Mutations in hematopoietic progenitor cells accumulate with age leading to clonal expansion, termed clonal hematopoiesis (CH). CH in the general population is associated with hematopoietic neoplasms and reduced overall survival (OS), predominantly through cardiovascular adverse events (CVAE). Because androgen receptor pathway inhibitors (ARPI) used in metastatic castration-resistant prostate cancer (mCRPC) are also associated with CVAEs and because CH negatively impacted survival in an advanced solid tumor cohort, we hypothesized that CH in mCRPC may be associated with increased CVAEs and inferior survival.
A targeted DNA sequencing panel captured common CH mutations in pretreatment blood samples from 957 patients enrolled in Alliance A031201: a randomized trial of enzalutamide ± abiraterone/prednisone in the first-line mCRPC setting. The primary outcome was the impact of CH on OS; the secondary outcomes were progression-free survival (PFS) and CVAEs.
Baseline comorbidities were similar by CH status. No differences in OS/progression-free survival were detected regardless of treatment arm or the variant allele frequency threshold used to define CH [primary: 2% (normal-CH, N-CH); exploratory: 0.5% (low-CH) and 10% (high-CH, H-CH)]. Patients with H-CH (7.2%) and TET2-mutated N-CH (6.0%) had greater odds of any CVAE (14.5% vs. 4.0%; P = 0.0004 and 12.3% vs. 4.2%; P = 0.010, respectively). More major CVAEs were observed in patients with H-CH (5.8% vs. 1.9%; P = 0.042) and N-CH (3.4% vs. 1.8%; P = 0.147).
CH did not affect survival in patients with mCRPC treated with ARPIs in A031201. H-CH and TET2-mutated CH were associated with more CVAEs. These findings inform the risk/benefit discussion about ARPIs in mCRPC.
Clinical cancer research : an official journal of the American Association for Cancer Research. 2024 Sep 17 [Epub ahead of print]
Jeffrey L Jensen, Olivia Bobek, Irenaeus C C Chan, Brian C Miller, David W Hillman, Glenn Heller, Todd Druley, Andrew J Armstrong, Michael J Morris, Matthew I Milowsky, Himisha Beltran, Kelly L Bolton, Catherine C Coombs
University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina., Alliance Statistics and Data Management Center, Mayo Clinic, Rochester, Minnesota., Washington University School of Medicine, St. Louis, Missouri., Memorial Sloan Kettering Cancer Center, New York, New York., Duke Cancer Institute Center for Prostate and Urologic Cancer, Duke University, Durham NC USA., Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts., University of California Irvine, Irvine, California.