Background: Treatment effects vary by volume of disease and timing of metastatic presentation in patients with mCSPC. Therefore, we updated the existing body of evidence to assess the comparative efficacy of systemic therapy in mCSPC by prognostic subgroups to inform clinical practice guidelines. Methods: This living systematic review was conducted using the living interactive evidence (LIvE) synthesis framework. Phase III clinical trials assessing contemporary systemic therapy in mCSPC and reporting overall survival (OS) by four prognostic subgroups were included. Prognostic subgroups included synchronous high volume (SHV), synchronous low volume (SLV), metachronous high volume (MHV), and metachronous low volume (MLV) disease. Mixed treatment comparisons were made using a network-meta-analytic approach in each subgroup. P-scores were used to assess relative treatment rankings in congruency with pairwise estimates. Higher scores indicated better efficacy. Results: This study included a total of nine trials with eight unique treatment options. In patients with SHV disease, darolutamide+docetaxel+ADT (DARO+D+ADT) significantly improved OS when compared to D+ADT (HR: 0.69; 0.57-0.85), enzalutamide (E)+ADT (HR: 0.67; 95% CI: 0.46-0.99), and apalutamide (APA)+ADT (HR: 0.65; 95% CI: 0.43-0.96). In patients with SLV disease, E+ADT (HR: 0.62; 95% CI: 0.42-0.91) and AAP+ADT (HR: 0.66; 95% CI: 0.49-0.89) significantly improved OS when compared to ADT. Although E+D+ADT trended toward improvement compared to other treatments, the results were not statistically significant. In patients withMHV disease, no statistically significant differences were observed among mixed treatment comparisons. However, OS with DARO+D+ADT trended toward improvement when compared to D+ADT (HR: 0.69; 95% CI: 0.39-1.23), APA+ADT (HR: 0.72; 95% CI: 0.23-2.33), E+ADT (HR: 0.67; 95% CI: 0.24-1.86), and E+D+ADT (HR: 0.59; 95% CI: 0.26-1.34). In patients with MLV disease, E+ADT significantly improved OS compared to ADT (HR: 0.51; 95% CI: 0.32-0.79), and D+ADT (HR: 0.48; 95% CI: 0.27-0.85). APA+ADT significant improved OS compared to ADT (HR: 0.22; 95% CI: 0.09-0.54), and D+ADT (HR: 0.21; 95% CI: 0.08-0.55). No other statistically significant differences were observed among mixed treatment comparisons. Conclusions: Current evidence suggests that triplet systemic therapy may be preferred in SHV, E systemic triplet and E hormonal doublet in SLV, DARO systemic triplet and APA hormonal doublet in MHV, and APA or E hormonal doublets in MLV mCSPC.