PURPOSE: Recent advancements in the management of biochemical recurrence (BCR) following local treatment for prostate cancer (PCa), including the use of androgen receptor signaling inhibitors (ARSIs), have broadened the spectrum of therapeutic options. We aimed to compare salvage therapies in patients with BCR after definitive local treatment for clinically non-metastatic PCa with curative intent. METHODS: In October 2023, we queried PubMed, Scopus, and Web of Science databases to identify randomized controlled trials (RCTs) and prospective studies reporting data on the efficacy of salvage therapies in PCa patients with BCR after radical prostatectomy (RP) or radiation therapy (RT). The primary endpoint was metastatic-free survival (MFS), and secondary endpoints included progression-free survival (PFS) and overall survival (OS). RESULTS: We included 19 studies (n = 9117); six trials analyzed RT-based strategies following RP, ten trials analyzed hormone-based strategies following RP ± RT or RT alone, and three trials analyzed other agents. In a pairwise meta-analysis, adding hormone therapy to salvage RT significantly improved MFS (HR: 0.69, 95% CI: 0.57-0.84, p < 0.001) compared to RT alone. Based on treatment ranking analysis, among RT-based strategies, the addition of elective nodal RT and androgen deprivation therapy (ADT) was found to be the most effective in terms of MFS. On the other hand, among hormone-based strategies, enzalutamide + ADT showed the greatest benefit for both MFS and OS. CONCLUSIONS: The combination of prostate bed RT, elective pelvic irradiation, and ADT is the preferred treatment for eligible patients with post-RP BCR based on our analysis. In remaining patients, or in case of post-RT recurrence, especially for those with high-risk BCR, the combination of ADT and ARSI should be considered.

Centre for Translational Medicine Semmelweis University Budapest Hungary

Collegium Medicum Faculty of Medicine WSB University Dąbrowa Górnicza Poland

Department of Biomedical Sciences Humanitas University Pieve Emanuele Italy

Department of Development and regeneration KU Leuven Leuven Belgium

Department of Radiation Oncology Oncology Institute of Southern Switzerland Ente Ospedaliero Cantonale Bellinzona Switzerland

Department of Radiation Oncology University Medical Center Utrecht Utrecht The Netherlands

Department of Urology 2nd Faculty of Medicine Charles University Prague Czechia

Department of Urology Clinico San Carlos Hospital Madrid Spain

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

Department of Urology Faculty of Medicine Shimane University Shimane Japan

Department of Urology Koc University Hospital Istanbul Turkey

Department of Urology Medical University of Silesia Zabrze Poland

Department of Urology Semmelweis University Budapest Hungary

Department of Urology Shariati Hospital Tehran University of Medical Science Tehran Iran

Department of Urology St Antonius Hospital Utrecht The Netherlands

Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology University Hospitals Leuven Leuven Belgium

Department of Urology University Medical Center Hamburg Eppendorf Hamburg Germany

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

Department of Urology Weill Cornell Medical College New York NY USA

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

Faculty of Medicine University of Geneva Geneva Switzerland

Institute for Urology and Reproductive Health Sechenov University Moscow Russia

Karl Landsteiner Institute of Urology and Andrology Vienna Austria

Martini Klinik Prostate Cancer Center University Hospital Hamburg Eppendorf Hamburg Germany

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

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