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

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.

INTERPRETATIONS - 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.

European journal of cancer (Oxford, England : 1990). 2016 Jan 29 [Epub ahead of print]

Alexander Meisel, Stefanie von Felten, Deborah R Vogt, Heike Liewen, Ronald de Wit, Johann de Bono, Oliver Sartor, Frank Stenner-Liewen

Department of Oncology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland; Department of Internal Medicine, Stadtspital Waid, Tièchestrasse 99, 8037 Zurich, Switzerland. , Clinical Trial Unit, CTU, University Hospital of Basel, Schanzenstrasse 55, 4031 Basel, Switzerland. , Clinical Trial Unit, CTU, University Hospital of Basel, Schanzenstrasse 55, 4031 Basel, Switzerland. , Department of Oncology, University Hospital of Basel, Petersgraben 4, 4031 Basel, Switzerland. , Erasmus MC, and ErasmusMC Cancer Institute, PO Box 5201, 3008 AE Rotterdam, The Netherlands. , Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5, UK. , Department of Medicine & Urology, Tulane Cancer Center, 1430 Tulane Avenue, SL-42, New Orleans, 70112 LA, USA. , Department of Oncology, University Hospital of Basel, Petersgraben 4, 4031 Basel, Switzerland.

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