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PFS Dominates Metastatic Breast Cancer Trials With Only Modest Gains, OS Rarely Used
An analysis of 267 phase 3 randomized controlled trials in metastatic breast cancer conducted between 2008 and 2025 found that progression-free survival (PFS) served as the primary endpoint in 85.4% of trials, yet among trials with available results, the median PFS improvement was just 2.8 months (interquartile range, 1.35–5.75). Overall survival (OS) was used as the primary endpoint in only 13.1% of trials, raising questions about whether the dominant surrogate measure adequately captures meaningful clinical benefit.
What Was Studied
This analysis examined the frequency and type of primary and secondary endpoints used in phase 3 randomized controlled trials evaluating systemic treatments for metastatic breast cancer. The central question was whether the choice of endpoint — particularly the widespread adoption of PFS over OS — reflects the clinical priorities of patients and the evidentiary standards required for regulatory and therapeutic decision-making.
How It Was Studied
This was a systematic registry-based review that identified eligible phase 3 RCTs through the WHO International Clinical Trials Registry Platform. The analysis included 267 trials of systemic treatments initiated between 2008 and 2025, spanning a range of breast cancer subtypes and treatment classes. Multivariable logistic regression was applied to identify variables — including treatment type, line of therapy, and tumor subtype — that were independently associated with the selection of a given primary endpoint. The comparators varied across the included trials, reflecting the broad diversity of treatment approaches under evaluation in this disease setting.
What Was Observed
- PFS was the overwhelmingly dominant primary endpoint, used in 228 of 267 trials (85.4%). Among the 107 PFS-based trials with available results, the median improvement in PFS over the comparator arm was 2.8 months (IQR 1.35–5.75), indicating that many trials are being powered around gains that may be modest in absolute terms.
- Chemotherapy trials were substantially less likely to use PFS as the primary endpoint compared with trials of conjugates — approximately 90% lower odds (adjusted OR 0.10, 95% CI 0.01–0.61), suggesting that endpoint selection varies meaningfully by treatment class.
- OS was used as the primary endpoint in only 35 trials (13.1%), but was significantly more likely to be selected in trials enrolling patients with triple-negative breast cancer (TNBC) relative to HER2-positive disease — more than fivefold higher odds (adjusted OR 5.54, 95% CI 1.57–21.93). Line of treatment, however, had no statistically significant impact on the likelihood of OS being chosen as the primary endpoint (p > 0.05).
- Secondary endpoint coverage was incomplete: while 81.1% of PFS-primary trials (185/228) included OS as a secondary endpoint, only 47.4% (108/228) incorporated quality of life (QoL) as a secondary measure, leaving a substantial proportion of trials without patient-reported outcome data.
Why This Matters
The near-complete displacement of OS by PFS as the standard primary endpoint in metastatic breast cancer trials is significant because modest PFS improvements — a median of under three months — may not reliably predict or translate into meaningful gains in survival or patient wellbeing. The authors specifically call for more frequent use of OS as a primary endpoint, particularly in TNBC and in later-line treatment settings. The underuse of QoL as a secondary endpoint further limits the ability of trial data to inform the full impact of treatment on patients’ daily lives.
How to Read This Result
This registry-based review provides a broad descriptive picture of endpoint practices across nearly two decades of metastatic breast cancer trials, but conclusions are constrained by the availability of registry-level data, which may not capture whether individual PFS improvements ultimately corresponded to OS or QoL benefits.
Limitations
The abstract does not explicitly report study limitations.