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

SIMPLE SUMMARY: Prostate cancer is a very common disease in men. Nowadays several life-prolonging therapies are available, also efficient in the metastatic setting. However, it is important to choose the best approach for each patient, and in this context molecular biomarkers are fundamental. Baseline high circulating tumor DNA (ctDNA) fraction in plasma and androgen receptor (AR) copy number (CN) gain correlates with worse outcomes. This study investigates correlation between PSA response endpoints, plasma DNA analysis and progression free/overall survival, underling the importance of a multimodal approach to early predict outcome. 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.