title: 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.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Oncology, University Hospital Zurich, Rämistrasse 100, 8091 Zurich, Switzerland; Department of Internal Medicine, Stadtspital Waid, Tièchestrasse 99, 8037 Zurich, Switzerland.
authors.forename: Alexander
authors.initials: A
authors.lastname: Meisel
authors.affiliation: Clinical Trial Unit, CTU, University Hospital of Basel, Schanzenstrasse 55, 4031 Basel, Switzerland.
authors.forename: Stefanie
authors.initials: S
authors.lastname: von Felten
authors.affiliation: Clinical Trial Unit, CTU, University Hospital of Basel, Schanzenstrasse 55, 4031 Basel, Switzerland.
authors.forename: Deborah R
authors.initials: DR
authors.lastname: Vogt
authors.affiliation: Department of Oncology, University Hospital of Basel, Petersgraben 4, 4031 Basel, Switzerland.
authors.forename: Heike
authors.initials: H
authors.lastname: Liewen
authors.affiliation: Erasmus MC, and ErasmusMC Cancer Institute, PO Box 5201, 3008 AE Rotterdam, The Netherlands.
authors.forename: Ronald
authors.initials: R
authors.lastname: de Wit
authors.affiliation: Royal Marsden NHS Foundation Trust and the Institute of Cancer Research, Downs Road, Sutton, Surrey SM2 5, UK.
authors.forename: Johann
authors.initials: J
authors.lastname: de Bono
authors.affiliation: Department of Medicine & Urology, Tulane Cancer Center, 1430 Tulane Avenue, SL-42, New Orleans, 70112 LA, USA.
authors.forename: Oliver
authors.initials: O
authors.lastname: Sartor
authors.affiliation: Department of Oncology, University Hospital of Basel, Petersgraben 4, 4031 Basel, Switzerland.
authors.forename: Frank
authors.initials: F
authors.lastname: Stenner-Liewen
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects*; D018572:Disease-Free Survival; D000077143:Docetaxel; D016179:Granulocyte Colony-Stimulating Factor / Q000627:therapeutic use; D006801:Humans; D007610:Kallikreins / Q000097:blood; D053208:Kaplan-Meier Estimate; D018655:Lymphocyte Count; D008214:Lymphocytes / Q000187:drug effects; D008297:Male; D008942:Mitoxantrone / Q000008:administration & dosage; D009362:Neoplasm Metastasis; D009503:Neutropenia / Q000097:blood / Q000139:chemically induced* / Q000175:diagnosis / Q000188:drug therapy; D009504:Neutrophils / Q000187:drug effects; D011241:Prednisone / Q000008:administration & dosage; D016016:Proportional Hazards Models; D017430:Prostate-Specific Antigen / Q000097:blood; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D012307:Risk Factors; D012720:Severity of Illness Index; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects*; D013997:Time Factors; D016896:Treatment Outcome
chemical_list: D043823:Taxoids; D016179:Granulocyte Colony-Stimulating Factor; D000077143:Docetaxel; C552428:cabazitaxel; D008942:Mitoxantrone; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen; D011241:Prednisone
keywords: Cabazitaxel chemotherapy; Granulocyte-colony stimulating factor (GCSF); Metastasized castration resistent prostate cancer; Neutropenia predictive; Post hoc analysis; TROPIC; mCRPC