Background: Multiple treatment options exist for mHSPC, including androgen receptor-axis-targeted (ARAT) therapies with or without docetaxel (DOC). Many ITCs have been published that compare efficacy and safety of treatment alternatives in mHSPC that have not been directly compared in head-to-head clinical trials. We assessed the methodology and findings of previously published ITCs, focusing on outcomes related to triple therapy with darolutamide (DARO) + androgen deprivation therapy (ADT) + DOC from the ARASENS clinical trial. Methods: We performed systematic literature review searches in MEDLINE, Embase and Cochrane databases to identify ITCs published from 1946 to May 2023 (PROSPERO, CRD42023429478). We focused on reporting ITCs that included ARASENS trial data and treatment versus treatment comparisons. Results: We included 12 ITCs across 17 publications. There was variation across the ITCs in the number of trials included (range: 2–10), and the statistical method used (frequentist or Bayesian network meta-analyses, random or fixed effects). Furthermore, reporting of treatment effect modifiers, network inconsistency/heterogeneity, and subgroup analysis was inconsistent across studies. Despite methodological differences, ITCs were consistent in showing a significant benefit in overall survival (OS) with DARO triple therapy compared with ADT (4 ITCs), and with DOC+ADT (7 ITCs; in line with ARASENS trial results). DARO triple therapy demonstrated a numerical benefit in OS compared with doublet (ARAT+ADT) and with other triple therapies (abiraterone acetate+prednisone [AAP] or enzalutamide [ENZ]+DOC+ADT) (Table 1). DARO triple therapy was consistently ranked highest, above other ARAT double and triple therapies, on OS across 9 ITCs. The risk of grade ≥3 adverse events (AEs) were numerically greater with DARO triplet therapy compared with ARAT doublets (6 ITCs). Available ITC evidence comparing AEs across triple therapies showed numerically fewer AEs for DARO compared with AAP (2 ITCs). Conclusions: Despite variability in their methodology, ITCs were consistent in showing OS benefit and highest ranking with DARO triple therapy, above the other ARAT therapies, and in reporting fewer AEs for DARO compared with AAP. As the number of mHSPC publications grows, so too does the need for standardizing ITC methodology to ensure robustness of findings and to optimize treatment decision-making.

ENZ triplet therapy is not mandated by current guidelines.