Elsevier

The Lancet

Volume 376, Issue 9747, 2–8 October 2010, Pages 1147-1154
The Lancet

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Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial

https://doi.org/10.1016/S0140-6736(10)61389-XGet rights and content

Summary

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/m2 mitoxantrone intravenously over 15–30 min or 25 mg/m2 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.

Findings

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.

Interpretation

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.

Funding

Sanofi-Aventis.

Introduction

Prostate cancer is the second most common cause of cancer death in men in the USA1 and the third most common cause of death in developed countries.2 For patients with metastatic prostate cancer, androgen deprivation therapy improves symptoms, but patients invariably develop progressive disease.3 On the basis of an improvement in survival compared with mitoxantrone plus prednisone in patients with metastatic castration-resistant prostate cancer,4, 5, 6 docetaxel in combination with prednisone is standard first-line chemotherapy in this setting. No treatment has been approved by the US Food and Drug Administration, however, for patients whose disease progresses after docetaxel treatment. Mitoxantrone is often administered because of its favourable effects on quality-of-life outcomes.7, 8 However, no intervention improves survival in this disease setting.

Cabazitaxel (XRP6258; TXD258; RPR116258A) is a tubulin-binding taxane drug as potent as docetaxel in cell lines.9 Additionally, the drug has antitumour activity in models resistant to paclitaxel and docetaxel.10, 11 Phase 1 and 2 clinical studies have shown that neutropenia is the primary dose-limiting toxicity, and the recommended phase 2 doses were 20 and 25 mg/m2, with antitumour activity in solid tumours including docetaxel-refractory metastatic castration-resistant prostate cancer.12, 13 We undertook a randomised, multicentre, multinational, phase 3 trial (EFC6193; TROPIC) with the aim of assessing whether cabazitaxel plus prednisone improves overall survival compared with mitoxantrone plus prednisone in men with metastatic castration-resistant prostate cancer who had progressed after docetaxel-based chemotherapy.

Section snippets

Patients

This randomised open-label phase 3 study was undertaken at 146 centres in 26 countries. Patients had pathologically proven prostate cancer with documented disease progression during or after completion of docetaxel treatment. Eligible patients were aged at least 18 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Patients who had previous mitoxantrone therapy, radiotherapy to 40% or more of the bone marrow, or cancer therapy (other than

Results

Between Jan 2, 2007, and Oct 23, 2008, 755 patients were randomly assigned to treatment groups (378 cabazitaxel and 377 mitoxantrone; figure 1). The treatment groups were well balanced at baseline with respect to demographic and disease characteristics and previous treatments (table 1). Roughly 50% of patients had measurable soft-tissue disease and 25% had visceral (poor prognosis) disease. The median dose of docetaxel received before the study was 576·6 mg/m2 (IQR 408·4–761·2) in the

Discussion

Cabazitaxel is the first drug to improve survival in patients with metastatic castration-resistant prostate cancer with progressive disease after docetaxel-based treatment, resulting in a 30% reduction in the risk of death and an improved median overall survival compared with mitoxantrone (panel). Currently, these patients have few therapeutic options, with no treatment able to prolong survival in this setting. The analysis of survival in subgroups defined by prognostic factors supports the

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