Wenzel M, Nocera L, Ruvolo CC, et al. - Via this systematic review and network meta-analysis, researchers analyzed most recent overall survival (OS) and adverse event data for comparing the three guideline-recommended high-risk non-metastatic castration-resistant prostate cancer treatment alternatives: apalutamide, enzalutamide, and darolutamide. They systematically assessed and compared apalutamide vs enzalutamide vs darolutamide efficacy and toxicity, compared with androgen deprivation therapy as per PRISMA. They analyzed data from 4117 observations made within the three trials. Findings revealed that darolutamide showed the highest OS efficacy and lowest grade 3+ toxicity. However, enzalutamide displayed the highest efficacy in the PSA-doubling time  ≤ 6 months subgroup. Notably, study design, study participants, and follow-up span are some of the potentially critical variations that differentiate between the three studies and remained statistically unaccounted for employing the network meta-analysis method. Strongly considering those differences while interpreting current and any network meta-analyses, is recommended.