UCA1 copy number gain in serum cfDNA predicts next-generation antiandrogen resistance in metastatic castration-resistant prostate cancer.

Enzalutamide (ENZA) is a second-generation antiandrogen therapy that provides overall survival (OS) benefit for prostate cancer (PC) patients. However, many patients have baseline or develop resistance to ENZA. Currently, no biomarkers are used in clinical decision making to predict the efficacy of ENZA therapy. We aimed to identify cell-free DNA (cfDNA) biomarkers for metastatic castration-resistant prostate cancer (mCRPC) predictive to ENZA response. Comparative whole-exome and transcriptome sequencing was performed on three ENZA-resistant and parental ENZA-sensitive PC cell line pairs. Bioinformatic analysis identified UCA1, ORM1, and androgen receptor (AR) as candidate markers for serum cfDNA testing. Digital droplet PCR was used to analyze UCA1, ORM1 and AR in cfDNA from serum samples of mCRPC patients who underwent ENZA (n = 20), abiraterone (ABI; n = 20) and 40 docetaxel (DOC; n = 40) treatment. UCA1 copy number gain was significantly associated with reduced OS in ENZA-treated patients (p = 0.030). AR gain correlated with poorer OS in ABI-treated patients (p = 0.039), whereas no association was observed in DOC-treated patients. Normal AR and UCA1 levels were associated with significantly better OS in ENZA and ABI-treated patients. These findings suggest that UCA1 gain may predict reduced efficacy of ENZA treatment, while AR gain indicates decreased effectiveness of ABI but not ENZA and DOC therapies. These results may help support therapeutic decisions in the clinical settings.