Clonal hematopoiesis after 177Lu-PSMA-617 radioligand therapy in prostate cancer

Background: Clonal hematopoiesis (CH) is a precursor state linked to risk of hematological 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). Methods: 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 deep error-corrected 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. 178 patients had a baseline sample; 107 (60 177Lu-PSMA-617; 47 cabazitaxel) had paired baseline–progression samples (median interval 29 versus 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 number of 177Lu-PSMA-617 cycles received (+2.9% per cycle; P=0.002). Conclusion: 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.