Association of PARP inhibitor treatment on the prevalence and progression of clonal hematopoiesis in patients with advanced prostate cancer

Catherine H. Marshall, Lukasz P. Gondek, Violet Daniels, Changxue Lu, Sergiu Pasca, Jiajun Xie, Mark C. Markowski, Channing J. Paller, Laura A. Sena, Samuel R. Denmeade, Jun Luo, Emmanuel S. Antonarakis

Research output: Contribution to journalArticlepeer-review

Abstract

Background: Poly ADP-ribose polymerase (PARP) inhibitors are approved for the treatment of some men with advanced prostate cancer. Rare but serious side effects include myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). The impact of PARP inhibitors on clonal hematopoiesis (CH), a potential precursor lesion associated with MDS and AML, is incompletely understood in prostate cancer. We hypothesized that PARP inhibitors would increase CH prevalence and abundance. Methods: We prospectively enrolled participants with advanced prostate cancer treated with PARP inhibitors. The presence of CH was assessed from leukocytes using an ultra-deep error-corrected dual unique molecular identifiers sequencing method targeting 49 genes most commonly mutated in CH and myeloid malignancies. Variant allele frequencies (VAF) of ≥0.5% were considered clinically significant. Blood samples were collected before and after PARP inhibitor treatment. Results: Ten men were enrolled; mean age of 67 years. Six patients had Gleason 7 disease, and four had Gleason ≥8 disease at diagnosis. Nine had localized disease at diagnosis, and eight had prior treatment with radiation. The mean time between pre- and post-treatment blood samples was 11 months (range 2.6–31 months). Six patients (60%) had CH identified prior to PARP inhibitor treatment, three with multiple clones. Of 11 CH clones identified in follow-up, 5 (45%) appeared or increased after treatment. DNMT3A, TET2, and PPM1D were the most common CH alterations observed. The largest post-treatment increase involved the PPM1D gene. Conclusion: CH alterations are frequently found after treatment with PARP inhibitors in patients with prostate cancer and this may be one mechanism by which PARP inhibitors lead to increased risk of MDS/AML.

Original languageEnglish (US)
Pages (from-to)954-958
Number of pages5
JournalProstate
Volume84
Issue number10
DOIs
StateAccepted/In press - 2024

Bibliographical note

Publisher Copyright:
© 2024 Wiley Periodicals LLC.

Keywords

  • PARP inhibitors
  • clonal hematopoiesis
  • prostate cancer

PubMed: MeSH publication types

  • Journal Article

Fingerprint

Dive into the research topics of 'Association of PARP inhibitor treatment on the prevalence and progression of clonal hematopoiesis in patients with advanced prostate cancer'. Together they form a unique fingerprint.

Cite this