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Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial

Summary Background Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases. We assessed denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or... Full description

Journal Title: The Lancet (British edition) 2012, Vol.379 (9810), p.39-46
Main Author: Smith, Matthew R, Prof
Other Authors: Saad, Fred, Prof , Coleman, Robert, Prof , Shore, Neal, MD , Fizazi, Karim, Prof , Tombal, Bertrand, Prof , Miller, Kurt, Prof , Sieber, Paul, MD , Karsh, Lawrence, MD , Damião, Ronaldo, Prof , Tammela, Teuvo L, Prof , Egerdie, Blair, MD , Van Poppel, Hendrik, Prof , Chin, Joseph, Prof , Morote, Juan, Prof , Gómez-Veiga, Francisco, MD , Borkowski, Tomasz, Prof , Ye, Zhishen, PhD , Kupic, Amy, MA , Dansey, Roger, MD , Goessl, Carsten, MD
Format: Electronic Article Electronic Article
Language: English
Subjects:
Men
Quelle: Alma/SFX Local Collection
Publisher: England: Elsevier Ltd
ID: ISSN: 0140-6736
Link: https://www.ncbi.nlm.nih.gov/pubmed/22093187
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title: Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial
format: Article
creator:
  • Smith, Matthew R, Prof
  • Saad, Fred, Prof
  • Coleman, Robert, Prof
  • Shore, Neal, MD
  • Fizazi, Karim, Prof
  • Tombal, Bertrand, Prof
  • Miller, Kurt, Prof
  • Sieber, Paul, MD
  • Karsh, Lawrence, MD
  • Damião, Ronaldo, Prof
  • Tammela, Teuvo L, Prof
  • Egerdie, Blair, MD
  • Van Poppel, Hendrik, Prof
  • Chin, Joseph, Prof
  • Morote, Juan, Prof
  • Gómez-Veiga, Francisco, MD
  • Borkowski, Tomasz, Prof
  • Ye, Zhishen, PhD
  • Kupic, Amy, MA
  • Dansey, Roger, MD
  • Goessl, Carsten, MD
subjects:
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal - administration & dosage
  • Antibodies, Monoclonal - adverse effects
  • Antibodies, Monoclonal, Humanized
  • Bone Neoplasms - secondary
  • Cancer therapies
  • Denosumab
  • Diagnosis
  • Disease Progression
  • Disease-Free Survival
  • Double-Blind Method
  • Drug therapy
  • Family medical history
  • Health aspects
  • Humans
  • Injections, Subcutaneous
  • Internal Medicine
  • Male
  • Men
  • Mortality
  • Orchiectomy
  • Prostate cancer
  • Prostate-Specific Antigen - blood
  • Prostatic Neoplasms - drug therapy
  • Prostatic Neoplasms - pathology
  • Prostatic Neoplasms - surgery
  • RANK Ligand - administration & dosage
  • RANK Ligand - adverse effects
ispartof: The Lancet (British edition), 2012, Vol.379 (9810), p.39-46
description: Summary Background Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases. We assessed denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or death in non-metastatic castration-resistant prostate cancer. Methods In this phase 3, double-blind, randomised, placebo-controlled study, men with non-metastatic castration-resistant prostate cancer at high risk of bone metastasis (prostate-specific antigen [PSA] ≥8·0 μg/L or PSA doubling time ≤10·0 months, or both) were enrolled at 319 centres from 30 countries. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous denosumab 120 mg or subcutaneous placebo every 4 weeks. Randomisation was stratified by PSA eligibility criteria and previous or ongoing chemotherapy for prostate cancer. Patients, investigators, and all people involved in study conduct were masked to treatment allocation. The primary endpoint was bone-metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause. Efficacy analysis was by intention to treat. The masked treatment phase of the trial has been completed. This trial was registered at ClinicalTrials.gov , number NCT00286091. Findings 1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo). Denosumab significantly increased bone-metastasis-free survival by a median of 4·2 months compared with placebo (median 29·5 [95% CI 25·4–33·3] vs 25·2 [22·2–29·5] months; hazard ratio [HR] 0·85, 95% CI 0·73–0·98, p=0·028). Denosumab also significantly delayed time to first bone metastasis (33·2 [95% CI 29·5–38·0] vs 29·5 [22·4–33·1] months; HR 0·84, 95% CI 0·71–0·98, p=0·032). Overall survival did not differ between groups (denosumab, 43·9 [95% CI 40·1–not estimable] months vs placebo, 44·8 [40·1–not estimable] months; HR 1·01, 95% CI 0·85–1·20, p=0·91). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two (
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0140-6736
fulltext: fulltext
issn:
  • 0140-6736
  • 1474-547X
url: Link


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titleDenosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial
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creatorSmith, Matthew R, Prof ; Saad, Fred, Prof ; Coleman, Robert, Prof ; Shore, Neal, MD ; Fizazi, Karim, Prof ; Tombal, Bertrand, Prof ; Miller, Kurt, Prof ; Sieber, Paul, MD ; Karsh, Lawrence, MD ; Damião, Ronaldo, Prof ; Tammela, Teuvo L, Prof ; Egerdie, Blair, MD ; Van Poppel, Hendrik, Prof ; Chin, Joseph, Prof ; Morote, Juan, Prof ; Gómez-Veiga, Francisco, MD ; Borkowski, Tomasz, Prof ; Ye, Zhishen, PhD ; Kupic, Amy, MA ; Dansey, Roger, MD ; Goessl, Carsten, MD
creatorcontribSmith, Matthew R, Prof ; Saad, Fred, Prof ; Coleman, Robert, Prof ; Shore, Neal, MD ; Fizazi, Karim, Prof ; Tombal, Bertrand, Prof ; Miller, Kurt, Prof ; Sieber, Paul, MD ; Karsh, Lawrence, MD ; Damião, Ronaldo, Prof ; Tammela, Teuvo L, Prof ; Egerdie, Blair, MD ; Van Poppel, Hendrik, Prof ; Chin, Joseph, Prof ; Morote, Juan, Prof ; Gómez-Veiga, Francisco, MD ; Borkowski, Tomasz, Prof ; Ye, Zhishen, PhD ; Kupic, Amy, MA ; Dansey, Roger, MD ; Goessl, Carsten, MD
descriptionSummary Background Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases. We assessed denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or death in non-metastatic castration-resistant prostate cancer. Methods In this phase 3, double-blind, randomised, placebo-controlled study, men with non-metastatic castration-resistant prostate cancer at high risk of bone metastasis (prostate-specific antigen [PSA] ≥8·0 μg/L or PSA doubling time ≤10·0 months, or both) were enrolled at 319 centres from 30 countries. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous denosumab 120 mg or subcutaneous placebo every 4 weeks. Randomisation was stratified by PSA eligibility criteria and previous or ongoing chemotherapy for prostate cancer. Patients, investigators, and all people involved in study conduct were masked to treatment allocation. The primary endpoint was bone-metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause. Efficacy analysis was by intention to treat. The masked treatment phase of the trial has been completed. This trial was registered at ClinicalTrials.gov , number NCT00286091. Findings 1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo). Denosumab significantly increased bone-metastasis-free survival by a median of 4·2 months compared with placebo (median 29·5 [95% CI 25·4–33·3] vs 25·2 [22·2–29·5] months; hazard ratio [HR] 0·85, 95% CI 0·73–0·98, p=0·028). Denosumab also significantly delayed time to first bone metastasis (33·2 [95% CI 29·5–38·0] vs 29·5 [22·4–33·1] months; HR 0·84, 95% CI 0·71–0·98, p=0·032). Overall survival did not differ between groups (denosumab, 43·9 [95% CI 40·1–not estimable] months vs placebo, 44·8 [40·1–not estimable] months; HR 1·01, 95% CI 0·85–1·20, p=0·91). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two (<1%) on placebo. Interpretation This large randomised study shows that targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer. Funding Amgen Inc.
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subjectAged ; Aged, 80 and over ; Antibodies, Monoclonal - administration & dosage ; Antibodies, Monoclonal - adverse effects ; Antibodies, Monoclonal, Humanized ; Bone Neoplasms - secondary ; Cancer therapies ; Denosumab ; Diagnosis ; Disease Progression ; Disease-Free Survival ; Double-Blind Method ; Drug therapy ; Family medical history ; Health aspects ; Humans ; Injections, Subcutaneous ; Internal Medicine ; Male ; Men ; Mortality ; Orchiectomy ; Prostate cancer ; Prostate-Specific Antigen - blood ; Prostatic Neoplasms - drug therapy ; Prostatic Neoplasms - pathology ; Prostatic Neoplasms - surgery ; RANK Ligand - administration & dosage ; RANK Ligand - adverse effects
ispartofThe Lancet (British edition), 2012, Vol.379 (9810), p.39-46
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1Saad, Fred, Prof
2Coleman, Robert, Prof
3Shore, Neal, MD
4Fizazi, Karim, Prof
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6Miller, Kurt, Prof
7Sieber, Paul, MD
8Karsh, Lawrence, MD
9Damião, Ronaldo, Prof
10Tammela, Teuvo L, Prof
11Egerdie, Blair, MD
12Van Poppel, Hendrik, Prof
13Chin, Joseph, Prof
14Morote, Juan, Prof
15Gómez-Veiga, Francisco, MD
16Borkowski, Tomasz, Prof
17Ye, Zhishen, PhD
18Kupic, Amy, MA
19Dansey, Roger, MD
20Goessl, Carsten, MD
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0Denosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial
1The Lancet (British edition)
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descriptionSummary Background Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases. We assessed denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or death in non-metastatic castration-resistant prostate cancer. Methods In this phase 3, double-blind, randomised, placebo-controlled study, men with non-metastatic castration-resistant prostate cancer at high risk of bone metastasis (prostate-specific antigen [PSA] ≥8·0 μg/L or PSA doubling time ≤10·0 months, or both) were enrolled at 319 centres from 30 countries. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous denosumab 120 mg or subcutaneous placebo every 4 weeks. Randomisation was stratified by PSA eligibility criteria and previous or ongoing chemotherapy for prostate cancer. Patients, investigators, and all people involved in study conduct were masked to treatment allocation. The primary endpoint was bone-metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause. Efficacy analysis was by intention to treat. The masked treatment phase of the trial has been completed. This trial was registered at ClinicalTrials.gov , number NCT00286091. Findings 1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo). Denosumab significantly increased bone-metastasis-free survival by a median of 4·2 months compared with placebo (median 29·5 [95% CI 25·4–33·3] vs 25·2 [22·2–29·5] months; hazard ratio [HR] 0·85, 95% CI 0·73–0·98, p=0·028). Denosumab also significantly delayed time to first bone metastasis (33·2 [95% CI 29·5–38·0] vs 29·5 [22·4–33·1] months; HR 0·84, 95% CI 0·71–0·98, p=0·032). Overall survival did not differ between groups (denosumab, 43·9 [95% CI 40·1–not estimable] months vs placebo, 44·8 [40·1–not estimable] months; HR 1·01, 95% CI 0·85–1·20, p=0·91). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two (<1%) on placebo. Interpretation This large randomised study shows that targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer. Funding Amgen Inc.
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2Antibodies, Monoclonal - administration & dosage
3Antibodies, Monoclonal - adverse effects
4Antibodies, Monoclonal, Humanized
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13Family medical history
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16Injections, Subcutaneous
17Internal Medicine
18Male
19Men
20Mortality
21Orchiectomy
22Prostate cancer
23Prostate-Specific Antigen - blood
24Prostatic Neoplasms - drug therapy
25Prostatic Neoplasms - pathology
26Prostatic Neoplasms - surgery
27RANK Ligand - administration & dosage
28RANK Ligand - adverse effects
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13Chin, Joseph, Prof
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15Gómez-Veiga, Francisco, MD
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titleDenosumab and bone-metastasis-free survival in men with castration-resistant prostate cancer: results of a phase 3, randomised, placebo-controlled trial
authorSmith, Matthew R, Prof ; Saad, Fred, Prof ; Coleman, Robert, Prof ; Shore, Neal, MD ; Fizazi, Karim, Prof ; Tombal, Bertrand, Prof ; Miller, Kurt, Prof ; Sieber, Paul, MD ; Karsh, Lawrence, MD ; Damião, Ronaldo, Prof ; Tammela, Teuvo L, Prof ; Egerdie, Blair, MD ; Van Poppel, Hendrik, Prof ; Chin, Joseph, Prof ; Morote, Juan, Prof ; Gómez-Veiga, Francisco, MD ; Borkowski, Tomasz, Prof ; Ye, Zhishen, PhD ; Kupic, Amy, MA ; Dansey, Roger, MD ; Goessl, Carsten, MD
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6Cancer therapies
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13Family medical history
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15Humans
16Injections, Subcutaneous
17Internal Medicine
18Male
19Men
20Mortality
21Orchiectomy
22Prostate cancer
23Prostate-Specific Antigen - blood
24Prostatic Neoplasms - drug therapy
25Prostatic Neoplasms - pathology
26Prostatic Neoplasms - surgery
27RANK Ligand - administration & dosage
28RANK Ligand - adverse effects
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7Sieber, Paul, MD
8Karsh, Lawrence, MD
9Damião, Ronaldo, Prof
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15Gómez-Veiga, Francisco, MD
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eissn1474-547X
codenLANCAO
abstractSummary Background Bone metastases are a major cause of morbidity and mortality in men with prostate cancer. Preclinical studies suggest that osteoclast inhibition might prevent bone metastases. We assessed denosumab, a fully human anti-RANKL monoclonal antibody, for prevention of bone metastasis or death in non-metastatic castration-resistant prostate cancer. Methods In this phase 3, double-blind, randomised, placebo-controlled study, men with non-metastatic castration-resistant prostate cancer at high risk of bone metastasis (prostate-specific antigen [PSA] ≥8·0 μg/L or PSA doubling time ≤10·0 months, or both) were enrolled at 319 centres from 30 countries. Patients were randomly assigned (1:1) via an interactive voice response system to receive subcutaneous denosumab 120 mg or subcutaneous placebo every 4 weeks. Randomisation was stratified by PSA eligibility criteria and previous or ongoing chemotherapy for prostate cancer. Patients, investigators, and all people involved in study conduct were masked to treatment allocation. The primary endpoint was bone-metastasis-free survival, a composite endpoint determined by time to first occurrence of bone metastasis (symptomatic or asymptomatic) or death from any cause. Efficacy analysis was by intention to treat. The masked treatment phase of the trial has been completed. This trial was registered at ClinicalTrials.gov , number NCT00286091. Findings 1432 patients were randomly assigned to treatment groups (716 denosumab, 716 placebo). Denosumab significantly increased bone-metastasis-free survival by a median of 4·2 months compared with placebo (median 29·5 [95% CI 25·4–33·3] vs 25·2 [22·2–29·5] months; hazard ratio [HR] 0·85, 95% CI 0·73–0·98, p=0·028). Denosumab also significantly delayed time to first bone metastasis (33·2 [95% CI 29·5–38·0] vs 29·5 [22·4–33·1] months; HR 0·84, 95% CI 0·71–0·98, p=0·032). Overall survival did not differ between groups (denosumab, 43·9 [95% CI 40·1–not estimable] months vs placebo, 44·8 [40·1–not estimable] months; HR 1·01, 95% CI 0·85–1·20, p=0·91). Rates of adverse events and serious adverse events were similar in both groups, except for osteonecrosis of the jaw and hypocalcaemia. 33 (5%) patients on denosumab developed osteonecrosis of the jaw versus none on placebo. Hypocalcaemia occurred in 12 (2%) patients on denosumab and two (<1%) on placebo. Interpretation This large randomised study shows that targeting of the bone microenvironment can delay bone metastasis in men with prostate cancer. Funding Amgen Inc.
copEngland
pubElsevier Ltd
pmid22093187
doi10.1016/S0140-6736(11)61226-9
oafree_for_read