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. We here used liquid biopsies to identify and characterize resistance to cabazitaxel. EXPERIMENTAL DESIGN: We analysed serial plasma from metastatic castration-resistant prostate cancer patients treated with cabazitaxel in a prospective biomarker study (NCT03381326, N=97). Circulating tumor DNA (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 (median OS: 26.8, 12.4, 8.2 months; median rPFS: 8.0, 5.3, 3.1 months). A ctDNA fraction increase at cycle 3 compared to patients who remained ctDNA negative associated with shorter OS (median 7.5 versus 29.9 months, HR, 4.60 [95% CI, 2.06-10.28], p<0.0001) and rPFS (median 2.6 versus 8.2 months, HR 3.73 [95% CI, 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 (AR) gene whilst, after a taxane (docetaxel pre-cabazitaxel or post-cabazitaxel), there was enrichment of copy number gains of genes sited on chromosome 3 (ATR, PIK3CB, MLH1,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 mCRPC patients treated with cabazitaxel. There was overlap of gene alterations selected for at progression on docetaxel or cabazitaxel, in part explaining cross-resistance.