Abstract PS1-10-17: Progression-free Survival by Local Investigators vs. Blinded Independent Central Review in Hormone-Positive, HER2-Negative Metastatic Breast Cancer: A Systematic Review and Meta-analysis

Abstract INTRODUCTION: Progression-free survival (PFS) is a widely accepted primary endpoint in breast cancer trials; however, it remains susceptible to assessment bias. To reduce this risk, blinded independent central review (BICR) is often incorporated into trial designs. Emerging evidence has suggested discordance between investigator- and BICR-assessed PFS, with BICR often producing more optimistic estimates, raising concerns about BICR-PFS as a definitive primary endpoint. We conducted a meta-analysis comparing BICR- and investigator-PFS in RCTs of patients with hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) following progression on CDK4/6 inhibitor (CDK4/6i) therapy. METHODS: We conducted a systematic review and meta-analysis searching PubMed, Embase, Cochrane, and major conference proceedings for phase II-III RCTs including patients HR+/HER2- mBC with progression following CDK4/6i. Eligible studies required or permitted prior CDK4/6i use and reported PFS assessed by both local investigators and BICR. For each trial, we calculated a discrepancy index (DI)—the ratio of hazard ratios (HR) for BICR- vs investigator-PFS—and the absolute difference in median PFS (mPFS) between the two assessments. A pooled DI was estimated using a mixed-effects model. Subgroup analysis of trials requiring prior CDK4/6i and meta-regression by bone-only disease, visceral metastases, control arm type (endocrine/targeted therapy vs chemotherapy), study design (open-label vs double-blinded), and primary endpoint (investigator- vs BICR-PFS) were performed. Results: Of 2,807 identified records, 19 RCTs with 7,599 patients met inclusion criteria. No statistically significant difference was observed between investigator- and BICR-PFS overall, with a pooled DI of 1.01 (95%CI, 0.93-1.01; p=0.66). In studies requiring prior CDK4/6i treatment, the pooled DI was 0.94 (95% CI, 0.80-1.11; p=0.81). Findings were consistent across meta-regression analyses (all p>0.05). The pooled PFS difference was 0.07 months (95%CI 0.38-0.52; p=0.76) in interventional arms and 0.33 months (95%CI 0.02-0.68; p=0.06) in control arms. Although major outliers, postMONARCH, SERENA-2, and SOLAR-1 did not exhibit statistically significant discrepancy. CONCLUSION: Although several recent RCTs in HR+/HER2- mBC have shown a trend toward longer mPFS with BICR—likely due to investigators incorporating additional clinical data, leading to censoring and exclusion from BICR analysis—our meta-analysis found no statistically significant differences between the two methods in this patient population. This consistency, demonstrated across meta-regression analyses adjusting for potential effect modifiers and in outlier trials, suggests that both approaches yield comparable PFS estimates. Citation Format: L. Ravani, Z. Bagheri, K. Kalinsky, H. Burstein, A. Bardia, J. A. Mouabbi, R. O’Regan, S. A. Wander. Progression-free Survival by Local Investigators vs. Blinded Independent Central Review in Hormone-Positive, HER2-Negative Metastatic Breast Cancer: A Systematic Review and Meta-analysis [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-10-17.