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

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.

Keywords: abiraterone; cabazitaxel; enzalutamide; metastatic castration-resistant prostate cancer; neutrophil-to-lymphocyte ratio; prognostic factor.

Conflict of interest statement

Disclosure 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.

Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure 1

rPFS by baseline NLR. CI, confidence interval; HR, hazard ratio; NLR, neutrophil-to-lymphocyte ratio; rPFS, radiographic progression-free survival.

Figure 2

OS by baseline NLR. ARTA, androgen-receptor-targeted agent; CI, confidence interval; HR, hazard ratio; NLR, neutrophil-to-lymphocyte ratio; OS, overall survival.

Figure 3

Time to PSA progression by baseline NLR. CI, confidence interval; HR, hazard ratio; NLR, neutrophil-to-lymphocyte ratio; PSA, prostate-specific antigen.

Figure 4

PSA response by baseline NLR. NLR, neutrophil-to-lymphocyte ratio; PSA, prostate-specific antigen.