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Updated: Jun 14, 2025

A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
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False-Positive Circulating Tumor DNA Results Do Not Explain Lack of Efficacy for PARP Inhibitors in Patients With

Jaleh Fallah1, Jianjin Xu1, Hee-Koung Joeng1

  • 1Center for Drug Evaluation and Research (CDER), U.S. Food and Drug Administration, Silver Spring, MD.

JCO Precision Oncology
|August 29, 2024
PubMed

Insights

False-positive circulating tumor DNA (ctDNA) results do not account for the lack of efficacy observed with poly (ADP-ribose) polymerase inhibitors (PARPi) in patients with metastatic castration-resistant prostate cancer (CRPC) who have ATM or CHEK2 mutations.

Area of Science:

  • Oncology
  • Genetics
  • Pharmacology

Background:

  • Metastatic castration-resistant prostate cancer (CRPC) is a significant clinical challenge.
  • Poly (ADP-ribose) polymerase inhibitors (PARPi) show efficacy in a subset of CRPC patients, particularly those with DNA repair gene mutations.
  • ATM and CHEK2 mutations are implicated in prostate cancer development and PARPi response.

Purpose of the Study:

  • To investigate whether false-positive circulating tumor DNA (ctDNA) results could explain the lack of response to PARPi in patients with ATM-mutated (ATMM) and CHEK2-mutated (CHEK2m) CRPC.
  • To assess the clinical significance of ctDNA detection timing and accuracy in relation to PARPi treatment outcomes.

Main Methods:

  • Retrospective analysis of ctDNA data from patients with ATMM and CHEK2m CRPC treated with PARPi.
  • Correlation of ctDNA results (including potential false positives) with treatment response, progression-free survival, and overall survival.

Main Results:

  • False-positive ctDNA results were identified but did not correlate with the observed lack of efficacy for PARPi.
  • The presence of specific mutations (ATMM, CHEK2m) remains a key factor, but other mechanisms likely contribute to PARPi resistance.

Conclusions:

  • False-positive ctDNA findings do not explain PARPi treatment failure in patients with ATMM and CHEK2m CRPC.
  • Further research is needed to elucidate mechanisms of PARPi resistance in this patient population, beyond ctDNA detection accuracy.

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