Efficacy and safety of neoadjuvant therapies for high-risk and locally advanced prostate cancer in older adults: a systematic review and network meta-analysis.

BACKGROUND

Brief overview of high-risk/locally advanced prostate cancer in older adults, current neoadjuvant therapies (NHT, NNHT, NCHT), and the uncertainty regarding their comparative efficacy on pathological outcomes.

OBJECTIVES

This study aims to compare the efficacy and safety profiles of various neoadjuvant treatments in improving pathological outcomes-including positive surgical margin (PSM) rates, minimal residual disease (MRD), clinical downstaging, and post-treatment prostate-specific antigen (PSA) reduction-in older adults with high-risk or locally advanced prostate cancer.

METHODS

We systematically searched PubMed, Embase, the Cochrane Library, and Web of Science for relevant randomized controlled trials and prospective comparative studies published from January 2010 to April 20, 2025. The primary pathological outcomes were positive surgical margin (PSM) rate and minimal residual disease (MRD). Secondary outcomes included clinical downstaging and prostate-specific antigen (PSA) response. All network meta-analyses were performed using Bayesian frameworks, with treatment ranking evaluated via the surface under the cumulative ranking curve (SUCRA).

RESULTS

The network meta-analysis of 15 studies revealed that, according to surface under the cumulative ranking curve (SUCRA) values, novel neoadjuvant hormonal therapy (NNHT) ranked highest for improving key pathological outcomes-notably surgical margin status and post-treatment prostate-specific antigen (PSA) response. While NNHT achieved the highest pathological response rates, it was associated with the most frequent and severe adverse events, highlighting a critical efficacy-toxicity trade-off in clinical decision-making.

CONCLUSIONS

Our analysis identifies NNHT as the most effective neoadjuvant approach for optimizing pathological endpoints, despite its association with the highest toxicity burden. This efficacy-safety profile supports its prioritization in subsequent trials designed to evaluate long-term survival and comprehensively assess safety outcomes in this population.

SYSTEMATIC REVIEW REGISTRATION: https://www.crd.york.ac.uk/prospero/, identifier CRD420251233339.