A living interactive systematic review and network meta-analysis evaluating systemic therapies in metastatic castration-sensitive prostate cancer (mCSPC).

193 Background: We maintain a network meta-analysis for the treatment of mCSPC using a living interactive evidence (LIvE) synthesis framework. Recently, the STAMPEDE trial presented evidence regarding a new triplet regimen (enzalutamide-abiraterone-androgen deprivation therapy [E+AAP+ADT]). Hence, in this report we provide the most-up-to-date evidence to inform the choice of optimal therapy in mCSPC patients. Methods: Phase III randomized controlled trials (RCTs) assessing treatment intensification with androgen pathway inhibitors (API), docetaxel (D), or both in patients with mCSPC were included. Mixed treatment comparisons for overall-survival (OS) and progression-free survival (PFS) were made across randomized comparisons using a frequentist network-meta-analysis. Additionally, subgroup data from three trials (ENZAMET, TITAN, ARCHES) by the receipt of docetaxel were abstracted to evaluate the comparative effectiveness of different triplet regimens. Treatment effects were expressed as hazard ratio (HR) and 95% confidence intervals (CI). Relative treatment rankings were evaluated using P-scores and assessed in congruency with the pairwise estimates. Results: This report includes 10 clinical trials (30 references) and over 11500 patients updated as of 1st October 2022. Using randomized data in overall patient population, AAP+D+ADT (rank 1; HR: 0.50; 95% CI: 0.35-0.72) and E+AAP+ADT (rank 4; HR: 0.76; 0.62-0.93) significantly improved PFS compared to D+ADT (rank 7) but not when compared to E+ADT (rank 2) and APA+ADT (rank 3). Similarly, darolutamide (DARO)+D+ADT (rank 1; HR: 0.68; 0.57-0.81), AAP+D+ADT (rank 2; HR: 0.75; 0.59-0.95) significantly improved OS when compared to D+ADT (rank 7). Efficacy by volume of disease and timing of metastatic presentation was consistent with prior update. Using subgroup data by the receipt of docetaxel, a total of five triplet regimens (DARO+D+ADT, AAP+D+ADT, E+D+ADT, apalutamide (APA)+D+ADT, and E+AAP+ADT) were evaluable for comparisons. E+D+ADT (rank 3) improved PFS compared to D+ADT (rank 9; HR: 0.52; 0.41-0.66) and E+AAP+ADT (rank 6; HR: 0.70; 0.52-0.94). Compared to AAP+ADT (rank 7), E+D+ADT (HR: 0.64; 0.49-0.84) and AAP+D+ADT (rank 2; 0.62; 0.42-0.91) significant improved PFS. However, no significant differences were observed among E+D+ADT, AAP+D+ADT, and APA+D+ADT. Similarly, DARO+D+ADT (rank 1) improved OS compared to APA+D+ADT (HR: 0.47; 0.24-0.93). Conclusions: Current evidence favors the use of emerging triplet regimens over docetaxel doublet but not API doublets in overall population. Among different triplets, E+AAP+ADT may not delay progression compared to docetaxel triplets. Hence, access to treatment, toxicity, disease volume and timing of metastases should be carefully considered in mCSPC patients.