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AR and Beyond: ctDNA Maps Resistance Evolution in mCRPC

Pradeep S Chauhan1,2, Russell K Pachynski3,4,5, Christopher A Maher3,4,6

  • 1Department of Radiation Oncology, Mayo Clinic, Rochester, Minnesota.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|April 17, 2026
PubMed

Insights

Longitudinal plasma cell-free DNA profiling in metastatic castration-resistant prostate cancer (mCRPC) shows distinct resistance pathways. Rapid progression is linked to non-androgen receptor (AR) alterations, while delayed progression involves AR amplification and DNA evolution, guiding targeted therapies.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Metastatic castration-resistant prostate cancer (mCRPC) poses significant treatment challenges.
  • Understanding resistance mechanisms is crucial for improving patient outcomes.
  • Plasma cell-free DNA (cfDNA) offers a non-invasive window into tumor evolution.

Purpose of the Study:

  • To investigate longitudinal cfDNA alterations in mCRPC patients.
  • To differentiate resistance trajectories based on cfDNA profiles.
  • To identify potential biomarkers for guiding treatment strategies.

Main Methods:

  • Analysis of plasma cfDNA from patients in the phase 3 Alliance A031201 trial.
  • Longitudinal monitoring of cfDNA to track genomic changes over time.
  • Detection of alterations including non-androgen receptor (AR) mutations, AR amplifications, structural rearrangements, and extrachromosomal DNA (ecDNA).

Main Results:

  • Rapid progressors exhibited non-AR alterations, suggesting intrinsic resistance.
  • Delayed progressors demonstrated progressive AR amplifications and structural rearrangements.
  • Extrachromosomal DNA-associated evolution was observed in delayed progressors.
  • Distinct cfDNA profiles correlated with different resistance mechanisms.

Conclusions:

  • Longitudinal cfDNA profiling reveals divergent resistance pathways in mCRPC.
  • Findings support the stratification of patients based on AR-dependent and AR-independent resistance mechanisms.
  • Biomarker-guided therapeutic strategies can be developed to target specific resistance states.

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