Clonal Hematopoiesis after 177Lu-PSMA-617 Radioligand Therapy in Prostate Cancer

Munzur, AD; Herberts, C; Kwan, EM; Emmett, L; Sandhu, S; Buteau, JP; Iravani, A; Joshua, AM; Francis, RJ; Lee, ST; Scott, AM; Martin, AJ; Stockler, MR; Zhang, AY; Williams, SG; Bernales, CQ; Donnellan, G; Koudjanian, M; Parekh, K; Bacon, JVW; Karsan, A; Azad, AA; Davis, ID; Hofman, MS; Wyatt, AW

Author(s): Munzur, AD; Herberts, C; Kwan, EM; Emmett, L; Sandhu, S; Buteau, JP; Iravani, A; Joshua, AM; Francis, RJ; Lee, ST; Scott, AM; Martin, AJ; Stockler, MR; Zhang, AY; Williams, SG; Bernales, CQ; Donnellan, G; Koudjanian, M; Parekh, K; Bacon, JVW; Karsan, A; Azad, AA; Davis, ID; Hofman, MS; Wyatt, AW;
Details: Publication Year 2026-07-01,Volume 32,Issue #13,Page 2644-2652
Journal Title: Clinical Cancer Research
Publication Type: Research article
Abstract: PURPOSE: Clonal hematopoiesis (CH) is a precursor state linked to risk of hematologic neoplasms and may be exacerbated by radiation exposure. We aimed to compare CH prevalence after the new radioligand therapy 177Lu-PSMA-617 versus the alternative standard-of-care cabazitaxel chemotherapy in metastatic castration-resistant prostate cancer (mCRPC). EXPERIMENTAL DESIGN: This post hoc correlative analysis used serial blood samples from TheraP (ANZUP 1603), a randomized phase II trial in docetaxel-refractory mCRPC. Cell-free DNA and leukocyte DNA underwent error-corrected deep targeted sequencing. CH mutations were called at variant allele frequency (VAF) ≥0.25%. Variants detected at progression but undetected at baseline were defined as treatment-emergent CH. A total of 178 patients had a baseline sample; 107 (60 177Lu-PSMA-617; 47 cabazitaxel) had paired baseline-progression samples (median interval, 29 vs. 27 weeks). RESULTS: Baseline CH was detected in 77% (138/178) of patients, with similar prevalence and gene distribution between arms. Treatment-emergent CH occurred more often after 177Lu-PSMA-617 than cabazitaxel [62% (37/60) vs. 40% (19/47); P = 0.03], and 83% (121/146) of all emergent mutations were detected after 177Lu-PSMA-617. The DNA damage response gene PPM1D accounted for 42% (51/121) of 177Lu-PSMA-617-emergent mutations, with odds ratios of 3.2 for any treatment-emergent CH and 5.4 for PPM1D, relative to cabazitaxel. CH clones expanded more frequently and to a greater magnitude with 177Lu-PSMA-617 (proportion expanding, 70.9% vs. 29.5%; P = 7.5 × 10-5), and increases in maximal CH VAF correlated with the number of 177Lu-PSMA-617 cycles received (+2.9% per cycle; P = 0.002). CONCLUSIONS: 177Lu-PSMA-617 strongly promotes CH, supporting integration of longitudinal monitoring for long-term hematologic sequelae as radioligand therapy is implemented earlier in prostate cancer care. See related commentary by Lückerath et al., p. 2527.
Publisher: American Association for Cancer Research
Keywords: Humans; Male; *Dipeptides/adverse effects/administration & dosage/therapeutic use; *Heterocyclic Compounds, 1-Ring/adverse effects/administration &; dosage/therapeutic use; *Prostatic Neoplasms, Castration-Resistant/pathology/radiotherapy/genetics/drug; therapy/blood; *Clonal Hematopoiesis/radiation effects/drug effects/genetics; *Radioisotopes/adverse effects; Aged; *Lutetium; Taxoids/adverse effects/administration & dosage; *Radiopharmaceuticals/adverse effects/administration & dosage; Middle Aged; Mutation; Prostate-Specific Antigen
Department(s): Medical Oncology; Cancer Imaging
Publisher's Version: https://doi.org/10.1158/1078-0432.Ccr-25-4001
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-02-26 02:13:19

Last Modified: 2026-07-07 05:56:14