Baseline Plasma Tumor DNA (ctDNA) Correlates with PSA Kinetics in Metastatic Castration-Resistant Prostate Cancer (mCRPC) Treated with Abiraterone or Enzalutamide

Abstract

Background: Baseline high circulating tumor DNA (ctDNA) fraction in plasma and androgen receptor (AR) copy number (CN) gain identify mCRPC patients with worse outcomes. This study aimed to assess if ctDNA associates with PSA kinetics. Methods: In this prospective biomarker study, we evaluate ctDNA fraction and AR CN from plasma samples. We divided patients into high and low ctDNA level and in AR gain and AR normal. Results: 220 baseline samples were collected from mCRPC treated with abiraterone (n = 140) or enzalutamide (n = 80). A lower rate of PSA decline ≥ 50% was observed in patients with high ctDNA (p = 0.017) and AR gain (p = 0.0003). Combining ctDNA fraction and AR CN, we found a different median PSA progression-free survival (PFS) among four groups: (1) low ctDNA/AR normal, (2) high ctDNA/AR normal, (3) low ctDNA/AR gain, and (4) high ctDNA/AR gain (11.4 vs. 5.0 vs. 4.8 vs. 3.7 months, p < 0.0001). In a multivariable analysis, high ctDNA, AR gain, PSA DT, PSA DT velocity remained independent predictors of PSA PFS. Conclusions: Elevated ctDNA levels and AR gain are negatively and independently correlated with PSA kinetics in mCRPC men treated with abiraterone or enzalutamide.

Cell-Free DNA Genomic Profiling and Its Clinical Implementation in Advanced Prostate Cancer

“…AR amplification is an important mechanism of castration resistance and an adverse prognostic factor occurring in 40% of CRPC but almost never in CSPC [ 42 ]. We detected AR amplifications in 31% of mCRPC patients, in agreement with previous reports [ 43 ]. Due to the small size of our panel, gene losses could not be investigated, which is one of our assay’s limitations.…”

Towards clinical implementation of circulating tumor DNA in metastatic prostate cancer: Opportunities for integration and pitfalls to interpretation

“…However, even when accounting for these poor-risk clinical features, higher pretreatment cfDNA concentration and ctDNA% independently predicts shorter progression-free and overall survival in patients commencing contemporaneous systemic therapies. These associations are evident in men receiving next-generation ARPIs such as abiraterone and enzalutamide (5,(40)(41)(42)(43)(44)(45), as well as taxane cytotoxic therapies docetaxel and cabazitaxel (16,39,46,47). Less well understood is the precise relationship between these metrics and life expectancy.…”

Evolving insights in blood-based liquid biopsies for prostate cancer interrogation

“…Several studies have shown an association between elevated baseline cfDNA concentrations and ctDNA% values (the proportion of ctDNA in total cfDNA) and reduced PFS and OS in mCRPC patients treated with ARSI (e.g., enzalutamide, abiraterone) and chemotherapy (e.g., docetaxel, cabazitaxel) [ 49 – 51 ]. Furthermore, it has been reported that patients with mCRPC patients who exhibit persistent ctDNA levels after four weeks of initial treatment with ARSI are at a higher risk of developing acquired resistance within six months of commencing treatment, resulting in shorter PFS and OS outcomes [ 51 ].…”