TY - JOUR
T1 - Cabazitaxel plus carboplatin for the treatment of men with metastatic castration-resistant prostate cancers
T2 - a randomised, open-label, phase 1–2 trial
AU - Corn, Paul G.
AU - Heath, Elisabeth I.
AU - Zurita, Amado
AU - Ramesh, Naveen
AU - Xiao, Lianchun
AU - Sei, Emi
AU - Li-Ning-Tapia, Elsa
AU - Tu, Shi Ming
AU - Subudhi, Sumit K.
AU - Wang, Jennifer
AU - Wang, Xuemei
AU - Efstathiou, Eleni
AU - Thompson, Timothy C.
AU - Troncoso, Patricia
AU - Navin, Nicholas
AU - Logothetis, Christopher J.
AU - Aparicio, Ana M.
N1 - Funding Information:
EIH reports personal fees from Bayer, Dendreon, Sanofi, Seattle Genetics, and Agensys, outside the submitted work. AZ reports personal fees from McKesson Specialty Health, Janssen-Cilag, Incyte, and Pfizer, outside the submitted work. EE reports grants, personal fees, research funding, and consulting fees from Janssen, Sanofi and Astellas, and Bayer and Tolmar, outside the submitted work. All other authors declare no competing interests.
Funding Information:
We thank patients and their family members, Sarah E Townsend (employee of the University of Texas MD Anderson Cancer Center) for editorial assistance and the agencies that supported this work: Sanofi Genzyme (drug and clinical trial costs), the University of Texas MD Anderson Prostate Cancer Moon Shot Program, the National Institutes of Health and National Cancer Institute (NCI; under award numbers P50 CA 140388 [University of Texas MD Anderson NCI Prostate Cancer SPORE Grant] and P30 CA16672 [University of Texas MD Anderson NCI Prostate Cancer Center Support Grant]), the Solon Scott III Prostate Cancer Research Fund, the Eckstein Tissue Acquisition Laboratory, the Joan Stanford Alexander Family Fund and the David H Koch Center for Applied Research of Genitourinary Cancers. NR is funded by the MD Anderson CPRIT Research Training Program (RP170067).
Funding Information:
We thank patients and their family members, Sarah E Townsend (employee of the University of Texas MD Anderson Cancer Center) for editorial assistance and the agencies that supported this work: Sanofi Genzyme (drug and clinical trial costs), the University of Texas MD Anderson Prostate Cancer Moon Shot Program, the National Institutes of Health and National Cancer Institute (NCI; under award numbers P50 CA 140388 [University of Texas MD Anderson NCI Prostate Cancer SPORE Grant] and P30 CA16672 [University of Texas MD Anderson NCI Prostate Cancer Center Support Grant]), the Solon Scott III Prostate Cancer Research Fund, the Eckstein Tissue Acquisition Laboratory, the Joan Stanford Alexander Family Fund and the David H Koch Center for Applied Research of Genitourinary Cancers. NR is funded by the MD Anderson CPRIT Research Training Program ( RP170067 ).
Funding Information:
This study was an investigator-initiated trial approved and funded by Sanofi Genzyme. The protocol and manuscript were reviewed by Sanofi Genzyme, but the funders had no role in data collection, analysis, or interpretation. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/10
Y1 - 2019/10
N2 - 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. This trial is registered at ClinicalTrials.gov, number NCT01505868. 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. Funding: Sanofi Genzyme, University of Texas MD Anderson Cancer Center Prostate Cancer Moon Shot Program, and Solon Scott III Prostate Cancer Research Fund.
AB - 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. This trial is registered at ClinicalTrials.gov, number NCT01505868. 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. Funding: Sanofi Genzyme, University of Texas MD Anderson Cancer Center Prostate Cancer Moon Shot Program, and Solon Scott III Prostate Cancer Research Fund.
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U2 - 10.1016/S1470-2045(19)30408-5
DO - 10.1016/S1470-2045(19)30408-5
M3 - Article
C2 - 31515154
AN - SCOPUS:85072663372
SN - 1470-2045
VL - 20
SP - 1432
EP - 1443
JO - The lancet oncology
JF - The lancet oncology
IS - 10
ER -