Does circulating DNA tumor fraction add value to prostate-specific antigen in metastatic castration-resistant prostate cancer?

The introduction of advanced androgen receptor pathway inhibitors (ARPIs), taxane chemotherapy, radioligand therapy, and molecularly targeted treatments has notably enhanced progression-free survival (PFS), overall survival (OS), and quality of life (QoL) for men with metastatic castration-resistant prostate cancer (mCRPC). However, the disease continues to be fatal for most patients. Although it is known that Enzalutamide has only a modest effect after Abiraterone, it is commonly used, especially in patients with an aversion to chemotherapy. Predictive biomarkers to guide chemotherapy decisions for mCRPC are lacking. Since “one size does not fit all” predictive biomarkers are needed to better personalize treatment. Liquid biopsy, which detects circulating tumor DNA (ctDNA) in the blood, is an emerging technology with great potential to personalize treatment strategies.

Sweeney et al. evaluated ctDNA (1) in patients from the phase III IMbassador250 study (NCT03016312) of enzalutamide with or without atezolizumab after abiraterone (2). The authors evaluated a novel methodology, measuring the tumor fraction (TF) in the blood of ctDNA, most suitable for evaluating metastases, such as bone lesions, which are very common in mCRPC and often difficult to assess and biopsy in 759 patients.

This work is based on a few studies in a variety of solid tumor types that have shown an association between TF and a patient’s tumor burden (3-6). In addition, ctDNA appears to correlate with response to treatment and OS. The investigators analyzed banked plasma from patients at baseline C1D1 (494 passed quality control) and 408 had both C1D1 and C3D1 sequencing results evaluating early changes in the ctDNA TF. They employed a unique and comprehensive ctDNA TF calculation, which has been assessed across four different cancer types. This approach used hybrid capture next-generation sequencing (NGS) along with a combination of aneuploidy, variant allele frequency, canonical alterations, and sequencing read fragment lengths (5). This is a tissue-agnostic ctDNA platform from FoundationOne Liquid companion diagnostic (CDx) and performed in a Clinical Laboratory Improvement Amendments (CLIA) certified, College of American Pathologists (CAP)-accredited laboratory in Cambridge, MA, USA.

In this post-hoc analysis, patients with ctDNA TF at baseline had worse radiographic PFS (rPFS) than those with ctDNA-undetected (median: 4.6 vs. 11.4 months, P<0.001). The concordance between baseline ctDNA TF [0.58, standard error (SE): 0.56–0.59] and a 50% reduction in prostate-specific antigen (PSA50) was high, with the latter being more cost-effective and quicker to measure. On cycle 3, day 1 (C3D1), elevated ctDNA TF was linked to poorer OS [median: 13.6 vs. 22.5 months, hazard ratio (HR) =3.25, P<0.001], even when PSA levels were reduced.

Novel strategies are actively being developed to facilitate the rapid assessment of prognosis and therapeutic response. For example, analyzing ctDNA markers to monitor treatment response may yield additional insights beyond those provided by current gene-centric ctDNA assays (7). Future studies should evaluate the prognostic and predictive value of ctDNA TF relative to prostate-specific antigen (PSA), to determine whether ctDNA offers superior or equivalent predictive power. This could be done by comparing the C-index of PSA and ctDNA TF in predicting OS. Additionally, incorporating ctDNA TF into a Halabi-type model could reveal whether it enhances the model’s C-index for survival prediction beyond what is achieved by the Halabi model alone (8).

Tools to better personalize treatment and care are critical to enhance outcomes for cancer patients. New validated technologies are needed. The ctDNA assay is a promising strategy. The paper underscores the potential of liquid biopsy as a complementary tool to PSA testing, providing a more comprehensive view of disease progression and treatment response. Integrating both modalities could enable more informed clinical decision-making, helping to minimize the risks of overtreatment and undertreatment, and ultimately enhancing patient outcomes. This data adds to the literature (9) and shows the impact of ctDNA TF, complementary to PSA, providing a minimally invasive biomarker that can inform treatment outcomes and risk stratification, if it becomes available in National guidelines. Early detection of therapeutic resistance in cancer enables timely modification of treatment strategies, thereby limiting patient exposure to ineffective therapies and potentially improving clinical outcomes. Prospective biomarker-based trials are needed to validate these observations.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Translational Cancer Research. The article has undergone external peer review.

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-295/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-2025-295/coif). C.N.S. has received funds from Astellas Pharma, AstraZeneca, Bayer, Bristol-Myers Squibb/Medarex, Foundation Medicine, Genzyme, Gilead, Merck, MSD, Pfizer, Janssen, Roche, Medscape, UroToday, and Tolmar. M.H. has received funds from Bayer, Convergent, Astra Zeneca, MJH, RTP, PER, BMS and is a trustee, member of Board of Prostate Cancer, UK and member of Steering Committee, MOVEMBER Global Collaborative Program in Disease Progression. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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