Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043)

A multicentre, randomised, double-blind, phase 3 trial

Eugene D. Kwon, Charles G. Drake, Howard I. Scher, Karim Fizazi, Alberto Bossi, Alfons J M Van den Eertwegh, Michael Krainer, Nadine Houede, Ricardo Santos, Hakim Mahammedi, Siobhan Ng, Michele Maio, Fabio A. Franke, Santhanam Sundar, Neeraj Agarwal, Andries M. Bergman, Tudor E. Ciuleanu, Ernesto Korbenfeld, Lisa Sengeløv, Steinbjorn Hansen & 6 others Christopher Logothetis, Tomasz (Tom) Beer, M. Brent McHenry, Paul Gagnier, David Liu, Winald R. Gerritsen

    Research output: Contribution to journalArticle

    598 Citations (Scopus)

    Abstract

    Background: Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. Methods: We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614. Findings: From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95% CI 9·5-12·7) with ipilimumab and 10·0 months (8·3-11·0) with placebo (hazard ratio [HR] 0·85, 0·72-1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0-5 months was 1·46 (95% CI 1·10-1·95), for 5-12 months was 0·65 (0·50-0·85), and beyond 12 months was 0·60 (0·43-0·86). The most common grade 3-4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3-4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group. Interpretation: Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation. Funding: Bristol-Myers Squibb.

    Original languageEnglish (US)
    Pages (from-to)700-712
    Number of pages13
    JournalThe Lancet Oncology
    Volume15
    Issue number7
    DOIs
    StatePublished - 2014

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    docetaxel
    Castration
    Prostatic Neoplasms
    Radiotherapy
    Placebos
    Drug Therapy
    Poisons
    Survival
    Research Personnel
    ipilimumab
    CTLA-4 Antigen
    Bone and Bones
    Intention to Treat Analysis

    ASJC Scopus subject areas

    • Oncology

    Cite this

    Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043) : A multicentre, randomised, double-blind, phase 3 trial. / Kwon, Eugene D.; Drake, Charles G.; Scher, Howard I.; Fizazi, Karim; Bossi, Alberto; Van den Eertwegh, Alfons J M; Krainer, Michael; Houede, Nadine; Santos, Ricardo; Mahammedi, Hakim; Ng, Siobhan; Maio, Michele; Franke, Fabio A.; Sundar, Santhanam; Agarwal, Neeraj; Bergman, Andries M.; Ciuleanu, Tudor E.; Korbenfeld, Ernesto; Sengeløv, Lisa; Hansen, Steinbjorn; Logothetis, Christopher; Beer, Tomasz (Tom); McHenry, M. Brent; Gagnier, Paul; Liu, David; Gerritsen, Winald R.

    In: The Lancet Oncology, Vol. 15, No. 7, 2014, p. 700-712.

    Research output: Contribution to journalArticle

    Kwon, ED, Drake, CG, Scher, HI, Fizazi, K, Bossi, A, Van den Eertwegh, AJM, Krainer, M, Houede, N, Santos, R, Mahammedi, H, Ng, S, Maio, M, Franke, FA, Sundar, S, Agarwal, N, Bergman, AM, Ciuleanu, TE, Korbenfeld, E, Sengeløv, L, Hansen, S, Logothetis, C, Beer, TT, McHenry, MB, Gagnier, P, Liu, D & Gerritsen, WR 2014, 'Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): A multicentre, randomised, double-blind, phase 3 trial', The Lancet Oncology, vol. 15, no. 7, pp. 700-712. https://doi.org/10.1016/S1470-2045(14)70189-5
    Kwon, Eugene D. ; Drake, Charles G. ; Scher, Howard I. ; Fizazi, Karim ; Bossi, Alberto ; Van den Eertwegh, Alfons J M ; Krainer, Michael ; Houede, Nadine ; Santos, Ricardo ; Mahammedi, Hakim ; Ng, Siobhan ; Maio, Michele ; Franke, Fabio A. ; Sundar, Santhanam ; Agarwal, Neeraj ; Bergman, Andries M. ; Ciuleanu, Tudor E. ; Korbenfeld, Ernesto ; Sengeløv, Lisa ; Hansen, Steinbjorn ; Logothetis, Christopher ; Beer, Tomasz (Tom) ; McHenry, M. Brent ; Gagnier, Paul ; Liu, David ; Gerritsen, Winald R. / Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043) : A multicentre, randomised, double-blind, phase 3 trial. In: The Lancet Oncology. 2014 ; Vol. 15, No. 7. pp. 700-712.
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    title = "Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043): A multicentre, randomised, double-blind, phase 3 trial",
    abstract = "Background: Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. Methods: We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614. Findings: From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95{\%} CI 9·5-12·7) with ipilimumab and 10·0 months (8·3-11·0) with placebo (hazard ratio [HR] 0·85, 0·72-1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0-5 months was 1·46 (95{\%} CI 1·10-1·95), for 5-12 months was 0·65 (0·50-0·85), and beyond 12 months was 0·60 (0·43-0·86). The most common grade 3-4 adverse events were immune-related, occurring in 101 (26{\%}) patients in the ipilimumab group and 11 (3{\%}) of patients in the placebo group. The most frequent grade 3-4 adverse events included diarrhoea (64 [16{\%}] of 393 patients in the ipilimumab group vs seven [2{\%}] of 396 in the placebo group), fatigue (40 [11{\%}] vs 35 [9{\%}]), anaemia (40 [10{\%}] vs 43 [11{\%}]), and colitis (18 [5{\%}] vs 0). Four (1{\%}) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group. Interpretation: Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation. Funding: Bristol-Myers Squibb.",
    author = "Kwon, {Eugene D.} and Drake, {Charles G.} and Scher, {Howard I.} and Karim Fizazi and Alberto Bossi and {Van den Eertwegh}, {Alfons J M} and Michael Krainer and Nadine Houede and Ricardo Santos and Hakim Mahammedi and Siobhan Ng and Michele Maio and Franke, {Fabio A.} and Santhanam Sundar and Neeraj Agarwal and Bergman, {Andries M.} and Ciuleanu, {Tudor E.} and Ernesto Korbenfeld and Lisa Sengel{\o}v and Steinbjorn Hansen and Christopher Logothetis and Beer, {Tomasz (Tom)} and McHenry, {M. Brent} and Paul Gagnier and David Liu and Gerritsen, {Winald R.}",
    year = "2014",
    doi = "10.1016/S1470-2045(14)70189-5",
    language = "English (US)",
    volume = "15",
    pages = "700--712",
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    issn = "1470-2045",
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    TY - JOUR

    T1 - Ipilimumab versus placebo after radiotherapy in patients with metastatic castration-resistant prostate cancer that had progressed after docetaxel chemotherapy (CA184-043)

    T2 - A multicentre, randomised, double-blind, phase 3 trial

    AU - Kwon, Eugene D.

    AU - Drake, Charles G.

    AU - Scher, Howard I.

    AU - Fizazi, Karim

    AU - Bossi, Alberto

    AU - Van den Eertwegh, Alfons J M

    AU - Krainer, Michael

    AU - Houede, Nadine

    AU - Santos, Ricardo

    AU - Mahammedi, Hakim

    AU - Ng, Siobhan

    AU - Maio, Michele

    AU - Franke, Fabio A.

    AU - Sundar, Santhanam

    AU - Agarwal, Neeraj

    AU - Bergman, Andries M.

    AU - Ciuleanu, Tudor E.

    AU - Korbenfeld, Ernesto

    AU - Sengeløv, Lisa

    AU - Hansen, Steinbjorn

    AU - Logothetis, Christopher

    AU - Beer, Tomasz (Tom)

    AU - McHenry, M. Brent

    AU - Gagnier, Paul

    AU - Liu, David

    AU - Gerritsen, Winald R.

    PY - 2014

    Y1 - 2014

    N2 - Background: Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. Methods: We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614. Findings: From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95% CI 9·5-12·7) with ipilimumab and 10·0 months (8·3-11·0) with placebo (hazard ratio [HR] 0·85, 0·72-1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0-5 months was 1·46 (95% CI 1·10-1·95), for 5-12 months was 0·65 (0·50-0·85), and beyond 12 months was 0·60 (0·43-0·86). The most common grade 3-4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3-4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group. Interpretation: Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation. Funding: Bristol-Myers Squibb.

    AB - Background: Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen 4 to enhance antitumour immunity. Our aim was to assess the use of ipilimumab after radiotherapy in patients with metastatic castration-resistant prostate cancer that progressed after docetaxel chemotherapy. Methods: We did a multicentre, randomised, double-blind, phase 3 trial in which men with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment were randomly assigned in a 1:1 ratio to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Non-progressing patients could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months until disease progression, unacceptable toxic effect, or death. Patients were randomly assigned to either treatment group via a minimisation algorithm, and stratified by Eastern Cooperative Oncology Group performance status, alkaline phosphatase concentration, haemoglobin concentration, and investigator site. Patients and investigators were masked to treatment allocation. The primary endpoint was overall survival, assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00861614. Findings: From May 26, 2009, to Feb 15, 2012, 799 patients were randomly assigned (399 to ipilimumab and 400 to placebo), all of whom were included in the intention-to-treat analysis. Median overall survival was 11·2 months (95% CI 9·5-12·7) with ipilimumab and 10·0 months (8·3-11·0) with placebo (hazard ratio [HR] 0·85, 0·72-1·00; p=0·053). However, the assessment of the proportional hazards assumption showed that it was violated (p=0·0031). A piecewise hazard model showed that the HR changed over time: the HR for 0-5 months was 1·46 (95% CI 1·10-1·95), for 5-12 months was 0·65 (0·50-0·85), and beyond 12 months was 0·60 (0·43-0·86). The most common grade 3-4 adverse events were immune-related, occurring in 101 (26%) patients in the ipilimumab group and 11 (3%) of patients in the placebo group. The most frequent grade 3-4 adverse events included diarrhoea (64 [16%] of 393 patients in the ipilimumab group vs seven [2%] of 396 in the placebo group), fatigue (40 [11%] vs 35 [9%]), anaemia (40 [10%] vs 43 [11%]), and colitis (18 [5%] vs 0). Four (1%) deaths occurred because of toxic effects of the study drug, all in the ipilimumab group. Interpretation: Although there was no significant difference between the ipilimumab group and the placebo group in terms of overall survival in the primary analysis, there were signs of activity with the drug that warrant further investigation. Funding: Bristol-Myers Squibb.

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