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

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.