Neoadjuvant Lutetium-PSMA-617 Radioligand Therapy for High-Risk Localized Prostate Cancer: Rationale, Early Clinical Evidence, and Future Directions.

Men with high-risk localized prostate cancer (PCa) often have poor long-term outcomes, underscoring the need for improved neoadjuvant strategies beyond the current standard of care. Radioligand therapy with Lutetium-PSMA-617 (Lu-PSMA-617) has emerged as a promising method to eliminate occult micrometastases while enhancing immune-mediated clearance of the primary tumor. Initial trials have affirmed the treatment's feasibility and safety; however, they have consistently reported a lack of pathological complete response. This absence of profound initial tumor reduction necessitates further therapeutic advancements. The underlying rationale for future strategies is clear, as Lu-PSMA-617 promotes immunogenic cell death, potentially sensitizing immunologically "cold" tumors to checkpoint inhibitors. However, caution is warranted. The synergy observed between these therapies in advanced, metastatic castration-resistant PCa stems from a different biological context, and similar outcomes cannot be presumed in treatment-naïve, localized disease without rigorous validation. Continued progress hinges on developing improved metrics for success and patient selection. Simple prostate-specific antigen reductions have demonstrated minimal correlation with significant pathological outcomes in this setting, underscoring the critical need for validated surrogate endpoints and predictive biomarkers. Ultimately, large-scale randomized trials are essential to determine whether this investigational approach impacts key clinical outcomes-namely, metastasis-free and overall survival. While the strategy is theoretically sound, its capacity to enhance cure rates for high-risk localized PCa remains unverified.