🚨⭐🔵 #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