Effect of enzalutamide and bipolar androgen therapy on clonal hematopoiesis and clinical outcomes among men with metastatic castration resistant prostate cancer.

Abstract

229 Background: Clonal hematopoiesis (CH) is frequently found in men with advanced prostate cancer and is associated with prior radiation, PARP inhibitors, and radioligand therapy. The effect of hormonal therapies on CH, the prognostic significance, and association with androgen receptor (AR) alterations in prostate cancer is not well established. Methods: This is a secondary analysis of the TRANSFORMER clinical trial (NCT02286921). 195 men with metastatic castration resistant prostate cancer (mCRPC) were randomly assigned 1:1 to enzalutamide or bipolar androgen therapy (BAT). Only patients with paired samples (baseline and 3-month) were included in this study. The presence of CH was assessed from leukocytes using an ultra-deep duplex sequencing targeting 49 genes most commonly mutated in CH and myeloid malignancies. To minimize false positive results, our initial filtering strategy included only variants present at any timepoint at VAF ≥ 1%. The presence of the same variant at other timepoint was confirmed manually in VCF or BAM files. Results: 157 patients with paired samples were included and had more favorable outcomes than those who did not have paired samples. CH was detected in 84 (54%) patients and most (n=42) had a single CH clone. Mutations in DNMT3A (n=38), PPM1 D (n=18), TET2 (n=18), ASXL 1 (n=9), and TP53 (n=8) were the most common. There was no difference in the presence of baseline CH by treatment arm (55% in BAT arm and 53% in enza arm; P=0.8). Those with CH were older (median age 74 vs 69, P<0.01) and had poorer functional status (ECOG >0 64% compared to 36%, P=0.05). There was no significant difference in the progression or development of CH over 3-months (P=0.6) and no association with the presence of AR alterations at baseline. After adjusting for age, there was no difference in overall survival between those with or without CH at baseline for the cohort overall (HR 1.41, 0.88-2.25; P=0.15). However, among those who received BAT, either as initial therapy or crossover, CH at baseline was associated with a higher risk of death (HR 1.87, 95% CI 1.05 – 3.32; P=0.34) after adjusting for age and ECOG performance status at baseline. Conclusions: Short term treatment with enzalutamide or BAT do not influence CH dynamics in men with mCRPC. CH was associated with poorer prognosis among those who received BAT and may help identify patients less likely to benefit from BAT therapy.