Neoadjuvant 177Lutetium-PSMA-617 Radioligand Therapy: A New Frontier in the Management of High-Risk Localized Prostate Cancer

Men with high-risk localized prostate cancer (PCa) often experience unfavorable long-term outcomes, highlighting the need for improved neoadjuvant strategies beyond the current standard of care. Radioligand therapy with 177Lutetium-PSMA-617 (177Lu-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, yet they consistently report a lack of pathologic complete responses. This absence of profound initial tumor reduction necessitates further therapeutic advancements. The underlying rationale for future strategies is clear, as 177Lu-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 arises from a distinctly different biological context, and similar outcomes cannot be assumed in treatment-naïve, localized disease without dedicated validation. Continued progress hinges on developing improved metrics for success and patient selection. Simple PSA reductions have shown minimal correlation with significant pathologic 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 an unverified proposition.