Background: Relugolix is the first oral GNRH antagonist approved by the FDA in 2021 for the treatment of advanced prostate cancer (PCa). Approval was based on HERO study, which showed a rapid and sustained testosterone suppression superior to that of Leuprolide coupled with a significantly shorter time to eugonad state after discontinuation. Relugolix was associated with a 54% lower risk of major adverse cardiovascular events as compared with Leuprolide. There is very little data available regarding the tolerability safety of Relugolix in combination Enhanced Androgen Signaling Inhibitors (ASI). Here we provide real world experience on the combination of Relugolix and ASIs in patients(pts) with advanced PCa, focusing on safety, tolerability and pharmacodynamic outcome measures. Methods: Houston Methodist Genitourinary Oncology records were reviewed for identification of pts treated with combination Relugolix plus ASI for at least 1 month, from 09/21 to 07/23. Data collected included pts’ baseline and tumor characteristics, cardiovascular and metabolic comorbidities concomitant medication. We recorded Adverse Events, potential Drug Drug Interaction (DDI) and Testosterone (T) and PSA decline. Results: We report 152 advanced hormone-naive PCa pts with median age of 71 (range 48-96). 81% were White or/and Hispanic, 17 % black, 2 % Asian. Majority (90%) had at least 1 cardiovascular risk factor; hypertension (72%), hyperlipidemia (52%), obesity (41 %), diabetes mellitus (26%), coronary artery disease (30%) and atrial fibrillation (13%). ASIs combined with Relugolix included: Darolutamide (78%), Abiraterone (14%), Apalutamide (7%) and Enzalutamide (1%). All but one pt were compliant (99%). Median treatment exposure is 8 months (range 1 -21). All pts had baseline Testosterone >150ng/dL. All pts reached castrate T levels and 90% of patients achieved a T < 20 ng/dL. 55% pts reached PSA <0.1 at median of 4ms, 75% PSA decline > 90% and 91% PSA decline ≥50%. 7% pts discontinued Relugolix due to adverse events. Three pts (2%) had a major adverse cardiovascular event, including one sudden death, one with congestive heart failure, and one with myocardial infarction. Two pts (1%) reported grade 3 fatigue. G3 LFT elevations recorded in 2 pts (1%). No clinical signals of DDI reported. Conclusions: This is the first large original report of the combination of Relugolix with ASIs in real world practice. The combination has a favorable safety and tolerability profile with no new safety concerns. No new DDI concerns were raised. These findings in combination with pharmacodynamic outcome measures of T / PSA support the use of Relugolix in combination with ASIs as standard of care in advanced PCa.