🚨⭐🔵 #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

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#ProstateCancer #mCRPC #Immunotherapy #TCellEngagers #PrecisionOncology #GUOncology