Background: Over the last decade,androgen receptor signaling inhibitors (ARSIs; apalutamide [APA], enzalutamide [ENZ], abiraterone acetate + prednisone [AAP]) in combination with androgen-deprivation therapy (ADT) have emerged as more effective life-prolonging treatment options for mCSPC. We examined the impact of ARSI starting therapy in mCSPC on long-term clinical outcomes in real-world clinical practice in the US. Methods: This retrospective, observational cohort study evaluated clinical outcomes in adult patients with mCSPC using the ConcertAI RWD 360 prostate cancer dataset. All patients with newly diagnosed mCSPC from 1 Jan 2018 to 30 Sept 2022 were enrolled and followed up until 31 Mar 2023. Among other outcomes, PSA50 and PSA90 (PSA response defined as a ≥50% and ≥90% decline from baseline, respectively) and undetectable PSA (PSA ≤0.2 ng/mL) were assessed using the Kaplan-Meier method. Relative risks of onset of castration resistance (CR) and death were estimated using multivariate Cox proportional hazard models adjusted for potential confounding factors (age, comorbidities, BMI, baseline PSA). Results: 165 patients with mCSPC started on APA + ADT, 643 started on ENZ + ADT, 1064 on AAP +ADT, 293 on docetaxel (DTX) + ADT, and 543 on ADT alone (Table). A higher proportion of patients initiating APA achieved PSA50, PSA90, or undetectable PSA compared with other treatments. CR-free survival was significantly longer in patients first treated with an ARSI + ADT than those treated with DTX + ADT or ADT alone. Reduced risk of developing CR was observed in patients starting with APA + ADT compared with ADT alone (adjusted hazard ratio [aHR] 0.36, 95% CI 0.19, 0.67; p=0.0016). OS was longer in patients started on ARSIs compared to ADT alone. Patients starting with APA + ADT were observed to have a lower risk of death compared with ENZ + ADT (aHR 0.48, 95% CI 0.23, 0.99; p<0.05) or AAP + ADT (aHR 0.43, 95% CI 0.21, 0.90; p<0.05). Conclusions: ADT alone continues to be used widely despite the availability of newer and more effective life prolonging therapies. Use of APA + ADT as starting treatment for mCSPC demonstrated significantly better clinical outcomes than other ARSIs, DXT + ADT, or ADT alone in real-world clinical practice in the US.