Surrogate Endpoints in Oncology

In drug development, an endpoint is a targeted outcome of a clinical trial that is statistically analyzed to help determine the efficacy and safety of the therapy being studied.¹ In oncology, overall survival (OS) is considered the “gold standard” of clinical endpoints.² OS tends to involve large clinical trial costs because it usually requires long-term follow-up to detect clinically meaningful differences. As a potential solution to increasing clinical trial costs, among other factors, surrogate endpoints have seen increasing use in clinical trials.  A surrogate endpoint (SEP) is a marker or measure that is thought to predict a clinical benefit but is not itself a measure of clinical benefit.³ SEPs are often used when a clinical endpoint is difficult or time-consuming to measure directly in a clinical trial. In oncology where disease progression and mortality are critical concerns, SEPs can enable expedited patient access to potentially life-saving therapies.

A large advantage of using SEPs is the accelerated pace of clinical research. Certain cancers may progress slowly, which can then make OS less effective as a primary endpoint in early or mid-stage trials. By using SEPs, sponsors can assess treatment effects earlier while reducing trial duration and cost. It is important to note that surrogate endpoints must be carefully validated to ensure they accurately predict long-term benefit instead of being a marker of short-term biological change.

Table 1 includes a non-exhaustive list of oncology surrogate endpoints with advantages, limitations, and regulatory considerations. A full list of surrogate endpoints within and outside of oncology can be found on the FDA website here.

Table 1. Advantages, Limitations, and Regulatory Considerations of Common Oncology Surrogate Endpoints^4,5,6(Alphabetical)

SEPs are classified into three categories: validated, reasonably likely, and candidate.⁷ The categories differ based on the strength of evidence linking the surrogate endpoint to true clinical benefit. Validated SEPs are supported by a “clear mechanistic rationale” and clinical data providing strong evidence that an effect on the SEP predicts a specific clinical benefit. Reasonably likely SEPs are supported by “strong mechanistic and/or epidemiologic rationale”, but the amount of clinical data available is not sufficient to show that they are a validated SEP. Candidate SEPs are under evaluation for their ability to predict clinical benefit. As seen in expedited programs such as Accelerated Approval, the FDA and other regulatory bodies use this classification framework to determine the acceptability of SEPs for regulatory decision-making of medications.  

A validated SEP has sound scientific evidence, usually from multiple randomized controlled trials, and shows that changes in the surrogate reliably predict changes in the desired clinical outcome. In oncology, pathologic complete response (PCR) in certain neoadjuvant breast cancer settings is a validated surrogate for event-free survival (EFS). Validated SEPs can be used to support traditional approvals because their ability to predict clinical benefit is well established. 

Reasonably likely SEPs have available evidence that suggests a correlation with clinical benefit, but the evidence is not yet definitive. These endpoints are often used in accelerated approval settings with the understanding that confirmatory trials must subsequently verify the predicted benefit. In oncology, progression-free survival (PFS) may be considered reasonably likely to predict OS in specific tumor types. At the same time, it is not universally accepted as a validated surrogate across all oncology indications. 

Candidate SEPs are investigational measures still undergoing evaluation. They are often used in early-phase clinical trials to generate hypotheses and assess biological activity, but they are not yet considered appropriate for regulatory decision-making. For example, circulating tumor DNA (ctDNA) clearance is an exploratory SEP that may, in the future, serve as a predictor of treatment efficacy but currently lacks robust validation across malignancies.

Table 2 organizes the common oncology surrogate endpoints by category, definition, and examples of FDA use cases.

Table 2. Common Surrogate Endpoints in Oncology and FDA Use Cases^4,8,9 (Alphabetical in Each Category)

The FDA’s Accelerated Approval pathway is a program that aims to expedite the approval of therapies for serious conditions with unmet medical needs.³ The approvals are based on effects on a surrogate endpoint that is “reasonably likely” to predict clinical benefit. In oncology, Accelerated Approval has played a major role in making innovative treatments available more quickly. This is important for aggressive cancers where delays in access can have direct consequences on health, including worsening conditions and increased medical costs. Accelerated Approval and SEPs can enhance drug development programs because sponsors can identify promising candidates earlier and deprioritize ineffective agents sooner. It is important to note that the use of SEPs under Accelerated Approval comes with the requirement that sponsors conduct post-marketing confirmatory trials to verify the anticipated benefit of their therapy. If sponsors fail to verify the anticipated benefit, they may risk withdrawal of their product’s respective indication. 

While SEPs can fast-track approval timelines, they carry the risk of overestimating benefit if the surrogate is weakly correlated with true clinical outcomes. Therapies have been approved based on SEPs but have failed to improve OS or QOL in confirmatory studies. As a result, the sponsor may proceed with a market withdrawal of the respective indication. For example, atezolizumab received accelerated approval for advanced triple-negative breast cancer but was withdrawn after a confirmatory study failed to show an improvement in both OS and PFS.¹⁰ In addition, relying on SEPs may complicate the understanding of the magnitude of real-world benefit. For example, improvements in measures such as tumor shrinkage may not translate into longer survival or better patient well-being.

Overall, surrogate endpoints play a critical role in modern drug development across therapeutic areas, including oncology. SEPs have a particularly important role in accelerated approval programs to expedite product approvals. While SEPs offer benefits for speed of approval and feasibility, their use demands careful scientific and regulatory scrutiny to ensure they truly reflect meaningful patient outcomes. A balanced approach, such as utilizing validated SEPs when possible, thoughtfully applying reasonably likely SEPs, and continuing research on candidate SEPs will help maximize both healthcare innovation and patient safety.

References:

1. US Department of Health and Human Services. National Institutes of Health. Toolkit For Patient-Focused Therapy Development: Endpoint. 2024.
2. Delgado A, Guddati AK. Clinical Endpoints in Oncology - a Primer. Am J Cancer Res. 2021;11(4):1121-1131.
3. US Food & Drug Administration. Accelerated Approval Program. 2024.
4. US Food & Drug Administration. Table of Surrogate Endpoints That Were the Basis of Drug Approval or Licensure. 2024.
5. Walia A, Haslam A, Prasad V. FDA Validation of Surrogate Endpoints in Oncology: 2005–2022. 2022; 34: 100364.
6. Cohen SA, Ahn DH. CancerNetwork. Is Clearance of ctDNA an Acceptable Surrogate End Point? 2024.
7. US Food & Drug Administration. Surrogate Endpoint Resources for Drug and Biologic Development. 2024.
8. US Food & Drug Administration. Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. Guidance for Industry; Final Guidance. 2018.
9. US Food & Drug Administration. Pathological Complete Response in Neoadjuvant Treatment of High-Risk Early-Stage Breast Cancer: Use as an Endpoint to Support Accelerated Approval. Guidance for Industry; Final Guidance. 2020.
10. Rosa K. OncLive. Roche Withdraws Atezolizumab PD-L1–Positive Metastatic TNBC Indication in the United States. 2021.

*Information presented on RxTeach does not represent the opinion of any specific company, organization, or team other than the authors themselves. No patient-provider relationship is created.