Current Status of Neoadjuvant Treatment Before Surgery in High-Risk Localized Prostate Cancer

Localized high-risk (HR) prostate cancer (PCa) is a heterogeneous disease whose likelihood of a biochemical recurrence, metastatic progression and cancer-related mortality after initial treatment is higher when compared with patients with low (LR) or intermediate-risk (IR) disease. In the past, neoadjuvant therapy has shown an improvement in postoperative oncological variables but failed to demonstrate any survival advantages. With the promising results from novel treatments in metastatic and non-metastatic castration resistant PCa settings, new evidence has appeared in the literature in the neoadjuvant setting. Background/Objectives: To describe the current evidence for different neoadjuvant treatments before a radical prostatectomy in high-risk prostate cancer. Methods: We performed a comprehensive English literature search for original and review articles through January-August 2024, using Pubmed, Medline and ClinicalTrials.gov databases, as well as a comprehensive review of different international guidelines, searching the following terms: "neoadjuvant ADT prostate cancer", "neoadjuvant ADT", "prostate cancer surgery" and "neoadjuvant high-risk prostate cancer". We included 61 papers for the final review. Results and Discussion: Neoadjuvant therapy is not recommended in daily practice by any international guideline. The National Comprehensive Cancer Network (NCCN) guidelines strongly discourage the use of ADT as a neoadjuvant therapy outside of clinical trials. ADT + ARTAs show promising data in phase-II trials, including favorable pCR, MRD, PSA relapse and salvage therapy rates. Clinical trials on chemotherapy, ¹⁷⁷Lu-PSMA, genomic-targeted therapies and markers of response leave room for further evidence acquisition due to their encouraging results. Conclusions: Currently, no phase III data supports systemic neoadjuvant therapy before RP. Phase II studies show promising data for ADT with second-generation agents, including favorable pCR, MRD, PSA relapse and salvage therapy rates.