Today’s molecular residual disease (MRD) assays for solid tumors, which test for circulating tumor DNA (ctDNA), are actively enabling precision clinical care. The level of ctDNA detectable in a patient’s blood offers a real-time, sensitive measure of cancer presence and activity, enabling more personalized treatment decisions.
In the coming years, a subset of MRD tests are likely to play a transformational role upstream of patient care as well. If regulatory bodies accept ctDNA-based tests as primary surrogate endpoints in solid tumor trials, these organizations will influence which therapeutic candidates are developed in the first place, and for whom.
MRD-based early endpoints will reshape the cancer treatment landscape
The acceptance of MRD testing as a primary surrogate endpoint could resolve a long-standing limitation on cancer research. Conventional clinical development paradigms rely on late-occurring endpoints — such as overall survival and progression-free survival — as determined by serial radiographic scans. While clinically meaningful, these endpoints are best suited to assessing the efficacy of single agents for late-stage disease.
Heterogeneous disease progression, delayed time to clinical event, and post-trial interventions can blur the relationship between an investigational therapy and observed outcomes, making development of some promising interventions operationally or economically infeasible. These include therapies intended for early-stage settings and adaptive interventions, in which an individual cancer’s sensitivity or resistance to treatment informs the therapeutic approach. [1]
In the future, regulatory approval of a sensitive early endpoint for solid tumors could enable more efficient evaluation of novel therapies in early-stage disease, supporting patient populations with the fewest options to access cutting-edge treatments. MRD tests are well positioned to make this future a reality. While ctDNA has not yet been accepted as a primary endpoint, 2024 guidance from the U.S. Food and Drug Administration provided sponsors with a framework for incorporating ctDNA into early-stage solid tumor trials. [2]
The growing consensus among researchers, regulators and medical practitioners is that ctDNA, as measured by MRD assays, is a promising predictive biomarker for cancer response. As long as the ctDNA dynamics of the target population are well understood, and a ctDNA-based endpoint appropriately defined for that population, MRD may demonstrate superior sensitivity than existing standards for solid tumors, including radiographic imaging and tissue biopsy. Already, the prognostic value of MRD testing is well established across solid tumor types, and evidence of predictive value for long-term clinical outcomes across tumor types is accumulating. [3,4]
However, for a ctDNA-based endpoint to achieve approval as a primary surrogate endpoint, it will need to clear significant evidentiary bars that will require coordinated and long-term investment by diverse stakeholders, including MRD companies.
In the future, regulatory approval of a sensitive early endpoint for solid tumors could enable more efficient evaluation of novel therapies in early-stage disease, supporting patient populations with the fewest options to access cutting-edge treatments.
Collective efforts are essential to early endpoint approval
From a regulatory perspective, the consequences of approving a harmful or ineffective therapy based on an inadequate surrogate are more consequential than delaying approval of a potentially beneficial treatment pending additional evidence. Consequently, biomarkers proposed as primary surrogate endpoints must demonstrate a robust and reproducible relationship with patient outcomes.
This is harder to establish than a biomarker’s prognostic value, which predicts a disease’s natural history independent of specific treatment and can be established with observational natural history data. In contrast, predictive value requires predicting the long-term clinical outcomes of a specific therapeutic intervention, which requires a precise definition and a randomized controlled trial. [5]
The specific relationship between ctDNA levels and patient outcomes may vary based on the context of tumor, the treatment, the patient population and the specifications of the MRD test. Consequently, the optimal MRD-based endpoint for one scenario may not generalize to others.6 For instance, in early stages of disease, prolonged ctDNA clearance may be predictive of treatment benefit using an MRD test with a very low limit of detection (1-10 parts per million), but inappropriate if the limit of detection is higher (100 parts per million). In late-stage disease, a test’s reliable quantification of ctDNA over the course of clonal evolution and diversification may be a more important determiner of predictive value. [6]
Regulatory approval is extremely hard to achieve, due to high evidentiary standards and the context-dependent nature of endpoint definitions. Meeting these standards will require the collaboration and pooling of data to develop consensus standards for MRD test performance and indication-specific endpoint definitions.
Consortiums capable of integrating meta-data across trials, assay platforms and heterogeneous patient populations will be central to producing the consensus and scale of evidence needed for the first regulatory approval of ctDNA as an early endpoint for a solid tumor trial. In recent years, Friends of Cancer Research have coordinated programs establishing ctDNA as a predictive marker in non-small cell lung cancer, and other consortia have done the same for muscle-invasive bladder cancer. [3,4]
If efforts to approve ctDNA as a primary surrogate endpoint succeed, an MRD company's early involvement will offer them a long-term competitive advantage in the market
Who should set the standard for ctDNA-based early endpoints?
The subset of companies who invest in these consortium-driven efforts will help define the regulatory standards against which future MRD tests will be judged. If efforts to approve ctDNA as a primary surrogate endpoint succeed, an MRD company’s early involvement will offer them a long-term competitive advantage in the market. However, in the short term, these companies may be better served by building durable value within clinical practice as it currently exists. Moreover, some MRD methodologies are more inherently suited to support outcomes assessment than others. For instance, an ultra-sensitive tumor-informed approach is more suitable for outcomes assessment in early-stage disease than a comparatively inexpensive, but less sensitive, tumor-naive approach.
For developers who do decide to compete to define the role of MRD as an early endpoint, their business strategy may diverge from a typical commercial playbook. Participation in multi-stakeholder efforts requires establishing trust with academics, clinical developers and regulators, as well as investing in the infrastructure to support those partnerships. It also may require informational exchange with competitors in service of pooled, cross-trial data that predictive evidence and consensus definitions require. This runs counter to the ingrained mindset of companies within a category built on protecting an edge.
Ultimately, MRD companies must align their ambitions with their strengths, and intentionally design their business to support their chosen path. No path is inherently more legitimate than another, but each calls for distinct long-term strategies that should be reflected in a company’s storytelling and the audiences to whom they speak. In fact, many developers are likely better served focusing their efforts on deepening their already tangible impact on medical practice — refining clinical utility evidence, and communicating value to clinicians and patients — rather than aligning their business strategy with a collaborative effort needed to achieve regulatory expectations.
MRD companies must align their ambitions with their strengths.
At HDMZ, our role is to help companies articulate the future a business is building toward, and use strategic communications and relationship-building to help them get there faster. Whether an MRD company is working to define the next clinical endpoint or transform the standard of care in recurrence monitoring, getting the story right will determine who is still standing when the next chapter is written.
References
- Gouda MA, Janku F, Wahida A, et al. Liquid Biopsy Response Evaluation Criteria in Solid Tumors (LB-RECIST). Ann Oncol. 2024;35(3):267-275. doi:10.1016/j.annonc.2023.12.007
- FDA. Use of Circulating Tumor Deoxyribonucleic Acid for Early-Stage Solid Tumor Drug Development; Guidance for Industry; Availability. FDA; 2024. Accessed June 25, 2026. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/use-circulating-tumor-deoxyribonucleic-acid-early-stage-solid-tumor-drug-development-guidance
- Andrews HS, Zariffa N, Nishimura KK, et al. ctDNA Clearance as an Early Indicator of Improved Clinical Outcomes in Advanced NSCLC Treated with TKI: Findings from an Aggregate Analysis of Eight Clinical Trials. Clin Cancer Res. 2025;31(11):2162-2172. doi:10.1158/1078-0432.CCR-24-3612
- Gao X, Qi W, Li J, et al. Prognostic and predictive role of circulating tumor DNA detection in patients with muscle invasive bladder cancer: a systematic review and meta-analysis. Cancer Cell Int. 2025;25:75. doi:10.1186/s12935-025-03707-z
- Sharma R, Gulati A, Chopra K. Era of surrogate endpoints and accelerated approvals: a comprehensive review on applicability, uncertainties, and challenges from regulatory, payer, and patient perspectives. Eur J Clin Pharmacol. 2025;81(5):605-623. doi:10.1007/s00228-025-03822-w
- Bartolomucci A, Nobrega M, Ferrier T, et al. Circulating tumor DNA to monitor treatment response in solid tumors and advance precision oncology. npj Precis Onc. 2025;9(1):84. doi:10.1038/s41698-025-00876-yt-guidance.
