Aslı D. Munzur, Cameron Herberts, Edmond M. Kwan, Louise Emmett, Shahneen Sandhu, James P Buteau, Amir Iravani, Anthony M. Joshua, Roslyn J. Francis, Sze-Ting Lee, A. Scott, Andrew Martin, Martin R. Stockler, A. Zhang, Scott G. Williams, Cecily Q. Bernales, Gráinne Donnellan, Melissa Koudjanian, Karan Parekh, Jack V.W. Bacon, Aly Karsan, Arun A. Azad, Ian D. Davis, Michael S. Hofman, Alexander W. Wyatt
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.