Integration of Darolutamide in the Treatment Landscape for Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review and Network Meta-analysis of Efficacy and Safety.

Background and objective: Recent advances have led to the introduction of multiple combination treatments for metastatic hormone-sensitive prostate cancer (mHSPC), but their comparative efficacy and toxicity remain uncertain owing to the absence of head-to-head comparisons. We evaluated the efficacy and safety profile of darolutamide plus androgen deprivation therapy (ADT) in comparison to other treatments. Methods: A systematic search was conducted in the Cochrane Library up to September 30, 2024 in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Hazard ratios (HRs) and confidence intervals (CIs) for progression-free survival (PFS) and overall survival (OS) were extracted. Odds ratios (ORs) for treatment-emergent adverse events (TEAEs) were calculated from the events reported. Key findings and limitations: Eleven trials involving 11 389 patients were included. Darolutamide triplet therapy was associated with the highest overall PFS (HR 0.24, 95% CI 0.20-0.29) and OS (HR 0.54, 95% CI 0.44-0.66). The highest PFS in low-volume disease was observed with enzalutamide (HR 0.29, 95% CI 0.21-0.38) and darolutamide (HR 0.30, 95% CI 0.15-0.60). All androgen receptor pathway inhibitors (ARPIs) had higher toxicity than ADT, except for darolutamide (OR 0.99, 95% CI 0.71-1.39). In comparison to darolutamide, enzalutamide (OR 2.03, 95% CI 1.08-3.80) and abiraterone (OR 3.18, 95% CI 1.74-5.80) were associated with higher risk of hypertension. Enzalutamide was associated with a higher risk of fatigue (OR 3.22, 95% CI 1.28-8.07). Limited direct comparisons between treatments may affect our conclusions regarding relative efficacy. Conclusions and clinical implications: Our findings support the role of darolutamide as an effective and well-tolerated ARPI for mHSPC, particularly in low-volume metachronous disease and comorbidity-limited cases. These results may assist clinicians in planning personalized treatment strategies that balance efficacy and safety. Patient summary: We compared different medical treatment options for metastatic hormone-sensitive prostate cancer, with a special focus on a drug called darolutamide. Darolutamide is well tolerated and is effective, particularly in patients with a low volume of metastasis and patients with other health conditions that may limit their treatment options.