Purpose: The addition of androgen receptor pathway inhibitors (ARPIs) to androgen deprivation therapy (ADT), with or without docetaxel (Doc), is currently recommended for metastatic, hormone-sensitive prostate cancer (mHSPC). Recently, the ARANOTE trial evaluated the efficacy and safety of Darolutamide + ADT in this setting. We aimed to update a network meta-analysis (NMA) of these combination therapies. Methods: We conducted a systematic search for RCTs on systemic therapies for mHSPC using MEDLINE, Embase, and the Web of Science Core Collection in September 2024. An NMA utilizing random-effects models was performed to compare progression-free survival (PFS), overall survival (OS), and adverse event (AE) incidence (PROSPERO: CRD42024591458). Results: A total of 12 RCTs (n = 11,954) were included in our NMAs. Triplet therapies were associated with significant improvements in PFS compared to ARPI-based doublet therapies (hazard ratio [HR]: 0.74; 95% confidence interval [CI]: 0.59-0.93; p = 0.01), but the difference did not reach the conventional levels of statistical significance for OS (HR: 0.82; 95% CI: 0.67-1.01; p = 0.059). In a subset analysis, compared to ARPI-based doublet therapies, triplet therapies showed a significant improvement in PFS in patients with high-volume disease (HR: 0.64; 95% CI: 0.47-0.88; p < 0.01), whereas no significant improvement was observed in those with low-volume disease (HR: 0.86; 95% CI: 0.45-1.67; p = 0.7). No significant difference in grade ≥ 3 AEs was observed between triplet therapies and ARPI-based doublet therapies. The main limitations include patient heterogeneity and limited follow-up in some studies. Conclusions: Triplet therapies can improve the oncologic outcomes of patients with mHSPC compared to ARPI-based doublet therapies, without significantly increasing severe AEs. These findings warrant further confirmation in a head-to-head trial powered for overall survival.

2nd Department of Urology Centre of Postgraduate Medical Education 01 813 Warsaw Poland

Collegium Medicum Faculty of Medicine WSB University 41 300 Dąbrowa Górnicza Poland

Department of Biomedical Sciences Humanitas University 20072 Pieve Emanuele Italy

Department of Medical Oral and Biotechnological Sciences G d'Annunzio University of Chieti 66013 Chieti Italy

Department of Urology 2nd Faculty of Medicine Charles University 15006 Prague Czech Republic

Department of Urology Azienda Ospedaliero Universitaria Ospedali Riuniti Di Ancona Università Politecnica Delle Marche 60126 Ancona Italy

Department of Urology Comprehensive Cancer Center Medical University of Vienna 1090 Vienna Austria

Department of Urology IRCCS Humanitas Research Hospital 20090 Milan Italy

Department of Urology Medical College Jagiellonian University 30 688 Krakow Poland

Department of Urology Semmelweis University 1082 Budapest Hungary

Department of Urology Shimane University Faculty of Medicine Izumo 693 8504 Shimane Japan

Department of Urology The Jikei University School of Medicine Tokyo 105 8461 Japan

Department of Urology The University of Texas Southwestern Medical Center Dallas TX 75390 USA

Department of Urology University Medical Center Hamburg Eppendorf 20251 Hamburg Germany

Department of Urology Weill Cornell Medical College New York NY 10065 USA

Division of Surgery and Interventional Science University College London London WC1E 6BT UK

Division of Urology Department of Special Surgery The University of Jordan Amman 11942 Jordan

Karl Landsteiner Institute of Urology and Andrology 1010 Vienna Austria

Research Center for Evidence Medicine Urology Department Tabriz University of Medical Sciences Tabriz 51656 65811 Iran

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