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

Abstract

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. 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). 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. 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.