BACKGROUND: Combination systemic therapies have become the standard for metastatic hormone-sensitive prostate cancer (mHSPC). However, the effect of age on oncologic outcomes remains unknown. Our aim was to perform a systematic review, meta-analysis, and network meta-analysis (NMA) on the effect of chronological age on overall survival (OS) in patients treated with combination therapies for mHSPC. METHODS: We searched the PubMed®, Web of ScienceTM, and Scopus® databases to identify randomized controlled trials (RCTs) that analyzed the efficacy of combination systemic therapies using ADT plus docetaxel and/or androgen receptor signaling inhibitor (ARSI) in patients with mHSPC. We included studies, which provided separate hazard ratios (HRs) for younger vs. older patients. The selected age cut-off was 70 years (±5 years). Our outcome of interest was OS. RESULTS: We included nine RCTs with a total of 9183 patients. Younger and older men constituted 51% and 49% of included patients, respectively. Docetaxel plus ADT significantly improved OS among both older (HR 0.79, 95% CI 0.63-0.99, p = 0.04) and younger patients (HR 0.79, 95% CI 0.69-0.90, p < 0.001) with no differences according to age. ARSI plus ADT improved OS in older (HR 0.72, 95% CI 0.64-0.80, p < 0.001) and younger (HR 0.58, 95% CI 0.51-0.66, p < 0.001) patients; younger patients did benefit more (p = 0.02). On NMA treatment ranking, triplet therapy showed the highest probability of OS benefit irrespective of age group; in older patients, the benefit of triplet therapy compared to doublet was less expressed. CONCLUSIONS: Patients with mHSPC benefit from combination systemic therapies irrespective of age; the effect is, however, more evident in younger patients. Chronological age alone seems not to be a selection criteria for the administration of combination systemic therapies.

Cancer Prognostics and Health Outcomes Unit Division of Urology University of Montreal Health Center Montreal QC Canada

Department of Oncology and Hemato Oncology University of Milan Milan Italy

Department of Surgery Oncology and Gastroenterology University of Padua Padua Italy

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

Department of Urology CHUV Lausanne Lausanne Switzerland

Department of Urology Jagiellonian University Krakow Poland

Department of Urology La Croix du Sud Hospital Quint Fonsegrives France

Department of Urology Medical University Innsbruck Innsbruck Austria

Department of Urology Medical University of Silesia Zabrze Poland

Department of Urology Medical University of Vienna Vienna Austria

Department of Urology Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences Okayama Japan

Department of Urology San Giovanni Battista Hospital University of Torino Torino Italy

Department of Urology Semmelweis University Budapest Hungary

Department of Urology St Antonius Hospital Utrecht The Netherlands

Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology University Hospital Essen Essen German Cancer Consortium University Hospital Essen Essen Germany

Department of Urology University of Texas Southwestern Dallas TX USA

Department of Urology Weill Cornell Medical College New York NY USA

Division of Nuclear Medicine European Institute of Oncology IRCCS Milan Italy

Division of Surgery and Interventional Science University College London London UK

Division of Urological Surgery and Center for Surgery and Public Health Brigham and Women's Hospital Harvard Medical School Boston MA USA

Hourani Center for Applied Scientific Research Al Ahliyya Amman University Amman Jordan

Institute for Urology and Reproductive Health Sechenov University Moscow Russia

Unit of Urology Division of Oncology IRCCS San Raffaele San Raffaele Hospital Milan Italy

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