Progression-Free Survival in Metastatic Breast Cancer by Local Investigators vs Blinded Independent Central Review: A Systematic Review and Meta-Analysis.

Abstract

Progression-free survival (PFS) is a widely accepted primary end point in metastatic breast cancer (mBC) trials; however, it remains susceptible to assessment bias. To reduce this risk, blinded independent central review (BICR) is often incorporated into trial designs, but emerging evidence has suggested discordance between investigator- and BICR-assessed PFS. To compare BICR- and investigator-assessed PFS of patients with hormone receptor-positive/ERBB2-negative mBC. PubMed, Embase, CENTRAL, and major conference proceedings were searched from database inception to November 27, 2025, to identify all potential eligible studies. Phase 2 or 3 randomized clinical trials (RCTs) including patients with hormone receptor-positive/ERBB2-negative mBC with progression following CDK4/6 inhibitor therapy. Eligible studies required or permitted prior CDK4/6 inhibitor use and reported PFS assessed by both local investigators and BICR. Data from the eligible RCTs were extracted by 2 reviewers (L.V.R. and Z.B.). A trial-level random-effect meta-analysis was performed. Outcomes were the discrepancy index (DI)-the ratio of hazard ratios for BICR- vs investigator-assessed PFS-and the absolute difference in median PFS between the 2 assessments. Of 4989 identified records, 21 RCTs with 9165 patients met inclusion criteria. Eleven RCTs used BICR as the primary assessment, 13 were open label, and 7 required prior treatment with CDK4/6 inhibitors as an inclusion criterion. No statistically significant difference was observed between investigator- and BICR-assessed PFS overall, with a DI of 1.02 (95% CI, 0.95-1.10; P = .57), which was consistent across meta-regression analyses. The pooled PFS difference was 0.26 months (95% CI, -0.16 to 0.68 months; P = .22) in interventional arms and 0.44 months (95% CI, 0.09-0.78 months; P = .01) in control arms. Results of this systematic review and meta-analysis show that despite a trend toward longer median PFS with BICR in recent RCTs of patients with hormone receptor-positive/ERBB2-negative mBC, there was no statistically significant DI between BICR- and investigator-assessed PFS. Results were consistent across meta-regression analyses and in outlier trials, suggesting that both approaches yield comparable PFS estimates.