Genetic Alterations Detected in Cell-Free DNA Are Associated With Enzalutamide and Abiraterone Resistance in Castration-Resistant Prostate Cancer.

Purpose: Androgen receptor () gene alterations, including ligand-binding domain mutations and copy number (CN) gain, have yet to be fully established as predictive markers of resistance to enzalutamide and abiraterone in men with metastatic castration-resistant prostate cancer (mCRPC). The goal of this study was to validate gene alterations detected in cell-free DNA (cfDNA) as markers of enzalutamide and abiraterone resistance in patients with mCRPC.

Methods: Patients with mCRPC (N = 62) were prospectively enrolled between 2014 and 2018. Blood was collected before therapies-enzalutamide (n = 25), abiraterone (n = 35), or enzalutamide and abiraterone (n -and at disease progression. We used deep next-generation sequencing to analyze cfDNA for sequence variants and CN status in and 45 additional cancer-associated genes. Primary end points were prostate-specific antigen response, progression-free survival (PFS), and overall survival (OS).

Results: Elevated tumor-specific cfDNA (circulating tumor DNA) was associated with a worse prostate-specific antigen response (hazard ratio [HR], 3.17; 95% CI, 1.11 to 9.05; = .031), PFS (HR, 1.76; 95% CI, 1.03 to 3.01; .039), and OS (HR, 2.92; 95% CI, 1.40 to 6.11; .004). ligand-binding domain missense mutations (HR, 2.51; 95% CI, 1.15 to 5.72; = .020) were associated with a shorter PFS in multivariable models. CN gain was associated with a shorter PFS; however, significance was lost in multivariable modeling. Genetic alterations in tumor protein p53 (HR, 2.70; 95% CI, 1.27 to 5.72; .009) and phosphoinositide 3-kinase pathway defects (HR, 2.62; 95% CI, 1.12 to 6.10; .026) were associated with a worse OS in multivariable models.

Conclusion: These findings support the conclusion that high circulating tumor DNA burden is associated with worse outcomes to enzalutamide and abiraterone in men with mCRPC. Tumor protein p53 loss and phosphoinositide 3-kinase pathway defects were associated with worse OS in men with mCRPC. status associations with outcomes were not robust, and additional validation is needed.