Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial
Identifieur interne : 004743 ( Main/Exploration ); précédent : 004742; suivant : 004744Docetaxel and dasatinib or placebo in men with metastatic castration-resistant prostate cancer (READY): a randomised, double-blind phase 3 trial
Auteurs : John C. Araujo ; Géralyn C. Trudel ; Fred Saad ; Andrew J. Armstrong ; Evan Y. Yu ; Joaquim Bellmunt ; George Wilding ; John Mccaffrey ; Sergio V. Serrano ; Vsevolod B. Matveev ; Eleni Efstathiou ; Stephane Oudard ; Michael J. Morris ; Bruce Sizer ; Peter J. Goebell ; Axel Heidenreich ; Johann S. De Bono ; Stephen Begbie ; Jun H. Hong ; Eduardo Richardet ; Enrique Gallardo ; Prashni Paliwal ; Susan Durham ; Shinta Cheng ; Christopher J. LogothetisSource :
- The Lancet. Oncology [ 1470-2045 ] ; 2013.
Abstract
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.
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
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
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.
Bristol-Myers Squibb.
Url:
DOI: 10.1016/S1470-2045(13)70479-0
PubMed: 24211163
PubMed Central: 5478530
Affiliations:
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Araujo</name></author><author><name sortKey="Trudel, Geralyn C" sort="Trudel, Geralyn C" uniqKey="Trudel G" first="Géralyn C" last="Trudel">Géralyn C. Trudel</name></author><author><name sortKey="Saad, Fred" sort="Saad, Fred" uniqKey="Saad F" first="Fred" last="Saad">Fred Saad</name></author><author><name sortKey="Armstrong, Andrew J" sort="Armstrong, Andrew J" uniqKey="Armstrong A" first="Andrew J" last="Armstrong">Andrew J. Armstrong</name></author><author><name sortKey="Yu, Evan Y" sort="Yu, Evan Y" uniqKey="Yu E" first="Evan Y" last="Yu">Evan Y. Yu</name></author><author><name sortKey="Bellmunt, Joaquim" sort="Bellmunt, Joaquim" uniqKey="Bellmunt J" first="Joaquim" last="Bellmunt">Joaquim Bellmunt</name></author><author><name sortKey="Wilding, George" sort="Wilding, George" uniqKey="Wilding G" first="George" last="Wilding">George Wilding</name></author><author><name sortKey="Mccaffrey, John" sort="Mccaffrey, John" uniqKey="Mccaffrey J" first="John" last="Mccaffrey">John Mccaffrey</name></author><author><name sortKey="Serrano, Sergio V" sort="Serrano, Sergio V" uniqKey="Serrano S" first="Sergio V" last="Serrano">Sergio V. Serrano</name></author><author><name sortKey="Matveev, Vsevolod B" sort="Matveev, Vsevolod B" uniqKey="Matveev V" first="Vsevolod B" last="Matveev">Vsevolod B. Matveev</name></author><author><name sortKey="Efstathiou, Eleni" sort="Efstathiou, Eleni" uniqKey="Efstathiou E" first="Eleni" last="Efstathiou">Eleni Efstathiou</name></author><author><name sortKey="Oudard, Stephane" sort="Oudard, Stephane" uniqKey="Oudard S" first="Stephane" last="Oudard">Stephane Oudard</name></author><author><name sortKey="Morris, Michael J" sort="Morris, Michael J" uniqKey="Morris M" first="Michael J" last="Morris">Michael J. Morris</name></author><author><name sortKey="Sizer, Bruce" sort="Sizer, Bruce" uniqKey="Sizer B" first="Bruce" last="Sizer">Bruce Sizer</name></author><author><name sortKey="Goebell, Peter J" sort="Goebell, Peter J" uniqKey="Goebell P" first="Peter J" last="Goebell">Peter J. Goebell</name></author><author><name sortKey="Heidenreich, Axel" sort="Heidenreich, Axel" uniqKey="Heidenreich A" first="Axel" last="Heidenreich">Axel Heidenreich</name></author><author><name sortKey="De Bono, Johann S" sort="De Bono, Johann S" uniqKey="De Bono J" first="Johann S" last="De Bono">Johann S. De Bono</name></author><author><name sortKey="Begbie, Stephen" sort="Begbie, Stephen" uniqKey="Begbie S" first="Stephen" last="Begbie">Stephen Begbie</name></author><author><name sortKey="Hong, Jun H" sort="Hong, Jun H" uniqKey="Hong J" first="Jun H" last="Hong">Jun H. Hong</name></author><author><name sortKey="Richardet, Eduardo" sort="Richardet, Eduardo" uniqKey="Richardet E" first="Eduardo" last="Richardet">Eduardo Richardet</name></author><author><name sortKey="Gallardo, Enrique" sort="Gallardo, Enrique" uniqKey="Gallardo E" first="Enrique" last="Gallardo">Enrique Gallardo</name></author><author><name sortKey="Paliwal, Prashni" sort="Paliwal, Prashni" uniqKey="Paliwal P" first="Prashni" last="Paliwal">Prashni Paliwal</name></author><author><name sortKey="Durham, Susan" sort="Durham, Susan" uniqKey="Durham S" first="Susan" last="Durham">Susan Durham</name></author><author><name sortKey="Cheng, Shinta" sort="Cheng, Shinta" uniqKey="Cheng S" first="Shinta" last="Cheng">Shinta Cheng</name></author><author><name sortKey="Logothetis, Christopher J" sort="Logothetis, Christopher J" uniqKey="Logothetis C" first="Christopher J" last="Logothetis">Christopher J. Logothetis</name></author></analytic><series><title level="j">The Lancet. Oncology</title><idno type="ISSN">1470-2045</idno><idno type="eISSN">1474-5488</idno><imprint><date when="2013">2013</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><title>Summary</title><sec id="S1"><title>Background</title><p id="P1">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.</p></sec><sec id="S2"><title>Methods</title><p id="P2">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/m<sup>2</sup> 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 <italic>vs</italic> 2), bisphosphonate use (yes <italic>vs</italic> no), and urinary N-telopeptide (uNTx) value (<60 μmol/mol creatinine <italic>vs</italic> ≥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 <ext-link ext-link-type="uri" xlink:href="ClinicalTrials.gov">ClinicalTrials.gov</ext-link>, number NCT00744497.</p></sec><sec id="S3"><title>Findings</title><p id="P3">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 <italic>vs</italic> 27 [4%] patients in the placebo group), fatigue (62 [8%] <italic>vs</italic> 42 [6%]), and asthenia (40 [5%] <italic>vs</italic> 23 [3%]); grade 3–4 pleural effusions were uncommon (ten [1%] <italic>vs</italic> three [<1%]).</p></sec><sec id="S4"><title>Interpretation</title><p id="P4">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.</p></sec><sec id="S5"><title>Funding</title><p id="P5">Bristol-Myers Squibb.</p></sec></div></front></TEI><affiliations><list></list><tree><noCountry><name sortKey="Araujo, John C" sort="Araujo, John C" uniqKey="Araujo J" first="John C" last="Araujo">John C. Araujo</name><name sortKey="Armstrong, Andrew J" sort="Armstrong, Andrew J" uniqKey="Armstrong A" first="Andrew J" last="Armstrong">Andrew J. Armstrong</name><name sortKey="Begbie, Stephen" sort="Begbie, Stephen" uniqKey="Begbie S" first="Stephen" last="Begbie">Stephen Begbie</name><name sortKey="Bellmunt, Joaquim" sort="Bellmunt, Joaquim" uniqKey="Bellmunt J" first="Joaquim" last="Bellmunt">Joaquim Bellmunt</name><name sortKey="Cheng, Shinta" sort="Cheng, Shinta" uniqKey="Cheng S" first="Shinta" last="Cheng">Shinta Cheng</name><name sortKey="De Bono, Johann S" sort="De Bono, Johann S" uniqKey="De Bono J" first="Johann S" last="De Bono">Johann S. De Bono</name><name sortKey="Durham, Susan" sort="Durham, Susan" uniqKey="Durham S" first="Susan" last="Durham">Susan Durham</name><name sortKey="Efstathiou, Eleni" sort="Efstathiou, Eleni" uniqKey="Efstathiou E" first="Eleni" last="Efstathiou">Eleni Efstathiou</name><name sortKey="Gallardo, Enrique" sort="Gallardo, Enrique" uniqKey="Gallardo E" first="Enrique" last="Gallardo">Enrique Gallardo</name><name sortKey="Goebell, Peter J" sort="Goebell, Peter J" uniqKey="Goebell P" first="Peter J" last="Goebell">Peter J. Goebell</name><name sortKey="Heidenreich, Axel" sort="Heidenreich, Axel" uniqKey="Heidenreich A" first="Axel" last="Heidenreich">Axel Heidenreich</name><name sortKey="Hong, Jun H" sort="Hong, Jun H" uniqKey="Hong J" first="Jun H" last="Hong">Jun H. Hong</name><name sortKey="Logothetis, Christopher J" sort="Logothetis, Christopher J" uniqKey="Logothetis C" first="Christopher J" last="Logothetis">Christopher J. Logothetis</name><name sortKey="Matveev, Vsevolod B" sort="Matveev, Vsevolod B" uniqKey="Matveev V" first="Vsevolod B" last="Matveev">Vsevolod B. Matveev</name><name sortKey="Mccaffrey, John" sort="Mccaffrey, John" uniqKey="Mccaffrey J" first="John" last="Mccaffrey">John Mccaffrey</name><name sortKey="Morris, Michael J" sort="Morris, Michael J" uniqKey="Morris M" first="Michael J" last="Morris">Michael J. Morris</name><name sortKey="Oudard, Stephane" sort="Oudard, Stephane" uniqKey="Oudard S" first="Stephane" last="Oudard">Stephane Oudard</name><name sortKey="Paliwal, Prashni" sort="Paliwal, Prashni" uniqKey="Paliwal P" first="Prashni" last="Paliwal">Prashni Paliwal</name><name sortKey="Richardet, Eduardo" sort="Richardet, Eduardo" uniqKey="Richardet E" first="Eduardo" last="Richardet">Eduardo Richardet</name><name sortKey="Saad, Fred" sort="Saad, Fred" uniqKey="Saad F" first="Fred" last="Saad">Fred Saad</name><name sortKey="Serrano, Sergio V" sort="Serrano, Sergio V" uniqKey="Serrano S" first="Sergio V" last="Serrano">Sergio V. Serrano</name><name sortKey="Sizer, Bruce" sort="Sizer, Bruce" uniqKey="Sizer B" first="Bruce" last="Sizer">Bruce Sizer</name><name sortKey="Trudel, Geralyn C" sort="Trudel, Geralyn C" uniqKey="Trudel G" first="Géralyn C" last="Trudel">Géralyn C. Trudel</name><name sortKey="Wilding, George" sort="Wilding, George" uniqKey="Wilding G" first="George" last="Wilding">George Wilding</name><name sortKey="Yu, Evan Y" sort="Yu, Evan Y" uniqKey="Yu E" first="Evan Y" last="Yu">Evan Y. Yu</name></noCountry></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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