BACKGROUND: Androgen deprivation therapy (ADT) improves outcomes in men undergoing definitive radiotherapy for prostate cancer but carries significant toxicities. Clinical parameters alone are insufficient to accurately identify patients who will derive the most benefit, highlighting the need for improved patient selection tools to minimize unnecessary exposure to ADT's side effects while ensuring optimal oncological outcomes. The ArteraAI Prostate Test, incorporating a multimodal artificial intelligence (MMAI)-driven digital histopathology-based biomarker, offers prognostic and predictive information to aid in this selection. However, its clinical utility in real-world settings has yet to be measured prospectively. METHODS: This multicentre implementation trial aims to collect real-world data on the use of the previously validated Artera MMAI-driven prognostic and predictive biomarkers in men with intermediate-risk prostate cancer undergoing curative radiotherapy. The prognostic biomarker estimates the 10-year risk of metastasis, while the predictive biomarker determines the likely benefit from short-term ADT (ST-ADT). A total of 800 participants considering ST-ADT in conjunction with curative radiotherapy will be recruited from multiple Australian centers. Eligible patients with intermediate-risk prostate cancer, as defined by the National Comprehensive Cancer Network, will be asked to participate. The primary endpoint is the percentage of patients for whom testing led to a change in the shared ST-ADT recommendation, analyzed using descriptive statistics and McNemar's test comparing recommendations before and after biomarker testing. Secondary endpoints include the impact on quality of life and 5-year disease control, assessed through linkage with the Prostate Cancer Outcomes Registry. The sample size will be re-evaluated at an interim analysis after 200 patients. DISCUSSION: ASTuTE will determine the impact of a novel prognostic and predictive biomarker on shared decision-making in the short term, and both quality of life and disease control in the medium term. If the biomarker demonstrates a significant impact on treatment decisions, it could lead to more personalized treatment strategies for men with intermediate-risk prostate cancer, potentially reducing overtreatment and improving quality of life. A potential limitation is the variability in clinical practice across different centers inherent in real-world studies. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12623000713695p. Registered 5 July 2023.