Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial.
BACKGROUND
Cabazitaxel is a novel tubulin-binding taxane drug with antitumour activity in docetaxel-resistant cancers. We aimed to compare the efficacy and safety of cabazitaxel plus prednisone with those of mitoxantrone plus prednisone in men with metastatic castration-resistant prostate cancer with progressive disease after docetaxel-based treatment.


METHODS
We undertook an open-label randomised phase 3 trial in men with metastatic castration-resistant prostate cancer who had received previous hormone therapy, but whose disease had progressed during or after treatment with a docetaxel-containing regimen. Participants were treated with 10 mg oral prednisone daily, and were randomly assigned to receive either 12 mg/m(2) mitoxantrone intravenously over 15-30 min or 25 mg/m(2) cabazitaxel intravenously over 1 h every 3 weeks. The random allocation schedule was computer-generated; patients and treating physicians were not masked to treatment allocation, but the study team was masked to the data analysis. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and safety. Analysis was by intention to treat. This study is registered at ClinicalTrials.gov, NCT00417079.


RESULTS
755 men were allocated to treatment groups (377 mitoxantrone, 378 cabazitaxel) and were included in the intention-to-treat analysis. At the cutoff for the final analysis (Sept 25, 2009), median survival was 15·1 months (95% CI 14·1-16·3) in the cabazitaxel group and 12·7 months (11·6-13·7) in the mitoxantrone group. The hazard ratio for death of men treated with cabazitaxel compared with those taking mitoxantrone was 0·70 (95% CI 0·59-0·83, p<0·0001). Median progression-free survival was 2·8 months (95% CI 2·4-3·0) in the cabazitaxel group and 1·4 months (1·4-1·7) in the mitoxantrone group (HR 0·74, 0·64-0·86, p<0·0001). The most common clinically significant grade 3 or higher adverse events were neutropenia (cabazitaxel, 303 [82%] patients vs mitoxantrone, 215 [58%]) and diarrhoea (23 [6%] vs one [<1%]). 28 (8%) patients in the cabazitaxel group and five (1%) in the mitoxantrone group had febrile neutropenia.


CONCLUSIONS
Treatment with cabazitaxel plus prednisone has important clinical antitumour activity, improving overall survival in patients with metastatic castration-resistant prostate cancer whose disease has progressed during or after docetaxel-based therapy.


BACKGROUND
Sanofi-Aventis.
de Bono
Johann Sebastian
JS
Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, Sutton, UK. johann.de-bono@icr.ac.uk
Oudard
Stephane
S
Ozguroglu
Mustafa
M
Hansen
Steinbjørn
S
Machiels
Jean-Pascal
JP
Kocak
Ivo
I
Gravis
Gwenaëlle
G
Bodrogi
Istvan
I
Mackenzie
Mary J
MJ
Shen
Liji
L
Roessner
Martin
M
Gupta
Sunil
S
Sartor
A Oliver
AO
D000284:Administration, Oral; D000368:Aged; D000726:Androgen Antagonists / Q000627:therapeutic use*; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D018450:Disease Progression; D018572:Disease-Free Survival; D000077143:Docetaxel; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007262:Infusions, Intravenous; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage / Q000009:adverse effects; D009503:Neutropenia / Q000139:chemically induced; D010147:Pain Measurement; D011241:Prednisone / Q000008:administration & dosage / Q000009:adverse effects; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D043823:Taxoids / Q000008:administration & dosage / Q000009:adverse effects; D017211:Treatment Failure; D016896:Treatment Outcome
D000726:Androgen Antagonists; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D043823:Taxoids; D000077143:Docetaxel; C552428:cabazitaxel; D008942:Mitoxantrone; D017430:Prostate-Specific Antigen; D011241:Prednisone