Liquid Biopsy Identifies Taxane Resistance and Clonal Selection in Castration-Resistant Prostate Cancer

Purpose: Taxanes are life-prolonging treatments for patients with advanced prostate cancer. However, treatment resistance and lethal disease invariably develop. Here we used liquid biopsies to identify and characterize resistance to cabazitaxel. Experimental Design: We analyzed serial plasma from patients with metastatic castration-resistant prostate cancer treated with cabazitaxel in a prospective biomarker study (NCT03381326, N = 97). ctDNA was studied using a bespoke, targeted genomic test (PCF_SELECT). Clinical and molecular variables were evaluated for associations with overall survival (OS) and radiographic progression-free survival (rPFS). Results: Patients categorized by median ctDNA fraction had progressively worse survival for ctDNA-negative versus-low versus-high patients (median OS: 26.8, 12.4, and 8.2 months; median rPFS: 8.0, 5.3, and 3.1 months). A ctDNA fraction increase at cycle 3 compared with patients who remained ctDNA negative associated with shorter OS [median, 7.5 vs. 29.9 months; HR, 4.60 (95% confidence interval, 2.06–10.28), P < 0.0001] and rPFS [median, 2.6 vs. 8.2 months; HR, 3.73 (95% confidence interval, 1.75–7.93), P < 0.0001]. Plasma DNA collected at progression on an androgen receptor pathway inhibitor was enriched for alterations in the androgen receptor gene, whereas after a taxane (docetaxel before cabazitaxel or after cabazitaxel), there was enrichment of copy-number gains of genes sited on chromosome 3 (ATR, PIK3CB, MLH1, and FANCD2) or involved in cell cycle regulation, including mutually exclusive alterations in CCND1 and CDKN1B. Conclusions: Sequential liquid biopsy identifies ctDNA features associated with treatment benefit in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel. There was overlap of gene alterations selected for at progression on docetaxel or cabazitaxel, in part explaining cross-resistance.