Clonal hematopoiesis (CH) in participants with metastatic castration-resistant prostate cancer (mCRPC) receiving ¹⁷⁷ Lu-PSMA-617 or cabazitaxel: An exploratory post-hoc analysis of a randomized phase II trial (TheraP; ANZUP 1603).

5020 Background: The prostate-specific membrane antigen (PSMA)-targeted radioligand [¹⁷⁷Lu]Lu-PSMA-617 ( 177 Lu-PSMA-617) is an effective new standard-of-care for mCRPC. Since radiation may cause CH, an age-related preleukemic condition, we hypothesized that 177 Lu-PSMA-617 drives an increase in CH compared to other mCRPC treatments. Here, we explored CH in the TheraP trial randomizing participants (pts) with docetaxel-refractory mCRPC to cabazitaxel or 177 Lu-PSMA-617 (NCT03392428). Methods: We performed targeted DNA sequencing with a CH gene panel on blood samples from trial baseline (n = 176) and disease progression (n = 103; 56 post- 177 Lu-PSMA-617, 47 post-cabazitaxel). Baseline CH mutations were detected in both cell-free DNA (cfDNA) and leukocyte DNA with variant allele frequency (VAF) ≥0.25%. Progression leukocyte DNA was unavailable at analysis, so progression CH mutations were identified via cfDNA only. We used Fisher’s exact test to compare proportions, and the Mann-Whitney U test for changes in VAF. Results: Data was evaluable in 174/176 pts with baseline samples, and 103/103 with progression samples. Median time between baseline and progression blood draws was 28 and 27 weeks for 177 Lu-PSMA-617 and cabazitaxel arms, respectively. CH was detected in 77% (135/174) of pts at baseline (median age: 72). 71 (41%) pts had baseline CH mutations with VAF≥2%. The most commonly mutated genes at baseline were DNMT3A (n = 67 pts, 38%), TET2 (n = 44, 25%), PPM1D (n = 26, 15%) and ASXL1 (n = 19, 11%), with no difference in gene mutation frequency between arms. At progression, new mutations of presumed CH origin were detected in 83% and 46% of 177 Lu-PSMA-617 and cabazitaxel pts, respectively (47 vs 22 pts, p=0.0001). The most frequently mutated gene at 177 Lu-PSMA-617 progression was the DNA damage repair gene PPM1D ; and new PPM1D CH mutations were 8 times more common after 177 Lu-PSMA-617 than cabazitaxel (p = 0.00032). Progression mutations in ATM or CHEK2 were also 5 times more commonly observed after 177 Lu-PSMA-617 (p = 0.01). Among CH variants concordantly detected at baseline and progression on 177 Lu-PSMA-617, the median VAF change for mutations in DNA damage repair genes was higher than in canonical CH genes DNMT3A , TET2 and ASXL1 (1.53% vs. 0.15%, p = 0.01). Conclusions: 177 Lu-PSMA-617 was associated with a greater number of new CH mutations, especially in DNA damage repair genes, compared to cabazitaxel. Whilst the clinical relevance of this finding in a population of patients with heavily-treated mCRPC is unclear, CH emergence and expansion may have implications as radioligand therapy is used as an earlier line of therapy. Clinical trial information: NCT03392428 .