurphy @KidneyCancer @salvolarosa @RenuEapen @seanmcbride @DrJaVallejo @crisbergerot @DrDanielHeng @apolo_andrea @DrChoueiri @PGrivasMDPhD @TiansterZhang @HHammersMD @neerajaiims @amerseburger @sonpavde @drenriquegrande @scserendipity1 @Silke_Gillessen @EfstathiouEleni @BraunMDPhD @cdanicas @AOmlin @montypal @gbanna74 @ravikanesvaran @Uromigos @gu_onc @ecancer @UrologyTimes @urotoday @wearemedsir @OpenMedicineHQ @UCSFCancer #BladderCancer #MIBC #ctDNA #GUOncology #PrecisionOncology #OncoAlertAF