CONTEXT: Several recent randomised trials have evaluated the role of combination systemic treatment using androgen deprivation therapy (ADT) plus chemotherapy or an androgen receptor signaling inhibitor (ARSI) in patients with high-risk and/or unfavourable nonmetastatic prostate cancer (nmPC). OBJECTIVE: To assess the outcomes associated with adding combination systemic treatment to primary definitive local therapy in patients with high-risk and/or unfavourable nmPC. EVIDENCE ACQUISITION: We queried the PubMed, Web of Science, and Scopus databases and conference abstracts to identify prospective randomised trials examining the value of adding chemotherapy or an ARSI to ADT and primary local therapy with curative intent for nmPC. The primary endpoints were overall survival (OS), cancer-specific survival (CSS), metastasis-free survival (MFS), and failure-free survival (FFS). Secondary endpoints included adverse events (AEs) and pathologic outcomes. EVIDENCE SYNTHESIS: We identified 15 randomised studies, of which nine evaluated chemohormonal and six investigated ARSI-based treatment strategies. In both radical prostatectomy (RP) and radiation therapy (RT) settings, addition of docetaxel to ADT was associated with significantly better CSS (pooled hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.49-0.95; p = 0.025), MFS (pooled HR 0.82, 95% CI 0.71-0.95; p = 0.008), and FFS (pooled HR 0.70, 95% CI 0.62-0.79; p < 0.001); the difference did not meet the conventional level of statistical significance for OS (pooled HR 0.86, 95% CI 0.73-1.01; p = 0.072). For patients treated with RT alone, docetaxel-based combination treatment did not meet the significance threshold set for OS (p = 0.3), CSS (p = 0.072), or MFS (p = 0.079), but the difference for FFS was statistically significant (pooled HR 0.72, 95% CI 0.63-0.84; p < 0.001). On network meta-analyses including RT studies, ARSI + ADT outperformed docetaxel + ADT for survival endpoints and had a more favourable AE profile. CONCLUSIONS: Intensification of systemic therapy with docetaxel or an ARSI in addition to ADT improves oncologic endpoints in high-risk and/or unfavourable nmPC treated with local definitive therapy. The highest efficacy was achieved with ARSI + ADT, specifically in patients treated with RT. PATIENT SUMMARY: Our findings highlight that selected patients with high-risk nonmetastatic prostate cancer benefit from intensification of systemic therapy beyond hormonal treatment.

Département des Innovations Thérapeutiques et Essais Précoces Gustave Roussy Université Paris Saclay Villejuif France

Department of Health and Medical Informatics Kyungnam University College of Health Sciences Changwon Republic of Korea

Department of Medical Oncology Institut Bergonié Bordeaux France

Department of Pathology Hôpital Tenon Sorbonne University Paris 6 Paris France

Department of Radiation Oncology Brigham and Women's Hospital and Dana Farber Cancer Institute Boston MA USA

Department of Radiation Oncology University Hospitals Seidman Cancer Center Case Western Reserve University Cleveland OH USA

Department of Urology and Pediatric Urology University Medical Center Johannes Gutenberg University Mainz Germany

Department of Urology La Croix du Sud Hospital Quint Fonsegrives France

Department of Urology Medical University of Silesia Zabrze Poland

Department of Urology Medical University of Vienna Vienna Austria

Department of Urology Medical University of Vienna Vienna Austria; Department of Urology King Fahad Specialist Hospital Dammam Saudi Arabia

Department of Urology Medical University of Vienna Vienna Austria; Department of Urology Medical University of Silesia Zabrze Poland

Department of Urology Medical University of Vienna Vienna Austria; Department of Urology The Jikei University School of Medicine Tokyo Japan

Department of Urology Medical University of Vienna Vienna Austria; Institute for Urology and Reproductive Health Sechenov University Moscow Russia

Department of Urology Medical University of Vienna Vienna Austria; Institute for Urology and Reproductive Health Sechenov University Moscow Russia; Karl Landsteiner Institute of Urology and Andrology Vienna Austria; Department of Urology 2nd Faculty of Medicine Charles University Prague Czech Republic; Hourani Center for Applied Scientific Research Al Ahliyya Amman University Amman Jordan; Department of Urology Weill Cornell Medical College New York NY USA; Department of Urology University of Texas Southwestern Dallas TX USA

Department of Urology Medical University of Vienna Vienna Austria; Research Center for Evidence Based Medicine Tabriz University of Medical Sciences Tabriz Iran

Department of Urology St Antonius Hospital Nieuwegein the Netherlands

Department of Urology University Hospital Schleswig Holstein Lübeck Germany

Department of Urology University Hospitals Leuven Leuven Belgium

Department of Urology Yale School of Medicine New Haven CT USA

Division of Urology and Urologic Oncology Centre Hospitalier de Université de Montréal University of Montreal Montreal QC Canada

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

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Eur Urol. 2022 Oct;82(4):e105-e106. doi: 10.1016/j.eururo.2022.06.024. PubMed

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