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Context: Active surveillance (AS) is a standard of care for patients with low-risk and selected intermediate-risk prostate cancer (PCa). Nevertheless, there is a lack of summary evidence on how to impact disease trajectory during AS., Objective: To assess which interventions prevent PCa progression effectively during AS., Evidence Acquisition: We queried PubMed, Scopus, and Web of Science databases to identify studies examining the impact of interventions aimed at slowing disease progression during AS. The primary endpoint was PCa progression, the definition of which must have included pathological upgrading. The secondary endpoint included treatment toxicities., Evidence Synthesis: We identified 22 studies, six randomized controlled trials and 16 observational studies, which analyzed the association between different interventions and PCa progression during AS. The interventions considered in the studies included 5-alpha reductase inhibitors (5-ARIs), statins, diet, exercise, chlormadinone, fexapotide triflutate (FT), enzalutamide, coffee, vitamin D3, and PROSTVAC. We found that administration of 5-ARIs was associated with improved progression-free survival (PFS; hazard ratio: 0.59; 95% confidence interval 0.48-0.72), with no increased toxicity signals. Therapies such as vitamin D3, chlormadinone, FT, and enzalutamide have shown some efficacy. However, these anticancer drugs have been associated with treatment-related adverse events in up to 88% of patients., Conclusions: The use of 5-ARIs in PCa patients on AS is associated with longer PFS. However, for the other interventions, it is difficult to draw clear conclusions based on the weak available evidence., Patient Summary: Patients with prostate cancer managed with active surveillance (AS) who are treated with 5-alpha reductase inhibitors have a lower risk of disease progression, with minimal adverse events. Other interventions require more studies to determine their efficacy and safety profile in men on AS., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)