# Progression-free survival 2 (PFS2) as a surrogate endpoint for overall survival (OS) in breast cancer randomized controlled clinical trials

## TL;DR

This study evaluates if PFS2 can reliably predict overall survival in breast cancer trials, finding a moderate correlation that improves with higher data maturity.

## Contribution

The paper provides the first evaluation of PFS2 as a surrogate for OS specifically in breast cancer trials.

## Key findings

- PFS2 and OS showed a strong correlation (r = 0.714) across 18 trials involving 9617 patients.
- Stronger correlations were observed when PFS2 maturity was ≥55% (r = 0.93) and OS information fraction ≥75% (r = 0.931).
- Surrogacy was consistent across treatment lines and OS maturity levels.

## Abstract

Overall survival (OS) is the gold-standard endpoint in oncology trials but often requires prolonged follow-up. Progression-free survival 2 (PFS2) has been proposed as an intermediate surrogate. While prior analyses report sufficient correlation of PFS2 with OS, no study has specifically evaluated its surrogacy in breast cancer.

A systematic search of Medline, Web of Science, and Cochrane Library was conducted to identify randomized controlled trials (RCTs) in breast cancer reporting both PFS2 and OS. Trial-level associations between log-transformed hazard ratios for PFS2 and OS were examined using sample size-weighted linear regression. Surrogacy strength was quantified using the coefficient of determination (R2) and Pearson correlation coefficient (r) with 95% bootstrap confidence intervals (CIs).

Eighteen RCTs including 9617 patients were analyzed. The correlation between PFS2 and OS was strong (r = 0.714, 95% CI 0.204-0.893, R2 = 0.509). Validation using long-term OS data showed a moderate but weaker correlation (r = 0.552, 95% CI –0.12 to 0.897, R2 = 0.305). Surrogacy was stronger in trials with PFS2 maturity ≥55% (r = 0.93, R2 = 0.864) versus <55% (r = –0.652, R2 = 0.425), and in those with OS information fraction ≥75% (r = 0.931, R2 = 0.866) versus <75% (r = 0.625, R2 = 0.391). Correlation was similar across OS maturity subgroups (<40%: r = 0.677, 40%-60%: r = 0.702).

PFS2 demonstrated a context-dependent association with OS, with stronger correlations observed only at higher levels of PFS2 maturity and OS information fraction.

•PFS2 shows a moderate and context-dependent association with OS across 15 randomized trials.•Higher PFS2 maturity (≥55%) yields stronger OS correlation (r = 0.93).•Improved surrogacy is observed with OS information fraction ≥75% (r = 0.931).•Consistent surrogacy is found across treatment lines and OS maturity levels.

PFS2 shows a moderate and context-dependent association with OS across 15 randomized trials.

Higher PFS2 maturity (≥55%) yields stronger OS correlation (r = 0.93).

Improved surrogacy is observed with OS information fraction ≥75% (r = 0.931).

Consistent surrogacy is found across treatment lines and OS maturity levels.