Enzalutamide alone or combined with other pharmacologic agents for metastatic castration-resistant prostate cancer: A systematic review and meta-analysis

BackgroundMetastatic castration-resistant prostate cancer (mCRPC) remains driven by persistent androgen receptor signaling. Although enzalutamide (ENZ) is widely used, the incremental benefit of adding other agents remains uncertain. We evaluated the efficacy and safety of specific pharmacologic agents added to ENZ in randomized trials.MethodsWe systematically searched PubMed/MEDLINE, Web of Science, CINAHL, and Scopus through September 2026 following PRISMA guidelines (PROSPERO: CRD420251231232). RCTs comparing ENZ plus another pharmacologic agent with ENZ monotherapy in mCRPC were included. Analyzed outcomes included overall survival (OS), progression-free survival (PFS), radiographic PFS (rPFS), PSA progression, and adverse events. Random-effects meta-analyses used restricted maximum likelihood estimation with Hartung-Knapp adjustment. Certainty of evidence was assessed using GRADE.ResultsNine trials involving 3779 patients were included. Adding specific agents to ENZ improved rPFS (HR = 0.76; 95% CI, 0.62-0.94; p = 0.02) but did not significantly improve OS, PFS, or PSA progression. Combination therapy increased the risk of any adverse event (RR = 1.03; 95% CI, 1.01-1.06) and grade ≥3 adverse events (RR = 1.37; 95% CI, 1.09-1.71). Estimates for individual adverse events were inconsistent and imprecise.ConclusionAdding specific agents to ENZ improved pooled rPFS but increased toxicity, without clear evidence of an OS benefit in unselected mCRPC populations (certainty of evidence ranging from very low to moderate across outcomes). These findings should be interpreted cautiously and do not exclude potential benefits from particular combinations in biomarker-selected populations.