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
, 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^*

^*Corresponding author for this work

Medical Oncology

Research output: Contribution to journal › Article › Academic › peer-review

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 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.

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 with ARPI.

CONCLUSION:

This 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 REGISTRATION:

ClinicalTrials.gov number NCT02485691.

Original language	English
Journal	JCI insight
Volume	10
Issue number	24
DOIs	https://doi.org/10.1172/jci.insight.196505
Publication status	Published - 4 Nov 2025

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Chromosomal instability in circulating tumor cells and cabazitaxel resistance in metastatic castration-resistant prostate cancerFinal published version, 1.36 MBLicence: CC BY

Cite this

Longoria, O., Rekowski, J., Gupta, S., Beije, N., Pantel, K., Efstathiou, E., Sternberg, C., Castellano, D., Fizazi, K., Tombal, B., Sharp, A., Sartor, O., Macé, S., Geffriaud-Ricouard, C., Wenstrup, R., de Wit, R., & de Bono, J. (2025). Chromosomal instability in circulating tumor cells and cabazitaxel resistance in metastatic castration-resistant prostate cancer. JCI insight, 10(24). https://doi.org/10.1172/jci.insight.196505

@article{3ba986d61f294b0889ac2b8866ea12ef,

title = "Chromosomal instability in circulating tumor cells and cabazitaxel resistance in metastatic castration-resistant prostate cancer",

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 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.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 with ARPI. CONCLUSION:This 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 REGISTRATION:ClinicalTrials.gov number NCT02485691.",

author = "Ossian Longoria and Jan Rekowski and Santosh Gupta and Nick Beije and Klaus Pantel and Eleni Efstathiou and Cora Sternberg and Daniel Castellano and Karim Fizazi and Bertrand Tombal and Adam Sharp and Oliver Sartor and Sandrine Mac{\'e} and Christine Geffriaud-Ricouard and Richard Wenstrup and \{de Wit\}, Ronald and \{de Bono\}, Johann",

year = "2025",

month = nov,

day = "4",

doi = "10.1172/jci.insight.196505",

language = "English",

volume = "10",

journal = "JCI insight",

issn = "2379-3708",

publisher = "American Society for Clinical Investigation",

number = "24",

}

Longoria, O, Rekowski, J, Gupta, S, Beije, N, Pantel, K, Efstathiou, E, Sternberg, C, Castellano, D, Fizazi, K, Tombal, B, Sharp, A, Sartor, O, Macé, S, Geffriaud-Ricouard, C, Wenstrup, R, de Wit, R & de Bono, J 2025, 'Chromosomal instability in circulating tumor cells and cabazitaxel resistance in metastatic castration-resistant prostate cancer', JCI insight, vol. 10, no. 24. https://doi.org/10.1172/jci.insight.196505

TY - JOUR

T1 - Chromosomal instability in circulating tumor cells and cabazitaxel resistance in metastatic castration-resistant prostate cancer

AU - Longoria, Ossian

AU - Rekowski, Jan

AU - Gupta, Santosh

AU - Beije, Nick

AU - Pantel, Klaus

AU - Efstathiou, Eleni

AU - Sternberg, Cora

AU - Castellano, Daniel

AU - Fizazi, Karim

AU - Tombal, Bertrand

AU - Sharp, Adam

AU - Sartor, Oliver

AU - Macé, Sandrine

AU - Geffriaud-Ricouard, Christine

AU - Wenstrup, Richard

AU - de Wit, Ronald

AU - de Bono, Johann

PY - 2025/11/4

Y1 - 2025/11/4

N2 - 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 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.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 with ARPI. CONCLUSION:This 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 REGISTRATION:ClinicalTrials.gov number NCT02485691.

AB - 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 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.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 with ARPI. CONCLUSION:This 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 REGISTRATION:ClinicalTrials.gov number NCT02485691.

UR - https://www.scopus.com/pages/publications/105025469236

U2 - 10.1172/jci.insight.196505

DO - 10.1172/jci.insight.196505

M3 - Article

C2 - 41186991

AN - SCOPUS:105025469236

SN - 2379-3708

VL - 10

JO - JCI insight

JF - JCI insight

IS - 24

ER -

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

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