# Prasad: most surrogate endpoints in cancer trials correlate poorly with survival

Source: https://onco.cc/key-papers/paper-prasad-surrogate-endpoints-jama-im-2015/  
OnCo record `paper-prasad-surrogate-endpoints-jama-im-2015` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

A systematic review of 36 trial-level meta-analyses found that in over half the surrogate endpoint (response rate, progression-free survival) had a low correlation with overall survival, and only about a quarter showed a strong correlation.

## Summary

Prasad and colleagues searched for trial-level meta-analyses that quantified the correlation between a surrogate endpoint and overall survival across randomised oncology trials. They identified 36 articles covering 65 surrogate-survival associations in many tumour types and settings.

Using a conventional threshold, 52% of reported correlations were low (r below 0.7), 25% medium (0.7 to 0.85) and 23% high (0.85 or more). Correlations were weakest in the metastatic setting and for response rate. A companion analysis by the same group (Kim and Prasad, JAMA Internal Medicine 2015) showed that of 54 FDA cancer drug approvals in 2008-2012, 36 were based on surrogates, and after a median 4.4 years only 5 had demonstrated an overall survival benefit.

The work catalysed the debate over accelerated approval, the FDA's 2023-2025 reforms requiring confirmatory trials to be under way at approval, and the growing use of quality-of-life and patient-reported endpoints.

## Fields

- Kind: Key paper
- Last checked: 2026-09-08
- Journal: JAMA Internal Medicine
- Year: 2015
- DOI: 10.1001/jamainternmed.2015.2829
- Authors: Prasad V, Kim C, Burotto M, Vandross A
- Findings: 36 trial-level meta-analyses covering 65 surrogate-OS associations reviewed; 52% of surrogate-survival correlations were low (r below 0.7), 25% medium, 23% high; Response rate and PFS in the metastatic setting were the weakest surrogates; Companion analysis: of 36 approvals on surrogates (2008-2012), 5 later showed an OS benefit, 18 failed to or were not tested, and 13 remained unknown
- What it means: A drug that shrinks tumours or delays progression on scans has not necessarily been shown to help patients live longer or better. Patients and clinicians should ask what the endpoint was; regulators should insist on timely confirmatory trials; and trialists should validate surrogates before relying on them.
- Caveats: Trial-level correlation is only one way to validate a surrogate; some settings (adjuvant DFS in colon cancer) have well-validated surrogates; Low correlation may reflect crossover and post-progression therapy diluting the OS signal rather than a useless surrogate; The review depended on published meta-analyses and their heterogeneous methods; PFS can be a meaningful endpoint in itself when progression is symptomatic and treatment is tolerable

## Sources

- DOI: https://doi.org/10.1001/jamainternmed.2015.2829
- Kim and Prasad: FDA approvals on surrogates (2015): https://doi.org/10.1001/jamainternmed.2015.5868

## Connected records

- ideas: [An independent programme that validates surrogate endpoints, setting by setting](https://onco.cc/ideas/idea-tr1-surrogate-validation-programme/), [Let MCED trials read out on late-stage incidence, with mortality follow-up mandated](https://onco.cc/ideas/idea-prev-mced-stage-endpoint-surrogate/), [Power trials to detect a benefit patients would value, not the smallest detectable one](https://onco.cc/ideas/idea-tr1-power-for-meaningful-benefit/), [Win-ratio endpoints that weigh survival, toxicity and quality of life together](https://onco.cc/ideas/idea-tr1-win-ratio-net-benefit-endpoint/)
- fronts: [Drug Discovery Platforms](https://onco.cc/fronts/drug-discovery/)
- terms: [Accelerated approval](https://onco.cc/terms/accelerated-approval/), [Hazard ratio (HR)](https://onco.cc/terms/hazard-ratio/), [Objective response rate (ORR)](https://onco.cc/terms/orr/), [Overall survival (OS)](https://onco.cc/terms/os/), [Progression-free survival (PFS)](https://onco.cc/terms/pfs/), [RECIST](https://onco.cc/terms/recist/)
- bottlenecks: [Patients lack understanding, navigation and agency](https://onco.cc/bottlenecks/b-patient-voice/), [Prices and value](https://onco.cc/bottlenecks/b-drug-pricing/), [Regulatory divergence between regions](https://onco.cc/bottlenecks/b-regulatory-fragmentation/), [Trial design, endpoints and cost](https://onco.cc/bottlenecks/b-trial-design/)
- journals: [JAMA Internal Medicine](https://onco.cc/journals/jama-internal-medicine/)
- people: [Christopher M. Booth](https://onco.cc/people/christopher-booth/), [Ian F. Tannock](https://onco.cc/people/ian-tannock/)

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