Background: While exposure to concomitant medications (conmeds) have been found to influence survival and treatment response in patients with metastatic prostate cancer, it is unclear if exposure to these medications affect treatment response and survival in men with non-metastatic castrate resistant prostate cancer (nmCRPC) treated with androgen receptor signaling inhibitors (ARSI). We performed an exploratory analysis of the SPARTAN trial to determine whether receipt of conmeds influenced the effect of apalutamide on overall survival (OS) and metastasis-free survival (MFS) in patients with nmCRPC. Methods: SPARTAN is a phase III randomized controlled trial in which nmCRPC patients were randomly assigned 2:1 to receive apalutamide or placebo in addition to androgen deprivation therapy (ADT). We focused on 5 groups of commonly prescribed classes of conmeds: biguanides (metformin), HMG-CoA reductase inhibitors (statins), angiotensin converting enzyme inhibitors (ACEI), acetylsalicylic acid derivatives (ASA), and proton pump inhibitors (PPI) given their plausible biologic and clinical rationale. To determine the potential effect-modification, we applied Cox regression models with interaction term between the conmed class, the randomized treatment in addition to a minimally sufficient set of confounders. To determine the independent association of each class of conmeds with outcome, we applied IPTW-based survival analysis and log-rank test. Results: Overall, 1152 patients (772 and 380 in the apalutamide and placebo arm, respectively) were eligible for this secondary analysis. For OS, we did not find any statistically significant heterogeneity of treatment effect from ADT plus apalutamide across subgroups stratified by concomitant exposure to the conmeds listed above. We noted a significant difference (p=0.01) in treatment effect from apalutamide on MFS between patients with concomitant receipt of statins (adjusted hazard ratio [aHR]: 0.20; 95% CI: 0.15-0.28) vs without statins (aHR: 0.31 [0.24-0.39]). On IPTW-based analysis, patients with concomitant metformin (median: NR vs 31 months (mos); p=0.002) and concomitant ACEI (median: 37 vs 29 mos; p=0.006) had significantly superior MFS. Patients with exposure to all of metformin, ACEI, and statin had significantly improved MFS (median: NR vs 31 mos; p<0.001). Conclusions: In this post-hoc exploratory analysis, treatment effects from apalutamide on MFS and OS were consistent across subgroups stratified by exposure to conmeds. Exposure to concomitant metformin or ACEI was associated with a significant improvement in MFS.