Clonal hematopoiesis in the phase 3 Alliance A031201 trial of metastatic castration resistant prostate cancer (mCRPC) treated with androgen receptor (AR)-targeted therapies.
Authors: Jensen Jeffrey Lee , Bobek Olivia , Chan Irenaeus Chi-Chung , Hillman David W. , Heller Glenn , Druley Todd E. , Morris Michael J. , Milowsky Matthew I. , Beltran Himisha , BOLTON KELLY L. , Coombs Catherine Callaghan 
Published: June 2023

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Background: Somatic mutations in hematopoietic progenitor cells accumulate with age leading to clonal expansion in a process called clonal hematopoiesis (CH). CH increases the risk of developing myeloid neoplasms and shortens overall survival (OS), primarily linked to increased cardiovascular (CV) mortality. The impact of CH in metastatic solid cancers has been conflicting, with shorter OS in a broad cancer cohort but prolonged OS in metastatic colorectal cancer, which may be influenced by prior cytotoxic therapy that can promote emergence of CH. As AR pathway inhibitors (ARPIs) are associated with CV adverse events (AE), exploring the impact of CH in patients (pts) with mCRPC is of interest. Methods: A 9 gene targeted DNA sequencing panel designed to capture common CH mutations ( DNMT3A, TET2, ASXL1, PPM1D, TP53, CHEK2, SRSF2, SF3B1, JAK2) was applied to pre-treatment peripheral blood samples of 957 pts enrolled in the Alliance A031201 phase 3 trial of enzalutamide versus enzalutamide plus abiraterone/prednisone in the first line mCRPC setting. No difference in OS was found between treatment arms. The primary endpoint was the impact of CH on OS; secondary and exploratory endpoints included progression-free survival (PFS) and associations with baseline comorbidities and AEs (hematologic and CV). Cox proportional-hazards and logit models were adjusted for treatment arm, age, and radiation therapy (RT). Results: CH was common with 57% of pts having low CH (VAF>0.5% in 1+ mutation, L-CH), 24% having standard CH (VAF>2%, CH), and 7% having high CH (VAF>10%, H-CH). 4% of pts had 2+ CH mutations and 1% had 3+ mutations. Patients with CH were older (73.1 vs 70.2) and had higher rates of prior RT (58.4% vs 55.7%) and prior chemotherapy (3.9% vs 2.2%). No differences in OS were detected in pts with L-CH, CH, or H-CH. Similarly, no differences in PFS or baseline CV comorbidities were seen in any CH group. Pts with H-CH and TET2-mutated CH had statistically higher odds of any CV event (adjusted p=0.0004 and p=0.010, respectively) There was also a difference in the occurrence of major adverse CV events (MACE) by H-CH status (5.8% vs. 1.9%, adjusted p=0.042), while there was no difference seen for CH (3.4% vs 1.8%, adjusted p=0.147). Regarding hematologic AEs, one pt with a TP53 mutation (VAF 0.94%) developed myelodysplastic syndrome. Conclusions: CH did not affect OS or PFS in pts with mCRPC treated with ARPIs in the A031201 trial. However, CH with VAF>10% and TET2-mutated CH were associated with an increased rate of all CV AEs, suggesting an additive effect of ARPI therapy and CH on adverse CV outcomes. Confirmatory studies are warranted to assess whether CH should be considered in the risk-benefit discussion for pts receiving ARPIs.