Background: Prior studies have shown that exposure to concomitant medications such as metformin and statins influences survival in metastatic castrate resistant prostate cancer treated with androgen receptor pathway inhibitors (ARPI). However, it is unclear if such exposure to concomitant medications influences treatment response and survival in metastatic hormone sensitive prostate cancer (mHSPC) treated with ARPI. Methods: We performed a secondary analysis of the LATITUDE trial to determine whether exposure to concomitant medications influenced the effect from abiraterone, in addition to ADT, on overall survival (OS) and prostate cancer specific mortality (PCSM) in men with de novo high risk mHSPC. We focused on 7 commonly prescribed classes of medications: metformin, statins, proton pump inhibitors, cyclooxygenase 2 (COX-2) inhibitors, aspirin, acetaminophen, and NSAIDs (nonselective COX inhibitors except aspirin). To identify effect modification, we applied Cox regression models for OS with an interaction term between the medication classes and the randomized treatment regimen. To determine the independent association of each medication with OS and PCSM, we applied separate multivariable Cox regression and competing risk regression models, respectively. To account for multiple testing, 2-sided p<0.0024 was set as the threshold for statistical significance. Results: Overall, 1135 men were eligible. There was a non-significant evidence of differential effect from abiraterone on OS among men with concomitant exposure to aspirin (Hazard ratio [HR]: 0.93; 95% CI: 0.63-1.36) vs. those who did not (HR: 0.61 [0.51-0.73]) (interaction p=0.04). Similarly, there was a non-significant evidence of a differential effect from abiraterone on OS among men exposed to NSAIDs (HR: 0.54 [0.42-0.70]) vs. those who did not (HR: 0.74 [0.60-0.91]) (interaction p=0.05). Exposure to concurrent NSAIDs was associated with a significantly inferior OS (HR: 1.37 [1.15-1.62]; p<0.001) and higher relative incidence of PCSM (subdistribution HR: 1.47 [1.21-1.78]; p<0.001) in the overall cohort. There was a significantly higher relative excess risk of grade ≥3 cardiovascular adverse events by interaction of concomitant exposure to aspirin with abiraterone (RERI: 3.39 [0.68-6.11]). Conclusions: In this secondary analysis, concomitant exposure to 7 classes of medications was not associated with any statistically significant modification of abiraterone effect on OS in de novo high risk mHSPC. Men who received concurrent NSAIDs had a higher risk of PCSM and inferior OS even after adjustment for skeletal metastases burden and pain score. The excess risk of serious cardiovascular adverse events by interaction of abiraterone and exposure to aspirin could be due to reverse causality due to underlying burden of cardiovascular comorbidity in the exposed group.