# Neoadjuvant 177Lutetium-PSMA-617 Radioligand Therapy for High-Risk Localized Prostate Cancer: Rationale, Early Clinical Evidence, and Future Directions

## TL;DR

Neoadjuvant 177Lu-PSMA-617 radioligand therapy shows promise for high-risk prostate cancer by targeting tumors and micrometastases, but more research is needed to confirm its effectiveness.

## Contribution

This paper explores the potential of 177Lu-PSMA-617 as a neoadjuvant therapy and outlines future directions to improve cure rates in high-risk localized prostate cancer.

## Key findings

- Early trials show 177Lu-PSMA-617 is safe and can reduce prostate-specific antigen levels.
- A single treatment cycle rarely leads to complete tumor response, prompting research into multi-cycle regimens and combinations with other therapies.
- The therapy may sensitize tumors to checkpoint inhibitors by inducing immunogenic cell death.

## Abstract

High-risk localized prostate cancer (PCa) often behaves more like an early systemic disease than a confined lesion, frequently rendering local therapy alone insufficient. Neoadjuvant 177Lutetium-PSMA-617 radioligand therapy (RLT) offers a theranostic approach to target both the primary tumor and occult micrometastases before surgery. Early trials, including the LuTectomy study, demonstrate that the therapy is safe and can induce significant prostate-specific antigen declines and partial histologic responses; however, a single cycle rarely achieves a complete pathological response. Ongoing studies are now testing multi-cycle regimens and combinations with checkpoint blockade or androgen deprivation therapy to boost pathological complete response rates. Key hurdles include optimizing patient selection, defining surrogate endpoints such as metastasis-free survival, and balancing cost, logistics, and long-term safety—especially if potent alpha-emitters enter the clinic. However, if these challenges are met, neoadjuvant RLT could meaningfully improve cure rates for the most aggressive forms of localized PCa.

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 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; 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 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 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.