Neoadjuvant Therapies for Prostate Cancer–Current Paradigms and Future Directions

High-risk and locally advanced prostate cancer represents 20-25% of new diagnoses of prostate cancer and is associated with high rates of recurrence, morbidity, and mortality. The neoadjuvant window provides a unique opportunity for systemic control prior to definitive therapy with radical prostatectomy or radiotherapy (RT). Early trials with first-generation androgen deprivation therapy (ADT) achieved pathological downstaging but no survival benefit. In the 2000s, the advent of chemohormonal regimes using docetaxel provided excitement but mixed results tempered expectations and is now not recommended prior to surgery. Second-generation androgen receptor pathway inhibitors (ARPIs) combined with ADT have demonstrated significant survival benefit in metastatic prostate cancer and are currently being evaluated in large phase III trials in the neoadjuvant setting. RT remains an alternative curative modality, and recent data highlights similar issues to surgery in eradicating micrometastatic disease despite excellent local control. This has driven parallel efforts to evaluate intensified systemic therapy in the pre-RT/neoadjuvant settings. In addition to the excitement surrounding ARPIs, radioligand therapy, such as [¹⁷⁷Lu]Lu-PSMA-617 has shown promise in the neoadjuvant setting and continues to be investigated. Future research aims to incorporate genomic and molecular factors to enable personalised neoadjuvant therapies by identifying damage immunologically responsive subtypes that may derive greater benefit from immune-directed therapies in the peri-operative setting. This narrative review synthesises current evidence for neoadjuvant therapies in high-risk prostate cancer and future directions.