Progression-free survival as a surrogate endpoint for overall survival in modern ovarian cancer trials: a meta-analysis

Abstract

Background: Progression-free survival (PFS) has been adopted as the primary endpoint in many randomized controlled trials, and can be determined much earlier than overall survival (OS). We investigated whether PFS is a good surrogate endpoint for OS in trials of first-line treatment for epithelial ovarian cancer (EOC), and whether this relationship has changed with the introduction of new treatment types.

Methods: In a meta-analysis, we identified summary data [hazard ratio (HR) and median time] from published randomized controlled trials. Linear regression was used to assess the association between treatment effects on PFS and OS overall, and for subgroups defined by treatment type, postprogression survival (PPS) and established prognostic factors.

Results: Correlation between HRs for PFS and OS, in 26 trials with 30 treatment comparisons comprising 24,870 patients, was modest (r² = 0.52, weighted by trial sample size). The correlation diminished with recency: preplatinum/paclitaxel era, r²= 0.66; platinum/paclitaxel, r²= 0.44; triplet combinations, r²= 0.22; biologicals, r²= 0.30. The median PPS increased over time for the experimental (P_trend = 0.03) and control arms (P_trend = 0.003). The difference in median PPS between treatment arms strongly correlated with the difference in median OS (r² = 0.83). In trials where the control therapy had median PPS of less than 18 months, correlation between PFS and OS was stronger (r² = 0.64) than where the median PPS was longer (r² = 0.48).

Conclusions: In EOC, correlation in the relative treatment effect between PFS and OS in first-line platinum-based chemotherapy randomized controlled trials is moderate and has weakened with increasing availability of effective salvage therapies.

Keywords: chemotherapy; clinical trials; ovarian cancer; therapy.

Figure 1.

PRISMA diagram/flow chart. PRISMA, preferred reporting items for systematic reviews and meta-analyses.

Figure 2.

Correlation between hazard ratios for progression-free and overall survival (all trials). The linear regression line is shown. The circles indicate the weighting according to trial size.

Figure 3.

(a). Median postprogression survival by treatment arm over time. The lines show predicted relationships in the experimental arm (solid line) and the control arm (dashed line). The weights according to trial size are shown by squares in the experimental arm and circles in the control arm. (b). Differences in median progression-free survival and median overall survival (months) between intervention and control arms. The line shows the linear regression line and the circles show the weight according to trial size.

Figure 4.

Correlation between hazard ratios for progression-free and overall survival by treatment regimen in different eras, weighted by sample size: (a) preplatinum/paclitaxel; (b) platinum/paclitaxel; (c) triplet combinations; (d) biological and other novel therapies. predicted linear relationship ideal relationship.

Figure 5.

Correlations between hazard ratios for progression-free and overall survival according to postprogression survival. (a) Median postprogression survival less than 18 months. (b) Median postprogression survival at least 18 months. predicted linear relationship ideal relationship ◯ weights according to trial size.

Figure 6.

Correlations between hazard ratios for progression-free and overall survival according to the proportion of patients with poor performance status. (a) Fewer than 10% of patients with Eastern Cooperative Oncology Group performance status ⩾2; (b) 10% or more patients with Eastern Cooperative Oncology Group performance status ⩾2. predicted linear relationship ideal relationship ◯ weights according to trial size.