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

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

doi:10.1172/jci.insight.196505

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

Ossian Longoria,¹ Jan Rekowski,² Santosh Gupta,³ Nick Beije,¹ Klaus Pantel,⁴ Eleni Efstathiou,⁵ Cora Sternberg,⁶ Daniel Castellano,⁷ Karim Fizazi,⁸ Bertrand Tombal,⁹ Adam Sharp,¹ Oliver Sartor,¹⁰ Sandrine Macé,¹¹ Christine Geffriaud-Ricouard,¹¹ Richard Wenstrup,³ Ronald de Wit,¹² and Johann de Bono¹

Published November 4, 2025 - More info

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Abstract

BACKGROUND. Predictive 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.

METHODS. The CARD trial randomized subjects 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 pre-planned biomarker analysis, CTCs were isolated from blood samples obtained at baseline; cycle two, and 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 (PRR) were assessed.

RESULTS. High 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 to ARPI.

CONCLUSION. This preplanned biomarker analysis of CARD 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 REGISTRATION. CARD ClinicalTrials.gov number, NCT02485691.

FUNDING. Funded by Sanofi and Epic Sciences.

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

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

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