Journal Article

Chromosomal instability in circulating tumor cells and cabazitaxel resistance in metastatic castration-resistant prostate cancer

Pantel, Klaus, de Wit, Ronald, Rekowski, Jan, Fizazi, Karim, Longoria, Ossian, Gupta, Santosh, Castellano, Daniel, Beije, Nick, de Bono, Johann, Tombal, Bertrand, Macé, Sandrine, Efstathiou, Eleni, Sharp, Adam, Sternberg, Cora, Sartor, Oliver, Geffriaud-Ricouard, Christine, Wenstrup, Richard

2025

Overview

BACKGROUNDPredictive biomarkers to guide chemotherapy decisions for metastatic castration-resistant prostate cancer (mCRPC) are lacking. Preclinical studies indicate that circulating tumor cell (CTC) studies of chromosomal instability (CTC-CIN) can predict taxane resistance.METHODSThe CARD trial randomized individuals with mCRPC progressing within a year of treatment with an androgen receptor pathway inhibitor (ARPI; enzalutamide or abiraterone acetate plus prednisolone/prednisone) to cabazitaxel or the alternative ARPI. As a preplanned biomarker analysis, CTCs were isolated from blood samples obtained at baseline, cycle 2, and the end of treatment. Associations between baseline CTC and CTC-CIN counts with imaging-based progression-free survival (ibPFS), overall survival (OS), time to prostate-specific antigen (PSA) progression, RECIST 1.1 objective response rate (ORR), and PSA50 response rate were assessed. RESULTSHigh baseline CTC-CIN counts significantly associated with worse OS after adjustment for confounding variables (median OS, 15.3 vs. 8.9 months; univariate HR, 2.16; 95% CI, 1.52-3.06; P < 0.001; multivariate HR, 1.56; 95% CI, 1.01-2.43; P = 0.047). Detectable CTC-CIN counts at baseline may predict a lack of ibPFS and OS benefit when comparing cabazitaxel with ARPI. CONCLUSIONThis preplanned analysis of biomarker data from the CARD trial confirms that CTC-CIN counts are a clinically useful prognostic and predictive biomarker of taxane resistance in mCRPC. Detectable CTC-CIN at baseline defines a patient subpopulation with unmet clinical needs in which alternative therapeutics should be tested.TRIAL REGISTRATIONClinicalTrials.gov number NCT02485691.FUNDINGFunded by Sanofi and Epic Sciences.

• Publisher: American Society for Clinical Investigation
• Subject: Abiraterone Acetate - therapeutic use / Acetic acid / Aged / Androgen Receptor Antagonists - therapeutic use / Androgen receptors / Androgens / Antigens / Benzamides / Biomarkers / Biomarkers, Tumor / Cancer therapies / Castration / Chemotherapy / Chromosomal Instability / Clinical outcomes / Drug Resistance, Neoplasm - genetics / Genomic instability / Humans / Male / Medical prognosis / Metastases / Metastasis / Middle Aged / Morphology / Neoplastic Cells, Circulating - drug effects / Neoplastic Cells, Circulating - metabolism / Neoplastic Cells, Circulating - pathology / Nitriles / Patients / Phenylthiohydantoin - analogs & derivatives / Phenylthiohydantoin - therapeutic use / Prednisolone / Prednisone / Prednisone - therapeutic use / Prostate cancer / Prostate-specific antigen / Prostate-Specific Antigen - blood / Prostatic Neoplasms, Castration-Resistant - blood / Prostatic Neoplasms, Castration-Resistant - drug therapy / Prostatic Neoplasms, Castration-Resistant - genetics / Prostatic Neoplasms, Castration-Resistant - mortality / Prostatic Neoplasms, Castration-Resistant - pathology / Response rates / Taxanes / Taxoids - pharmacology / Taxoids - therapeutic use / Tumor cells / Tumors