BACKGROUND: The most recent overall survival (OS) and adverse event (AE) data have not been compared for the three guideline-recommended high-risk non-metastatic castration-resistant prostate cancer (nmCRPC) treatment alternatives. METHODS: We performed a systematic review and network meta-analysis focusing on OS and AE according to the most recent apalutamide, enzalutamide, and darolutamide reports. We systematically examined and compared apalutamide vs. enzalutamide vs. darolutamide efficacy and toxicity, relative to ADT according to PRISMA. We relied on PubMed search for most recent reports addressing prospective randomized trials with proven predefined OS benefit, relative to ADT: SPARTAN, PROSPER, and ARAMIS. OS represented the primary outcome and AEs represented secondary outcomes. RESULTS: Overall, data originated from 4117 observations made within the three trials that were analyzed. Regarding OS benefit relative to ADT, darolutamide ranked first, followed by enzalutamide and apalutamide, in that order. In the subgroup of PSA-doubling time (PSA-DT) ≤ 6 months patients, enzalutamide ranked first, followed by darolutamide and apalutamide in that order. Conversely, in the subgroup of PSA-DT 6-10 months patients, darolutamide ranked first, followed by apalutamide and enzalutamide, in that order. Regarding grade 3+ AEs, darolutamide was most favorable, followed by enzalutamide and apalutamide, in that order. CONCLUSION: The current network meta-analysis suggests the highest OS efficacy and lowest grade 3+ toxicity for darolutamide. However, in the PSA-DT ≤ 6 months subgroup, the highest efficacy was recorded for enzalutamide. It is noteworthy that study design, study population, and follow-up duration represent some of the potentially critical differences that distinguish between the three studies and remained statistically unaccounted for using the network meta-analysis methodology. Those differences should be strongly considered in the interpretation of the current and any network meta-analyses.

Department of Neurosciences Reproductive Sciences and Odontostomatology University of Naples Federico 2 Naples Italy

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

Department of Urology and Division of Experimental Oncology URI Urological Research Institute IRCCS San Raffaele Scientific Institute Milan Italy

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

Department of Urology Goethe University Hospital Frankfurt Frankfurt am Main Germany

Department of Urology University Hospital Hamburg Eppendorf Hamburg Germany

Department of Urology University of Texas Southwestern Dallas TX USA

Department of Urology Weill Cornell Medical College New York NY USA

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

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

Institute for Urology and Reproductive Health 1 M Sechenov 1st Moscow State Medical University Moscow Russia

Martini Klinik Prostate Cancer Center University Hospital Hamburg Eppendorf Hamburg Germany

Prostate Cancer Prostatic Dis. 2023 Dec;26(4):807-808. doi: 10.1038/s41391-023-00656-4. PubMed

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