Severe neutropenia during cabazitaxel treatment is associated with survival benefit in men with metastatic castration-resistant prostate cancer (mCRPC): A post-hoc analysis of the TROPIC phase III trial. (March 2016)

• Record Type: Journal Article
• Authors: Meisel, Alexander; von Felten, Stefanie; Vogt, Deborah R.; Liewen, Heike; de Wit, Ronald; de Bono, Johann; Sartor, Oliver; Stenner-Liewen, Frank
• Is Part Of: European journal of cancer. Volume 56(2016)
• Page Start: 93
• Page End: 100
• Publication Date: 2016-03
• Subjects: TROPIC -- Post hoc analysis -- Cabazitaxel chemotherapy -- Metastasized castration resistent prostate cancer -- Neutropenia predictive -- Granulocyte-colony stimulating factor (GCSF) -- mCRPC; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2015.12.009
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: Background: Cabazitaxel significantly improves overall survival (OS) in men with metastatic castration-resistant prostate cancer (mCRPC) progressing during or after docetaxel, but is associated with a higher rate of grade ≥3 neutropenia compared with docetaxel. We thus examined the relationship between cabazitaxel-induced grade ≥3 neutropenia, baseline neutrophil-lymphocyte ratio (NLR) and treatment outcomes. Methods: Data from the experimental arm of the TROPIC phase 3 trial which randomly assigned men with mCRPC to cabazitaxel or mitoxantrone every 3 weeks, both combined with daily prednisone, were analysed. The influence on OS (primary end-point) and progression-free survival (PFS) of at least one episode of grade ≥3 neutropenia during cabazitaxel therapy was investigated using Cox regression models, adjusted for pain at baseline. The relationships with prostate-specific antigen (PSA) responses during cabazitaxel therapy and baseline NLR were also analysed. Findings: The occurrence of grade ≥3 neutropenia during cabazitaxel therapy was associated with a prolonged OS (median 16.3 versus 14.0 months, hazard ratio (HR) [95% confidence interval] = 0.65 [0.43–0.97], p = 0.035), a twice longer PFS (median 5.3 versus 2.6 months, HR = 0.56 [0.40–0.79], p = 0.001) and a higher confirmed PSA response ≥50% (49.8% versus 24.4%, p = 0.005), as compared with patients who did not develop grade ≥3 neutropenia. Grade ≥3 neutropenia was more common in case of NLR <3 as compared with NLR ≥3 at baseline (88.8% versus 75.3%, p = 0.002). Combining low NLR at baseline and grade ≥3 neutropenia during therapy was associated with the longest OS (median 19.2 months) while high NLR at baseline and no grade ≥3 neutropenia was associated with a poor OS (median 12.9 months, HR 0.46 [0.28–0.76], p = 0.002). In the subgroup of neutropenic patients the median OS was 19.7 months in those treated with granulocyte colony-stimulating factor (G-CSF) and 16 months on those without G-CSF support. Interpretation: This post-hoc analysis of TROPIC suggests that the occurrence of grade ≥3 neutropenia with cabazitaxel is associated with improved OS and PFS. Patients with a low NLR at baseline were more likely to develop grade ≥3 neutropenia during cabazitaxel therapy and showed the longest OS. High NLR at baseline and no grade ≥3 neutropenia during therapy was associated with poor outcomes which may suggest insufficient drug exposure or a limited impact on the tumour-associated immune response. Primary or secondary prophylactic use of G-CSF had no adverse impact for outcome. If prospectively confirmed, these results would justify maintaining the intended cabazitaxel dose of 25 mg/m 2 whenever possible. Highlights: Cabazitaxel is an option in metastasized castration resistant prostate cancer (mCRPC). The occurrence of cabazitaxel induced neutropenia (CIN) is a positive predictive factor. Severe CIN is associated with better progression-free and overall survival. Prophylactic use of filgrastim (G-CSF) after first CIN shows a survival advantage. A model of neutrophil-to-lymphocyte ratio and CIN defines three risk categories in mCRPC.