Neutropenia, neutrophilia, and neutrophil-lymphocyte ratio as prognostic markers in patients with metastatic castration-resistant prostate cancer

Abstract

Background and purpose: Chemotherapy-induced neutropenia and neutrophil-to-lymphocyte ratio (NLR) are potentially useful prognostic markers in patients with metastatic castration-resistant prostate cancer (mCRPC). This post hoc analysis investigated whether these markers can be utilized for dose considerations and evaluated the prognostic impact of leukocyte subtypes.

Patients and methods: PROSELICA assessed the non-inferiority of cabazitaxel 20 mg/m2 (C20; n = 598) versus 25 mg/m2 (C25; n = 602) for overall survival (OS) in patients with mCRPC previously treated with docetaxel. The association of grade ⩾ 3 neutropenia, NLR, baseline neutrophilia and lymphopenia with OS, progression-free survival (PFS), and prostate-specific antigen response rate (PSArr) was investigated by an unplanned uni- and multivariate analyses.

Results: PROSELICA confirmed the negative prognostic value of increased baseline NLR [⩾3, hazard ratio (HR) 1.40; p < 0.0001], but did not identify a subgroup of patients benefiting more from C20 or C25. In this post hoc analysis, patients who developed grade ⩾3 neutropenia (n = 673) had a significantly improved OS [∆OS = 2.7 months, HR = 0.78 (95% CI 0.68-0.89)] with the greatest advantage observed in patients with baseline neutrophilia [n = 85; 5.3 months, 0.60 (0.42-0.84)]. After adjustment for the Halabi criteria, neutropenia grade ⩾ 3 was the only biomarker that remained significantly associated with OS [ (HR 0.86 (0.75-0.98)], PFS [HR 0.78 (0.68-0.88)], and PSArr [odds ratio (OR) 1.82 (1.37-2.41)] while neutrophilia showed the strongest association with OS [1.53 (1.29-1.81)].

Conclusions: Grade ⩾ 3 neutropenia was the only leukocyte-based biomarker associated with all key outcome parameters in mCRPC patients receiving cabazitaxel and might be able to overcome the negative prognostic effect of baseline neutrophilia.

Nct number: NCT01308580.

Keywords: cabazitaxel; mCRPC; neutropenia; neutrophil-to-lymphocyte ratio; neutrophilia; prostate cancer.

Conflict of interest statement

Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AM has provided a consulting, advisory or speaker role for Amgen, Astellas, Boehringer Ingelheim, Celgene, Janssen, Gerresheimer, Glaxo-Smith-Kline, Merck, MSD, Novartis, Roche, Sanofi, Servier, Takeda, and Vifor, has received research funding from Bayer (personal) and Merck & Cie (institutional), has intellectual property interests relating to Merck (not related to this report), has been paid to provide expert testimony for Sanofi, and has reported travel/accommodation expenses paid for by Amgen, Astellas, Boehringer Ingelheim, Janssen, Merck, Roche, Sanofi, and Servier. RdW has provided a consulting or advisory role for Sanofi, Merck Sharp & Dohme, Roche/Genetech, Janssen, Bayer and Clovis Oncology. RdW has also received honoraria and/or research funding from Sanofi and Bayer. SO has provided a consulting or advisory role for AstraZeneca, Sanofi, Roche/Genetech, Janssen, Bayer and Astellas, Pfizer, Merck Sharp & Dohme, Novartis, Bristol Myers Squib. SO has also received honoraria and/or research funding from Sanofi, AstraZeneca, Bayer, Pfizer, Janssen, and Bristol Myers Squib. OS has provided a consulting role for Advanced Accelerator Applications (AAA), Astellas, AstraZeneca, Bayer, Blue Earth Diagnostics, Inc., Bavarian Nordic, Bristol Myers Squibb, Clarity Pharmaceuticals, Clovis, Constellation, Dendreon, EMD Serono, Fusion, Isotopen Technologien Meunchen, Janssen, Merck, Moyvant, Myriad, Noria Therapeutics, Inc., Novartis, Noxopharm, Progenics, POINT Biopharma, Pfizer, Sanofi, Tenebio, Telix, Theragnostics. OS has received grant/research support from Advanced Accelerator Applications, Amgen, AstraZeneca, Bayer, Constellation, Endocyte, Invitae, Janssen, Lantheus, Merck, Progenics, and Tenebio. FS-L has provided a consulting or advisory role for Bayer, BMS, Janssen, MSD, AstraZeneca and Sanofi. FS-L has also reported travel/other expenses from BMS, Sanofi, and Roche. ZS was an employee of Sanofi. MF and AO are current/former Sanofi employees. AO owns stocks in Sanofi. ME is on the board of directors for VERU Inc. JSdB has provided a consulting or advisory role for AstraZeneca, Sanofi, Roche, Astellas Pharma, Bayer, Pfizer, Merck Sharp & Dohme, Merck Serono, Boehringer Ingelheim, Sierra Oncology, Menarini Silicon Biostystems, Celgene, Taiho Pharmaceuticals, Daiichi Sankyo, Janssen, Genmab, GSK, Orion Pharma GmbH, Eisai, and BioXCel therapeutics, and received travel/accommodation/expenses from AstraZeneca, Astellas Pharma, GSK, Orion Pharma GmbH, Sanofi, Genmab, Taiho Pharmaceuticals, Qiagen, and Vertex. JSdB is also associated with patents/royalties/other IP for abiraterone, PARP inhibitors, IL-23 targeting in prostate cancer, CHK1 inhibitor. JSdB has also received honoraria and/or research funding from AstraZeneca, Sanofi, Astellas Pharma, Pfizer, Roche/Genentech, Janssen, Menarini Silicon Biosystems, Daiichi Sankyo, Sierra Oncology, Taiho Pharmaceuticals, Merck Serono, Astex Pharmaceuticals, Merck Sharp & Dohme, Orion Pharma GmbH, CellCentric, Celgene, Bayer, MedImmune, Medivation, and BioExcel.

© The Author(s), 2022.

Figures

Figure 1.

Kaplan–Meier curves for OS for (a) the overall population and (b) patients with baseline neutrophilia grouped by development of grade ⩾ 3 neutropenia during treatment. C20, cabazitaxel 20 mg/m2; C25, cabazitaxel 25 mg/m2; ITT, intention-to-treat; OS, overall survival.

Figure 2.

Impact of grade ⩾ 3 neutropenia on patient outcomes in the overall study population and in patients with baseline neutrophilia. CI, confidence interval; C20, cabazitaxel 20 mg/m2; C25, cabazitaxel 25 mg/m2; HR, hazard ratio; ITT, intention-to-treat; OR, odds ratio; OS, overall survival; PFS, progression-free survival; PSA, prostate-specific antigen.

Figure 3.

Waterfall plot of maximum percent change in PSA in patients with baseline neutrophilia for (a) the ITT population, (b) patients who received C20, and (c) patients who received C25. Patients with ⩾3 neutropenia show the deepest responses. In contrast, many patients without ⩾3 neutropenia show no PSA response or progressive disease as their best response to therapy. C20, cabazitaxel 20 mg/m2; C25, cabazitaxel 25 mg/m2; ITT, intention-to-treat; PSA, prostate-specific antigen.

Figure 4.

Linear regression analysis of nadir ANC with percentage change in PSA from baseline in the PROSELICA ITT population (n = 1134;R2 = 0.0487). ANC, absolute neutrophil count; ITT, intention-to-treat; PSA, prostate-specific antigen.