Abstract Introduction: Randomized trials have shown that physical activity can improve quality of life (QOL) among individuals with cancer. In the absence of a randomized trial of adequate size and follow-up to comprehensively evaluate this relationship for prostate cancer, we aim to emulate a target trial of guideline-based physical activity strategies and 6-year physical QOL. Methods: We will use observational data on individuals in the Health Professionals Follow-up Study diagnosed with nonmetastatic prostate cancer between 2010-2016 and free of conditions that could preclude following current physical activity recommendations at baseline (first post-diagnostic questionnaire). The physical activity strategies of interest are (1) engage in ≥150 minutes of moderate activity, or ≥75 minutes of vigorous activity per week, or an equivalent combination (i.e., ≥7.5 metabolic equivalent of task [MET]-hours/week of vigorous or moderate activity) and (2) no physical activity intervention. The outcomes of interest are 6-year mean physical QOL scores (based on EPIC-CP measures of bowel function, urinary incontinence, urinary irritation/obstruction, sexual function, and vitality/hormonal function). We will adjust for baseline and time-varying risk factors using the parametric g-formula. Conclusion: These findings may help to inform clinical recommendations to improve QOL among individuals with nonmetastatic prostate cancer. Further, the proposed approach will provide a framework for future studies designed to evaluate the effectiveness of any intervention strategies to improve patient-reported outcome measures in cancer survivorship research. Table 1. Specification and emulation of a target trial using observational data from HPFS Protocol component Target trial specification Target trial emulation Eligibility criteria (1) Individuals diagnosed with non-metastatic prostate cancer between 2010 and 2016; (2) No history of other cancers (Except nonmelanoma skin cancer); (3) No history of conditions that could preclude high levels of physical activity: myocardial infarction, stroke, congestive heart failure, amyotrophic lateral sclerosis, or functional impairment (defined as difficulty climbing a flight of stairs or walking eight blocks due to physical impairment) Same as for the target trial, except: We required complete data on physical activity, birth date, and other risk factors on the pre-diagnostic questionnaire and the first post-diagnostic (baseline) questionnaire. Physical activity strategies Each individual is assigned to one of the following strategies at baseline: (1) No intervention (usual physical activity) (2) Engage in ≥1.25 hours/week of vigorous activity or ≥2.5 hours/week of moderate activity or ≥7.5 MET-hours/week of vigorous or moderate activity (an equivalent combination). Strategies are initiated at baseline and continued over follow-up. Individuals are excused from following the physical activity intervention upon the development of myocardial infarction, stroke, congestive heart failure, amyotrophic lateral sclerosis, cancer metastasis, or functional impairment. Individuals must respond to surveys at every follow-up period to assess time-varying variables. Same as for the target trial, except: (1) Follow-up periods correspond to the questionnaire cycles in the cohort study. (2) We assumed that each 2-year physical activity questionnaire accurately reflects the individual's (1) average physical activity over the previous 2-year period and (2) intended physical activity that the individual would have reported at the start of the current period under no intervention. Strategy assignment Individuals are randomly assigned to a strategy at baseline and are aware of their assigned strategy. We assumed randomization conditional on the following baseline covariates: age; employment status; primary treatment; stage; Gleason score, and prostate-specifc antigen level at diagnosis; pre-baseline values of body-mass index and physical activity. Outcomes 6-year mean quality of life scores in the following physical domains: (1) Bowel function, (2) Urinary incontinence, (3) Urinary irritation/obstruction, (4) Sexual function, (5) Vitality/hormonal function. Individuals self-report their physical quality of life on EPIC (The Explanded Prostate Cancer Index Composite) questionnaires at every follow-up period. Same as for the target trial. Follow-up periods correspond to the questionnaire cycles in the cohort study. Follow-up For each eligible individual, follow-up starts at strategy assignment (baseline) and ends upon death, loss to follow-up, or the end of follow up in December 2018, whichever happens first. Same as for the target trial. Loss to follow-up was defined as questionnaire non-response. Causal contrasts Intention-to-treat and per-protocol effect. Observational analogue of per-protocol effect. Statistical analysis Intention-to-treat analysis. Per protocol analysis: Parametric g-formula to compare 6-year physical quality of life under each strategy via mean differences, with adjustment for pre- and post-baseline prognostic factors associated with adherence and loss to follow-up. Same as for the per-protocol analysis of the target trial. Citation Format: Naiyu Chen, Rachel C. Nethery, Lorelei A. Mucci, Barbra A. Dickerman. Guideline-based physical activity and physical quality of life among individuals with nonmetastatic prostate cancer: A target trial emulation in the Health Professionals Follow-up Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2256.