Clinical Impact and Dynamics of Clonal Hematopoiesis with ¹⁷⁷ Lu-PSMA-617 Therapy in Advanced Prostate Cancer

The prevalence, clinical impact, and clonal dynamics of clonal hematopoiesis (CH) in patients receiving ¹⁷⁷Lu-PSMA-617 (LuPSMA) for metastatic castration-resistant prostate cancer (mCRPC) are unknown. <b>Methods:</b> Targeted next-generation sequencing of 21 genes recurrently mutated in CH was performed on DNA extracted from the peripheral blood of patients who received at least 4 cycles of LuPSMA for mCRPC at our institution between 2022 and 2023. Pathogenic somatic mutations with a variant allele fraction of at least 1% were identified using a standardized pipeline. Clinical outcomes pertaining to efficacy (overall survival [OS], measured from date of planned cycle 5) and hematologic toxicity of LuPSMA were collected from the electronic medical record. <b>Results:</b> Fifty patients treated with LuPSMA were eligible, with a median follow-up of 23 mo. At least 1 CH variant was detected in 33 patients (66%). The most common mutations were <i>TET2</i> (<i>n</i> = 16), <i>PPM1D</i> (<i>n</i> = 15), and <i>DNMT3A</i> (<i>n</i> = 6). OS was similar in patients with or without CH (12-mo OS, 92% vs. 80%; hazard ratio, 0.89; 95% CI, 0.3–2.68). There was a trend toward greater hematologic toxicity in patients with CH, with a greater need for growth factor support (12% vs. 0%). In patients with serial samples available, the emergence of new clones or expansion of preexisting CH variants was detected in most patients, particularly with <i>PPM1D</i> and <i>TP53</i>-mutant clones. The key limitation was the small sample size and short follow-up. <b>Conclusion:</b> CH was highly prevalent and tended to lead to greater hematologic toxicity in patients with mCRPC receiving LuPSMA. Expansion or emergence of DNA damage repair CH clones was very common during and after LuPSMA therapy. Further study of the impact of CH on radiopharmaceutical therapy, particularly when used in earlier prostate cancer disease settings, is warranted.