Neoadjuvant Systemic Therapy in High-risk Localised Prostate Cancer: Current Evidence and Future Directions.

High-risk localised and locally advanced prostate cancer (PC) accounts for nearly 25% of new PC diagnoses and is associated with significantly greater mortality in comparison to lower-risk disease. Radical prostatectomy (RP) remains central to curative treatment, but many patients experience biochemical relapse or develop metastases within a decade, which reflects undetected micrometastatic disease at diagnosis. The perioperative period offers an opportunity to intensify systemic therapy and potentially improve long-term outcomes. Early neoadjuvant trials of first-generation androgen deprivation therapy improved pathological findings, but not survival. Chemotherapy with docetaxel is feasible, with some evidence of a long-term benefit, but data for short-term endpoints remain inconclusive. The strongest evidence is from trials of androgen receptor pathway inhibitors, which have revealed pathological downstaging, biological activity, and translational insights; the phase 3 PROTEUS trial will determine the impact of these agents on survival. Radioligand therapy with [177Lu]-labelled prostate-specific membrane antigen ligands and genomically guided approaches are feasible and safe, but remain exploratory. Currently, no phase 3 data support systemic neoadjuvant therapy before RP, and this strategy is not recommended by international guidelines. Ongoing and future large-scale trials will be critical to define the role of neoadjuvant therapy in this PC setting in clinical practice. PATIENT SUMMARY: We reviewed studies of systemic therapies given before surgery for men with high-risk prostate cancer. These treatments can shrink tumours and improve surgical outcomes, but clear survival benefits have not yet been shown. Ongoing large trials, especially with new hormone-blocking drugs, will help in determining if this approach should become part of routine care.