INTRODUCTION: The incidence of synchronous metastatic hormone-sensitive prostate cancer (mHSPC) is rising with the increasing use of next-generation imaging. Local radiotherapy (RT) was shown to improve survival in patients with mHSPC; however, new data require a re-assessment of the indication and value of local RT in mHSPC. METHODS: In this prospectively registered systematic review and meta-analysis (CRD42025648251), we searched MEDLINE, Scopus, CENTRAL, and Google Scholar in March 2025 for phase 3 RCTs evaluating the addition of RT to systemic therapy to improve OS in mHSPC patients. Hazard ratios (HRs) were pooled using random-effects meta-analysis. Risk of Bias was assessed with Cochrane's RoB 2 tool. RESULTS: Out of the 10,615 individual records, we identified three RCTs: HORRAD (n = 432), STAMPEDE (n = 2,061), and PEACE-1 (n = 1,173). The systemic treatment included androgen deprivation therapy (ADT) in HORRAD, ADT ± Docetaxel in STAMPEDE, and ADT ± Docetaxel ± Abiraterone in PEACE-1 trial. Local RT was not associated with significantly improved OS in all patients (HR = 0.92; 95 % confidence interval [CI] 0.85-1.00; p = 0.06), or in those with low metastatic burden (HR = 0.74; 95 %CI 0.51-1.06; p = 0.1); however, exploratory analyses showed a significant improvement in androgen deprivation resistance-free survival (HR = 0.76; 95 %CI 0.70-0.82; p < 0.001). Local RT was associated with significant reduction in local prostate cancer related events in the HORRAD (18 % vs. 30 %) and PEACE-1 (12 % vs. 22 %) trials, but not in the STAMPEDE trial (49 % vs. 51 %). CONCLUSION: Local RT does not improve OS in unselected patients treated with modern systemic therapies for mHSPC. However, it delays ADT resistance and reduces local adverse events, with relatively tolerable toxicity. Future studies should refine selection criteria, ideally using PSMA-PET imaging, dynamic response markers, and/or genomic profiling, to identify mHSPC patients most likely to benefit from local RT.

Centre for Translational Medicine Semmelweis University Budapest Hungary

Collegium Medicum Faculty of Medicine WSB University Dąbrowa Górnicza Poland

Department of Medicine University of Padua Padua Italy

Department of Oncology and Hemato oncology University of Milan Milan Italy

Department of Radiation Oncology IEO European Institute of Oncology IRCCS Milan Italy

Department of Radiation Oncology University Medical Center Utrecht Utrecht the Netherlands

Department of Surgery Oncology and Gastroenterology Clinic of Urology University of Padua Padua Italy

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

Department of Urology 2nd Health Cluster Riyadh Ministry of Health KSA

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

Department of Urology Centre of Postgraduate Medical Education Warsaw Poland

Department of Urology Città della Salute e della Scienza University of Torino School of Medicine Torino Italy

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

Department of Urology Medical University Center Hamburg Eppendorf Hamburg Germany

Department of Urology Prince Saud Bin Jalawi Hospital Al Ahsa Health Cluster Al Ahsa KSA

Department of Urology Semmelweis University Budapest Hungary

Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology University of Texas Southwestern Dallas TX USA

Department of Urology Yale University New Haven CT USA

Division of Surgery and Interventional Sciences University College London London UK

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

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

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

Robotic Surgery Center Military Institute of Medicine National Research Institute Warsaw Poland

Unit of Urology Division of Oncology Urological Research Institute IRCCS San Raffaele Scientific Institute Vita Salute San Raffaele University Milan Italy

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