Cabazitaxel Plus Carboplatin for the Treatment of Men With Metastatic Castration-Resistant Prostate Cancer

[Balsam01]

TAKE-HOME MESSAGE

•This phase I/II trial evaluated the combination of cabazitaxel and carboplatin for patients with metastatic castration-resistant prostate cancer. The combination of cabazitaxel and carboplatin was associated with longer median progression-free survival over cabazitaxel alone (7.3 months vs 4.5 months).

•The combination was associated with increased toxicity, but there were no dose-limiting toxicities, and the treatment was generally safe and well-tolerated.

– Neil Majithia, MD

abstract

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BACKGROUND

Taxane-platinum combinations have shown promising activity in metastatic castration-resistant prostate cancers in single-group clinical studies but not in randomised trials. Distinct biological subsets of the disease might derive the greatest benefit from the addition of platinum. We aimed to determine whether adding carboplatin to cabazitaxel would improve the outcomes of men with metastatic castration-resistant prostate cancer.

METHODS

We did a phase 1-2, open label, randomised study at two centres in men with progressive metastatic castration-resistant prostate cancer. In phase 1, patients received intravenous cabazitaxel 20-25 mg/m2 and intravenous carboplatin area under the curve (AUC) 3-4 mg/mL per min every 21 days. The maximum tolerated dose was defined as the highest dose cohort studied in which one of six or fewer patients experienced a dose-limiting toxicity. In phase 2, patients were randomly assigned (1:1) centrally by a computerised algorithm to intravenous cabazitaxel 25 mg/m2 with or without intravenous carboplatin AUC 4 mg/mL per min. All patients received growth factor support and oral prednisone 10 mg daily. The primary endpoints were the maximum tolerated dose of the combination in phase 1 and investigator-assessed progression-free survival in phase 2.

FINDINGS

Between Aug 17, 2012, and May 11, 2015, nine patients completed phase 1 as planned, and 160 were randomly assigned to cabazitaxel (n=79) or cabazitaxel plus carboplatin (n=81) in phase 2. During phase I, grade 3 adverse events were anaemia (n=2), fatigue (n=1), thrombocytopenia (n=1), hypomagnesaemia (n=1), diarrhoea (n=1), hypokalaemia (n=1), anorexia (n=1), and dehydration (n=1), and no grade 4 adverse events occurred. No dose-limiting toxicities were observed, therefore, a maximum tolerated dose of cabazitaxel of 25 mg/m2 and carboplatin of AUC 4 mg/mL per min was selected for phase 2. At a median follow-up of 31·0 months (IQR 20·5-37·1), the combination improved the median progression-free survival from 4·5 months (95% CI 3·5-5·7) to 7·3 months (95% CI 5·5-8·2; hazard ratio 0·69, 95% CI 0·50-0·95, p=0·018). In the phase 2 study, the most common grade 3-5 adverse events were fatigue (7 [9%] of 79 in the cabazitaxel group vs 16 [20%] of 81 in the combination group), anaemia (3 [4%] vs 19 [23%]), neutropenia (3 [4%] vs 13 [16%]), and thrombocytopenia (1 [1%] vs 11 [14%]). There were no treatment-related deaths.

INTERPRETATION

Carboplatin added to cabazitaxel showed improved clinical efficacy compared with cabazitaxel alone for men with metastatic castration-resistant prostate cancer. Although adverse events were more common with the combination, the treatment was safe and generally well tolerated. Our data suggest that taxane-platinum combinations have a clinically beneficial role in advanced prostate cancer and a randomised phase 3 study is planned.

The Lancet Oncology

Cabazitaxel Plus Carboplatin for the Treatment of Men With Metastatic Castration-Resistant Prostate Cancers: A Randomised, Open-Label, Phase 1-2 Trial

Lancet Oncol 2019 Sep 09;[EPub Ahead of Print], PG Corn, EI Heath, A Zurita, N Ramesh, L Xiao, E Sei, E Li-Ning-Tapia, SM Tu, SK Subudhi, J Wang, X Wang, E Efstathiou, TC Thompson, P Troncoso, N Navin, CJ Logothetis, AM Aparicio

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.