Clinical outcomes of sequential androgen receptor pathway inhibitors (ARPIs) versus novel therapies in metastatic castration-resistant prostate cancer after progression on second-generation ARPIs: A systematic review and meta-analysis.

5075 Background: Most recent pivotal, randomized controlled trials (RCTs) testing novel therapies in ARPI pretreated mCRPC patients have incorporated sequential ARPI as the comparator. Given that sequential ARPI could be an inferior control arm based on CARD data, we conducted a meta-analysis to quantify the treatment effect of novel agents vs sequential ARPI and to evaluate whether sequential ARPI constitutes an appropriate control arm for future trials. Methods: A systematic search of PubMed, Europe PMC, and ClinicalTrials.gov up to August 14, 2025, identified 2,904 records. After removal of duplicates and exclusions, 17 RCTs met the inclusion criteria. Eligible studies enrolled patients with mCRPC who had progressed after prior exposure to second-generation ARPIs, comparing a novel agent (chemotherapy, targeted therapy, Immunotherapy and radioligands) with sequential ARPI treatment. Three independent reviewers screened the studies and extracted data in accordance with PRISMA guidelines. The primary endpoints were overall survival (OS) and progression-free survival (PFS), and the hazard ratios (HRs) were pooled using a random-effects model. Results: We included a total of 6,725 patients in this meta-analysis, with 3,579 (53.2%) receiving novel agents and 3,146 (46.8%) receiving ARPIs. Analysis revealed the pooled HR for OS was 0.86 (95% CI: 0.76–0.96; p<0.01). Substantial heterogeneity was observed (I2= 64.05%). This heterogeneity reflects the inclusion of trials with different novel agents and molecular selection criteria, with some highly selective trials (e.g., PROfound HR 0.58) showing greater benefit than others (e.g., ERA 223 HR 1.22). In addition, the pooled PFS analysis demonstrated a highly significant clinical advantage for novel therapies, resulting in a pooled HR of 0.72 (95% CI: 0.61–0.86; p<0.01). This PFS analysis exhibited very high heterogeneity (I2= 84.44%), driven by exceptional outcomes observed in trials targeting specific biomarkers. Conclusions: Across RCTs, novel therapies consistently outperform sequential ARPI for both OS and PFS in post-ARPI mCRPC. These pooled effects, and their amplification in biomarker-selected populations, suggest that sequential ARPI is a suboptimal control arm in this setting. Future trials should consider more appropriate, biomarker-driven or guideline-concordant active comparators, enabling fairer tests of clinical benefit and more generalizable results