Background: Androgen deprivation therapy (ADT) is the standard of care for men with androgen-sensitive Stage IV metastatic (S4M1) prostate cancer. There is a sizable degree of variation in survival (2-4 years) among patients treated with ADT depending on patient factors. It is not clear how this heterogeneity of treatment effect can impact cost effectiveness and payer decision making in oncology. The study was conducted to estimate the survival and cost effectiveness of ADT in men with incident S4M1 prostate cancer across levels of Gleason score and age and to explore how payers use HTE evidence when making coverage decisions in oncology. Methods: Using Surveillance, Epidemiology, and End Results-Medicare datasets, we estimated stratified hazard ratios (HR) and adjusted median survival using inverse probability of treatment weighted Cox proportional hazard models. For cost analyses, we used partitioned inverse probability of uncensored weighted generalized linear models to estimate 3-year ADT costs. Incremental cost effectiveness ratios (ICERs) expressed as $/life years gained (LYG) and bootstrapped confidence intervals were calculated. Results: Among 4,691 S4M1 men, patients treated with ADT had a 52%, 39%, 59%, and 62% relative reduction in the risk of all-cause death in men aged 66-70, 71-75, 76-80, and 80+, respectively compared to untreated men. ADT provided overall survival benefit to men with Gleason 7 (HR: 0.83; 95% confidence interval (CI): 0.63-1.02) and 8-10 (HR: 0.45; 95% CI: 0.41-0.50). The ICER in $/LYG of ADT ranged from $5,806 (95% CI: -4,007-15,929) in 80+ age subgroup to $15,615 (95% CI: -49-37,376) in the 71-75 age subgroup and $24,155 (95% CI: 13,953-34,975) in the Gleason 8-10 subgroup to $39,630 (95% CI: -61-98,505) in the Gleason 7 subgroup. Payers cited multiple factors that may impact the use of HTE evidence into coverage policy, especially the Food and Drug Administration label. Conclusions: ADT provided survival benefit to all subgroups except men with Gleason 2-6. ADT was cost effective in all men with S4M1 prostate cancer at a willingness-to-pay threshold of $50,000/LYG, with the greatest uncertainty in men with Gleason 7. Many factors determined payers' ability to use HTE evidence to inform coverage policy.