Background: Untreated depression and anxiety are associated with worse outcomes in patients with cancer. Despite recommendations for longitudinal screening, many patients are only assessed at the start of care. Men with PC often experience many phases of disease or treatment over a span of years, and androgen deprivation therapy (ADT) is associated with mood changes and depression. How depressive or anxiety symptoms fluctuate in men with PC, influenced by disease and treatment factors, is not well-described. Methods: Men with ≥1 Urology or Medical Oncology clinic visit for PC in the prior 6 months were emailed the PHQ-9 and GAD-7 depression and anxiety screening tools every 60 days; a score of ≥10 (moderate to severe symptoms) on either was considered a positive screen. Baseline characteristics and disease/treatment changes (PSA, radiographic, or biopsy progression, treatment change or start, or discontinuation of treatment due to lack of efficacy or toxicity) were collected by survey and chart review. We report early findings of factors associated with a positive screen or change in screening status with χ² and forward stepwise binary logistic regression (model inputs: receipt of ADT or disease/treatment change during study, and variables previously associated with depression or anxiety: age, race, marital status, education, income, history of psychiatric disorder, use of psychoactive medication, time since diagnosis, and localized, biochemically recurrent, or metastatic disease). Results: From 6/2021-12/2021, 201 men enrolled. At baseline, 50.7% had localized, 18.9% biochemically recurrent, and 30.3% metastatic disease; 40.8% were on ADT; 30.8% had a history of psychiatric disorder (22.9% depression, 19.9% anxiety, 9.0% other); and 24.9% were on psychoactive medication (19.9% antidepressant, 8.5% anxiolytic, 2.0% antipsychotic). 184 men completed at least 2 screens with mean follow-up 6.5 months (SD 1.3). 32 men (15.9%) screened positive at least once (15.4% PHQ-9, 4.5% GAD-7), of which half (N = 16) initially screened negative and later positive. Changing from a negative to positive screen was more likely when a disease/treatment change occurred during the study (18.3% vs 4.5%, p = 0.003). A higher proportion of men on ADT screened positive, especially if newly started during the study or in the 60 days preceding (35.7% new ADT vs 24.7% continuing ADT vs 8.0% no ADT, p = 0.002). In fully adjusted multivariable analyses, factors associated with a positive screen were history of psychiatric disorder (OR 6.3, 95% CI 2.6-15.4, p < 0.001), receipt of ADT (OR 3.8, 95% CI 1.5-9.5, p = 0.005), and lower income bracket (OR 1.7, 95% CI 1.3-2.5, p = 0.002). Conclusions: Longitudinal screening for depression and anxiety in PC identifies men who initially screen negative. Symptoms are associated with ADT and disease or treatment changes, which may inform optimal screening practices.