Baseline neutrophil-to-lymphocyte ratio as a predictive and prognostic biomarker in patients with metastatic castration-resistant prostate cancer treated with cabazitaxel versus abiraterone or enzalutamide in the CARD study

R. de Wit*, C. Wülfing, D. Castellano, G. Kramer, J. C. Eymard, C. N. Sternberg, K. Fizazi, B. Tombal, A. Bamias, J. Carles, R. Iacovelli, B. Melichar, Sverrisdóttir, C. Theodore, S. Feyerabend, C. Helissey, M. C. Foster, A. Ozatilgan, C. Geffriaud-Ricouard, J. de Bono

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Background: There is growing evidence that a high neutrophil-to-lymphocyte ratio (NLR) is associated with poor overall survival (OS) for patients with metastatic castration-resistant prostate cancer (mCRPC). In the CARD study (NCT02485691), cabazitaxel significantly improved radiographic progression-free survival (rPFS) and OS versus abiraterone or enzalutamide in patients with mCRPC previously treated with docetaxel and the alternative androgen-receptor-targeted agent (ARTA). Here, we investigated NLR as a biomarker. Patients and methods: CARD was a multicenter, open-label study that randomized patients with mCRPC to receive cabazitaxel (25 mg/m2 every 3 weeks) versus abiraterone (1000 mg/day) or enzalutamide (160 mg/day). The relationships between baseline NLR [< versus ≥ median (3.38)] and rPFS, OS, time to prostate-specific antigen progression, and prostate-specific antigen response to cabazitaxel versus ARTA were evaluated using Kaplan–Meier estimates. Multivariable Cox regression with stepwise selection of covariates was used to investigate the prognostic association between baseline NLR and OS. Results: The rPFS benefit with cabazitaxel versus ARTA was particularly marked in patients with high NLR {8.5 versus 2.8 months, respectively; hazard ratio (HR) 0.43 [95% confidence interval (CI) 0.27-0.67]; P < 0.0001}, compared with low NLR [7.5 versus 5.1 months, respectively; HR 0.69 (95% CI 0.45-1.06); P = 0.0860]. Higher NLR (continuous covariate, per 1 unit increase) independently associated with poor OS [HR 1.05 (95% CI 1.02-1.08); P = 0.0003]. For cabazitaxel, there was no OS difference between patients with high versus low NLR (15.3 versus 12.9 months, respectively; P = 0.7465). Patients receiving an ARTA with high NLR, however, had a worse OS versus those with low NLR (9.5 versus 13.3 months, respectively; P = 0.0608). Conclusions: High baseline NLR predicts poor outcomes with an ARTA in patients with mCRPC previously treated with docetaxel and the alternative ARTA. Conversely, the activity of cabazitaxel is retained irrespective of NLR.

Original languageEnglish
Article number100241
JournalESMO Open
Volume6
Issue number5
DOIs
Publication statusPublished - 1 Oct 2021

Bibliographical note

Funding Information:
This work was supported by Sanofi Genzyme (no grant number). The authors were responsible for all content and editorial decisions and received no honoraria for development of this manuscript.

Funding Information:
Medical writing assistance was provided by Annie Berkley of Meditech Media, funded by Sanofi .

Funding Information:
Medical writing assistance was provided by Annie Berkley of Meditech Media, funded by Sanofi. This work was supported by Sanofi Genzyme (no grant number). The authors were responsible for all content and editorial decisions and received no honoraria for development of this manuscript. This work was supported by Sanofi Genzyme, which funded the CARD study, provided the study treatments, and collaborated with the co-authors on study design, data analysis, data interpretation, and writing of the report. The manuscript was written with editorial support from medical writers, funded by the sponsor. The corresponding author had full access to the data and was responsible for the decision to submit for publication. RdW provided an advisory role for Sanofi, Janssen, Merck, Bayer, and Astellas, and received institutional grants from Sanofi and Bayer. DC has received personal fees from Pfizer, Roche, Sanofi, Janssen, Astellas, Bayer, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Merck Serono, Pierre Fabre, AstraZeneca, and Lilly. GK received personal fees from Sanofi, Astellas, Takeda, Bayer, Janssen, Novartis, Ipsen, and AstraZeneca, and has received grants from Sanofi and Bayer. J-CE has received honoraria from and provided an advisory role for Astellas, BMS, Ipsen, Janssen, Pfizer, and Sanofi Aventis, and has received travel and accommodation fees from Pfizer and BMS. CNS has received honoraria from Janssen, AstraZeneca, Sanofi and Astellas, received consultancy fees from Sanofi, Bayer, and Pfizer, and received institutional funding from Genentech/Roche, Bayer, Sanofi Genzyme, Janssen, Medivation, MSD, and Exelixis. KF has received honoraria and provided an advisory role for Astellas, AAA Pharmaceutical Inc, Bayer, Essa, Janssen, Orion, CureVac, Clovis, Sanofi, and Endocyte. BT has received personal fees and research grants from Astellas, Janssen, Sanofi Genzyme, Amgen, and Ferring, and received non-financial support from Sanofi Genzyme. AB has received honoraria and research support from and provided an advisory role to Astellas, Janssen, and Sanofi. JC has provided an advisory role for Astellas, AstraZeneca, Bayer, BMS, MSD Oncology, Johnson & Johnson, Sanofi, Roche, and Pfizer, and has attended speaker bureaus for Asofarma, Astellas, Bayer, and Johnson & Johnson. RI received honoraria and provided an advisory role for Sanofi, Janssen, Pfizer, Ipsen, Novartis, BMS, and MSD. BM received travel fees, honoraria, and provided an advisory role for BMS and Merck Serono, and received honoraria and provided an advisory role for MSD, Sanofi, Roche, Janssen, Bayer, Astellas, Amgen, Novartis, Servier, AstraZeneca, Eisai, E. Lilly, Ipsen, Pierre Fabre, and Pfizer. CH has received consultancy fees from Sanofi, Janssen, and Astellas. MCF and CG-R are employees of Sanofi. AO is an employee and stockholder of Sanofi. JdB has received honoraria from AstraZeneca, Sanofi, Astellas Pharma, Pfizer, Genentech/Roche, Janssen Oncology, Menarini Silicon Biosystems, Daiichi Sankyo, Sierra Oncology, and BioXcel Therapeutics, and provided an advisory role for AstraZeneca, Sanofi, Genentech/Roche, Astellas Pharma, Bayer, Pfizer, MSD, Merck Serono, Boehringer Ingelheim, Sierra Oncology, Menarini Silicon Biosystems, Celgene, Taiho Pharmaceutical, Daiichi Sankyo, Janssen Oncology, Genmab, GlaxoSmithKline, Orion Pharma GmbH, Eisai, and BioXcel Therapeutics. All other authors have declared no conflicts of interest. Qualified researchers may request access to patient-level data and related documents (including, e.g. the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications). Patient-level data will be anonymized, and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at https://www.clinicalstudydatarequest.com.

Funding Information:
RdW provided an advisory role for Sanofi, Janssen, Merck, Bayer, and Astellas, and received institutional grants from Sanofi and Bayer. DC has received personal fees from Pfizer, Roche, Sanofi, Janssen, Astellas, Bayer, Bristol-Myers Squibb (BMS), Merck Sharp & Dohme (MSD), Merck Serono, Pierre Fabre, AstraZeneca, and Lilly. GK received personal fees from Sanofi, Astellas, Takeda, Bayer, Janssen, Novartis, Ipsen, and AstraZeneca, and has received grants from Sanofi and Bayer. J-CE has received honoraria from and provided an advisory role for Astellas, BMS, Ipsen, Janssen, Pfizer, and Sanofi Aventis, and has received travel and accommodation fees from Pfizer and BMS. CNS has received honoraria from Janssen, AstraZeneca, Sanofi and Astellas, received consultancy fees from Sanofi, Bayer, and Pfizer, and received institutional funding from Genentech/Roche, Bayer, Sanofi Genzyme, Janssen, Medivation, MSD, and Exelixis. KF has received honoraria and provided an advisory role for Astellas, AAA Pharmaceutical Inc, Bayer, Essa, Janssen, Orion, CureVac, Clovis, Sanofi, and Endocyte. BT has received personal fees and research grants from Astellas, Janssen, Sanofi Genzyme, Amgen, and Ferring, and received non-financial support from Sanofi Genzyme. AB has received honoraria and research support from and provided an advisory role to Astellas, Janssen, and Sanofi. JC has provided an advisory role for Astellas, AstraZeneca, Bayer, BMS, MSD Oncology, Johnson & Johnson, Sanofi, Roche, and Pfizer, and has attended speaker bureaus for Asofarma, Astellas, Bayer, and Johnson & Johnson. RI received honoraria and provided an advisory role for Sanofi, Janssen, Pfizer, Ipsen, Novartis, BMS, and MSD. BM received travel fees, honoraria, and provided an advisory role for BMS and Merck Serono, and received honoraria and provided an advisory role for MSD, Sanofi, Roche, Janssen, Bayer, Astellas, Amgen, Novartis, Servier, AstraZeneca, Eisai, E. Lilly, Ipsen, Pierre Fabre, and Pfizer. CH has received consultancy fees from Sanofi, Janssen, and Astellas. MCF and CG-R are employees of Sanofi. AO is an employee and stockholder of Sanofi. JdB has received honoraria from AstraZeneca, Sanofi, Astellas Pharma, Pfizer, Genentech/Roche, Janssen Oncology, Menarini Silicon Biosystems, Daiichi Sankyo, Sierra Oncology, and BioXcel Therapeutics, and provided an advisory role for AstraZeneca, Sanofi, Genentech/Roche, Astellas Pharma, Bayer, Pfizer, MSD, Merck Serono, Boehringer Ingelheim, Sierra Oncology, Menarini Silicon Biosystems, Celgene, Taiho Pharmaceutical, Daiichi Sankyo, Janssen Oncology, Genmab, GlaxoSmithKline, Orion Pharma GmbH, Eisai, and BioXcel Therapeutics. All other authors have declared no conflicts of interest.

Publisher Copyright:
© 2021

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