TY - JOUR
T1 - Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY)
T2 - A randomised, double-blind phase 3 trial
AU - Araujo, John C.
AU - Trudel, Géralyn C.
AU - Saad, Fred
AU - Armstrong, Andrew J.
AU - Yu, Evan Y.
AU - Bellmunt, Joaquim
AU - Wilding, George
AU - McCaffrey, John
AU - Serrano, Sergio V.
AU - Matveev, Vsevolod B.
AU - Efstathiou, Eleni
AU - Oudard, Stephane
AU - Morris, Michael J.
AU - Sizer, Bruce
AU - Goebell, Peter J.
AU - Heidenreich, Axel
AU - de Bono, Johann S.
AU - Begbie, Stephen
AU - Hong, Jun H.
AU - Richardet, Eduardo
AU - Gallardo, Enrique
AU - Paliwal, Prashni
AU - Durham, Susan
AU - Cheng, Shinta
AU - Logothetis, Christopher J.
N1 - Funding Information:
GCT, PP, SD, and SC are full-time employees of Bristol-Myers Squibb, and own company stocks and stock options. AJA has served as a consultant for Sanofi-Aventis, and has received research funding from Bristol-Myers Squibb and Sanofi-Aventis. FS has received research funding from Bristol-Myers Squibb. GW has received honoraria from Bristol-Myers Squibb. EE has received honoraria from Johnson & Johnson, Sanofi-Aventis, and Takeda; has participated on the speakers' bureau for Johnson & Johnson; and has received research funding from Sanofi-Aventis and Astellas/Medivation. SO has received honoraria from Bristol-Myers Squibb. MJM has served as a consultant for Bayer, Janssen, and Takeda and has received research funding from Algeta, Bayer, Sanofi-Aventis, and Takeda. BS has received honoraria and travel support from Bristol-Myers Squibb. All other authors declare that they have no conflicts of interest.
PY - 2013/12
Y1 - 2013/12
N2 - Background: Src kinase-mediated interactions between prostate cancer cells and osteoclasts might promote bone metastasis. Dasatinib inhibits tyrosine kinases, including Src kinases. Data suggests that dasatinib kinase inhibition leads to antitumour activity, affects osteoclasts, and has synergy with docetaxel, a first-line chemotherapy for metastatic castration-resistant prostate cancer. We assessed whether dasatinib plus docetaxel in chemotherapy-naive men with metastatic castration-resistant prostate cancer led to greater efficacy than with docetaxel alone. Methods: In this double-blind, randomised, placebo-controlled phase 3 study, we enrolled men of 18 years or older with chemotherapy-naive, metastatic, castration-resistant prostate cancer, and adequate organ function from 186 centres across 25 countries. Eligible patients were randomly assigned (1:1) via an interactive voice response system to receive docetaxel (75 mg/m2 intravenously every 3 weeks, plus oral prednisone 5 mg twice daily), plus either dasatinib (100 mg orally once daily) or placebo until disease progression or unacceptable toxicity. Randomisation was stratified by Eastern Cooperative Oncology Group performance status (0-1 vs 2), bisphosphonate use (yes vs no), and urinary N-telopeptide (uNTx) value (<60 μmol/mol creatinine vs ≥60 μmol/mol creatinine). All patients, investigators, and personnel involved in study conduct and data analyses were blinded to treatment allocation. The primary endpoint was overall survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00744497. Findings: Between Oct 30, 2008, and April 11, 2011, 1522 eligible patients were randomly assigned to treatment; 762 patients were assigned to dasatinib and 760 to placebo. At final analysis, median follow-up was 19·0 months (IQR 11·2-25·1) and 914 patients had died. Median overall survival was 21·5 months (95% CI 20·3-22·8) in the dasatinib group and 21·2 months (20·0-23·4) in the placebo group (stratified hazard ratio [HR] 0·99, 95·5% CI 0·87-1·13; p=0·90). The most common grade 3-4 adverse events included diarrhoea (58 [8%] patients in the dasatinib group vs 27 [4%] patients in the placebo group), fatigue (62 [8%] vs 42 [6%]), and asthenia (40 [5%] vs 23 [3%]); grade 3-4 pleural effusions were uncommon (ten [1%] vs three [<1%]). Interpretation: The addition of dasatinib to docetaxel did not improve overall survival for chemotherapy-naive men with metastatic castration-resistant prostate cancer. This study does not support the combination of dasatinib and docetaxel in this population of patients. Funding: Bristol-Myers Squibb.
AB - Background: Src kinase-mediated interactions between prostate cancer cells and osteoclasts might promote bone metastasis. Dasatinib inhibits tyrosine kinases, including Src kinases. Data suggests that dasatinib kinase inhibition leads to antitumour activity, affects osteoclasts, and has synergy with docetaxel, a first-line chemotherapy for metastatic castration-resistant prostate cancer. We assessed whether dasatinib plus docetaxel in chemotherapy-naive men with metastatic castration-resistant prostate cancer led to greater efficacy than with docetaxel alone. Methods: In this double-blind, randomised, placebo-controlled phase 3 study, we enrolled men of 18 years or older with chemotherapy-naive, metastatic, castration-resistant prostate cancer, and adequate organ function from 186 centres across 25 countries. Eligible patients were randomly assigned (1:1) via an interactive voice response system to receive docetaxel (75 mg/m2 intravenously every 3 weeks, plus oral prednisone 5 mg twice daily), plus either dasatinib (100 mg orally once daily) or placebo until disease progression or unacceptable toxicity. Randomisation was stratified by Eastern Cooperative Oncology Group performance status (0-1 vs 2), bisphosphonate use (yes vs no), and urinary N-telopeptide (uNTx) value (<60 μmol/mol creatinine vs ≥60 μmol/mol creatinine). All patients, investigators, and personnel involved in study conduct and data analyses were blinded to treatment allocation. The primary endpoint was overall survival, analysed by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT00744497. Findings: Between Oct 30, 2008, and April 11, 2011, 1522 eligible patients were randomly assigned to treatment; 762 patients were assigned to dasatinib and 760 to placebo. At final analysis, median follow-up was 19·0 months (IQR 11·2-25·1) and 914 patients had died. Median overall survival was 21·5 months (95% CI 20·3-22·8) in the dasatinib group and 21·2 months (20·0-23·4) in the placebo group (stratified hazard ratio [HR] 0·99, 95·5% CI 0·87-1·13; p=0·90). The most common grade 3-4 adverse events included diarrhoea (58 [8%] patients in the dasatinib group vs 27 [4%] patients in the placebo group), fatigue (62 [8%] vs 42 [6%]), and asthenia (40 [5%] vs 23 [3%]); grade 3-4 pleural effusions were uncommon (ten [1%] vs three [<1%]). Interpretation: The addition of dasatinib to docetaxel did not improve overall survival for chemotherapy-naive men with metastatic castration-resistant prostate cancer. This study does not support the combination of dasatinib and docetaxel in this population of patients. Funding: Bristol-Myers Squibb.
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U2 - 10.1016/S1470-2045(13)70479-0
DO - 10.1016/S1470-2045(13)70479-0
M3 - Article
C2 - 24211163
AN - SCOPUS:84888130823
SN - 1470-2045
VL - 14
SP - 1307
EP - 1316
JO - The lancet oncology
JF - The lancet oncology
IS - 13
ER -