First-Line Systemic Treatments for Metastatic Hormone-Sensitive Prostate Cancer: Updated Systematic Review and Network Meta-analysis

PURPOSE: The therapeutic landscape of metastatic hormone-sensitive prostate cancer (mHSPC) has expanded rapidly with the introduction of intensified combination regimens. This updated systematic review and network meta-analysis aimed to compare the efficacy and safety of first-line systemic combination therapies for mHSPC. MATERIAL AND METHODS: We systematically searched MEDLINE, Embase, and Web of Science in March 2026 to identify randomized controlled trials evaluating first-line combination therapies for mHSPC. The outcomes of interest were progression-free survival (PFS) and/or overall survival (OS) and severe adverse events (AEs). We conducted frequentist random-effects network meta-analyses, specifically limited to RCTs involving the all-comer population, and a systematic review for targeted and biomarker- driven strategies. The certainty of evidence (CoE) was assessed via the CINeMA framework. (PROSPERO: CRD420251161933). RESULTS AND CONCLUSION: sTwenty-three trials (n=18,689) were included. In the all-comer NMA, docetaxel+ARPI+ADT (HR 0.66, 95%CI 0.43-1.01, CoE: Moderate) and PARPi+ ARPI+ADT (HR 0.55, 95%CI 0.23-1.34, CoE: Low) showed clinically relevant but not statistically significant PFS improvements compared with ARPI+ADT. No triplet regimen demonstrated a statistically significant OS benefit over ARPI+ADT, although docetaxel + ARPI+ADT significantly improved OS in the high-volume subgroup (HR 0.76, 95%CI 0.61-0.95; High CoE). While adding docetaxel or PARPi did not result in statistical significance for severe AE risk, the safety estimates were characterized by substantial imprecision, and a clinically meaningful increase in toxicity cannot be excluded. Overall, evidence certainty was downgraded due to risk of bias from open-label designs, clinical inconsistency in prior docetaxel exposure across comparator arms, and imprecision, particularly for PARPi-based regimens due to small sample sizes in phase II data. Targeted and biomarker-driven strategies (AMPLITUDE, CAPItello-281, and PSMAddition) further supported the benefit of intensification in selected or target-positive populations.Triplet intensification suggests a potential improvement in mHSPC, but OS benefits appear limited to specific subgroups, such as high-volume disease. The lack of a clear survival advantage in all-comers and the varying CoE support a selective, biomarker-driven or targeted approach. Treatment decisions should balance potential oncological gains against distinct toxicity profiles.