Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer

Tomasz M Beer, Eugene D Kwon, Charles G Drake, Karim Fizazi, Christopher Logothetis, Gwenaelle Gravis, Vinod Ganju, Jonathan Polikoff, Fred Saad, Piotr Humanski, Josep M Piulats, Pablo Gonzalez Mella, Siobhan S Ng, Dirk Jaeger, Francis X Parnis, Fabio A Franke, Javier Puente, Roman Carvajal, Lisa Sengeløv, M Brent McHenryArvind Varma, Alfonsus J van den Eertwegh, Winald Gerritsen, Laura Ridolfi

Research output: Contribution to journalArticle

166 Citations (Scopus)

Abstract

Purpose Ipilimumab increases antitumor T-cell responses by binding to cytotoxic T-lymphocyte antigen 4. We evaluated treatment with ipilimumab in asymptomatic or minimally symptomatic patients with chemotherapy-naive metastatic castration-resistant prostate cancer without visceral metastases. Patients and Methods In this multicenter, double-blind, phase III trial, patients were randomly assigned (2:1) to ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Ipilimumab 10 mg/kg or placebo maintenance therapy was administered to nonprogressing patients every 3 months. The primary end point was overall survival (OS). Results Four hundred patients were randomly assigned to ipilimumab and 202 to placebo; 399 were treated with ipilimumab and 199 with placebo. Median OS was 28.7 months (95% CI, 24.5 to 32.5 months) in the ipilimumab arm versus 29.7 months (95% CI, 26.1 to 34.2 months) in the placebo arm (hazard ratio, 1.11; 95.87% CI, 0.88 to 1.39; P = .3667). Median progression-free survival was 5.6 months in the ipilimumab arm versus 3.8 with placebo arm (hazard ratio, 0.67; 95.87% CI, 0.55 to 0.81). Exploratory analyses showed a higher prostate-specific antigen response rate with ipilimumab (23%) than with placebo (8%). Diarrhea (15%) was the only grade 3 to 4 treatment-related adverse event (AE) reported in ≥ 10% of ipilimumab-treated patients. Nine (2%) deaths occurred in the ipilimumab arm due to treatment-related AEs; no deaths occurred in the placebo arm. Immune-related grade 3 to 4 AEs occurred in 31% and 2% of patients, respectively. Conclusion Ipilimumab did not improve OS in patients with metastatic castration-resistant prostate cancer. The observed increases in progression-free survival and prostate-specific antigen response rates suggest antitumor activity in a patient subset.

Original languageEnglish
Pages (from-to)40-47
Number of pages8
JournalJournal of Clinical Oncology
Volume35
Issue number1
DOIs
Publication statusPublished - Jan 2017

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Castration
Prostatic Neoplasms
Placebos
Drug Therapy
Prostate-Specific Antigen
Disease-Free Survival
Survival
ipilimumab
CTLA-4 Antigen
Therapeutics
Diarrhea
Neoplasm Metastasis

Keywords

  • Adult
  • Aged
  • Aged, 80 and over
  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Asymptomatic Diseases
  • Bone Neoplasms
  • Diarrhea
  • Disease-Free Survival
  • Double-Blind Method
  • Humans
  • Ipilimumab
  • Male
  • Middle Aged
  • Prostate-Specific Antigen
  • Prostatic Neoplasms, Castration-Resistant
  • Survival Rate
  • Clinical Trial, Phase III
  • Journal Article
  • Multicenter Study
  • Randomized Controlled Trial

Cite this

Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer. / Beer, Tomasz M; Kwon, Eugene D; Drake, Charles G; Fizazi, Karim; Logothetis, Christopher; Gravis, Gwenaelle; Ganju, Vinod; Polikoff, Jonathan; Saad, Fred; Humanski, Piotr; Piulats, Josep M; Gonzalez Mella, Pablo; Ng, Siobhan S; Jaeger, Dirk; Parnis, Francis X; Franke, Fabio A; Puente, Javier; Carvajal, Roman; Sengeløv, Lisa; McHenry, M Brent; Varma, Arvind; van den Eertwegh, Alfonsus J; Gerritsen, Winald; Ridolfi, Laura.

In: Journal of Clinical Oncology, Vol. 35, No. 1, 01.2017, p. 40-47.

Research output: Contribution to journalArticle

Beer, TM, Kwon, ED, Drake, CG, Fizazi, K, Logothetis, C, Gravis, G, Ganju, V, Polikoff, J, Saad, F, Humanski, P, Piulats, JM, Gonzalez Mella, P, Ng, SS, Jaeger, D, Parnis, FX, Franke, FA, Puente, J, Carvajal, R, Sengeløv, L, McHenry, MB, Varma, A, van den Eertwegh, AJ, Gerritsen, W & Ridolfi, L 2017, 'Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer', Journal of Clinical Oncology, vol. 35, no. 1, pp. 40-47. https://doi.org/10.1200/JCO.2016.69.1584
Beer, Tomasz M ; Kwon, Eugene D ; Drake, Charles G ; Fizazi, Karim ; Logothetis, Christopher ; Gravis, Gwenaelle ; Ganju, Vinod ; Polikoff, Jonathan ; Saad, Fred ; Humanski, Piotr ; Piulats, Josep M ; Gonzalez Mella, Pablo ; Ng, Siobhan S ; Jaeger, Dirk ; Parnis, Francis X ; Franke, Fabio A ; Puente, Javier ; Carvajal, Roman ; Sengeløv, Lisa ; McHenry, M Brent ; Varma, Arvind ; van den Eertwegh, Alfonsus J ; Gerritsen, Winald ; Ridolfi, Laura. / Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer. In: Journal of Clinical Oncology. 2017 ; Vol. 35, No. 1. pp. 40-47.
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abstract = "Purpose Ipilimumab increases antitumor T-cell responses by binding to cytotoxic T-lymphocyte antigen 4. We evaluated treatment with ipilimumab in asymptomatic or minimally symptomatic patients with chemotherapy-naive metastatic castration-resistant prostate cancer without visceral metastases. Patients and Methods In this multicenter, double-blind, phase III trial, patients were randomly assigned (2:1) to ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Ipilimumab 10 mg/kg or placebo maintenance therapy was administered to nonprogressing patients every 3 months. The primary end point was overall survival (OS). Results Four hundred patients were randomly assigned to ipilimumab and 202 to placebo; 399 were treated with ipilimumab and 199 with placebo. Median OS was 28.7 months (95{\%} CI, 24.5 to 32.5 months) in the ipilimumab arm versus 29.7 months (95{\%} CI, 26.1 to 34.2 months) in the placebo arm (hazard ratio, 1.11; 95.87{\%} CI, 0.88 to 1.39; P = .3667). Median progression-free survival was 5.6 months in the ipilimumab arm versus 3.8 with placebo arm (hazard ratio, 0.67; 95.87{\%} CI, 0.55 to 0.81). Exploratory analyses showed a higher prostate-specific antigen response rate with ipilimumab (23{\%}) than with placebo (8{\%}). Diarrhea (15{\%}) was the only grade 3 to 4 treatment-related adverse event (AE) reported in ≥ 10{\%} of ipilimumab-treated patients. Nine (2{\%}) deaths occurred in the ipilimumab arm due to treatment-related AEs; no deaths occurred in the placebo arm. Immune-related grade 3 to 4 AEs occurred in 31{\%} and 2{\%} of patients, respectively. Conclusion Ipilimumab did not improve OS in patients with metastatic castration-resistant prostate cancer. The observed increases in progression-free survival and prostate-specific antigen response rates suggest antitumor activity in a patient subset.",
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author = "Beer, {Tomasz M} and Kwon, {Eugene D} and Drake, {Charles G} and Karim Fizazi and Christopher Logothetis and Gwenaelle Gravis and Vinod Ganju and Jonathan Polikoff and Fred Saad and Piotr Humanski and Piulats, {Josep M} and {Gonzalez Mella}, Pablo and Ng, {Siobhan S} and Dirk Jaeger and Parnis, {Francis X} and Franke, {Fabio A} and Javier Puente and Roman Carvajal and Lisa Sengel{\o}v and McHenry, {M Brent} and Arvind Varma and {van den Eertwegh}, {Alfonsus J} and Winald Gerritsen and Laura Ridolfi",
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TY - JOUR

T1 - Randomized, Double-Blind, Phase III Trial of Ipilimumab Versus Placebo in Asymptomatic or Minimally Symptomatic Patients With Metastatic Chemotherapy-Naive Castration-Resistant Prostate Cancer

AU - Beer, Tomasz M

AU - Kwon, Eugene D

AU - Drake, Charles G

AU - Fizazi, Karim

AU - Logothetis, Christopher

AU - Gravis, Gwenaelle

AU - Ganju, Vinod

AU - Polikoff, Jonathan

AU - Saad, Fred

AU - Humanski, Piotr

AU - Piulats, Josep M

AU - Gonzalez Mella, Pablo

AU - Ng, Siobhan S

AU - Jaeger, Dirk

AU - Parnis, Francis X

AU - Franke, Fabio A

AU - Puente, Javier

AU - Carvajal, Roman

AU - Sengeløv, Lisa

AU - McHenry, M Brent

AU - Varma, Arvind

AU - van den Eertwegh, Alfonsus J

AU - Gerritsen, Winald

AU - Ridolfi, Laura

PY - 2017/1

Y1 - 2017/1

N2 - Purpose Ipilimumab increases antitumor T-cell responses by binding to cytotoxic T-lymphocyte antigen 4. We evaluated treatment with ipilimumab in asymptomatic or minimally symptomatic patients with chemotherapy-naive metastatic castration-resistant prostate cancer without visceral metastases. Patients and Methods In this multicenter, double-blind, phase III trial, patients were randomly assigned (2:1) to ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Ipilimumab 10 mg/kg or placebo maintenance therapy was administered to nonprogressing patients every 3 months. The primary end point was overall survival (OS). Results Four hundred patients were randomly assigned to ipilimumab and 202 to placebo; 399 were treated with ipilimumab and 199 with placebo. Median OS was 28.7 months (95% CI, 24.5 to 32.5 months) in the ipilimumab arm versus 29.7 months (95% CI, 26.1 to 34.2 months) in the placebo arm (hazard ratio, 1.11; 95.87% CI, 0.88 to 1.39; P = .3667). Median progression-free survival was 5.6 months in the ipilimumab arm versus 3.8 with placebo arm (hazard ratio, 0.67; 95.87% CI, 0.55 to 0.81). Exploratory analyses showed a higher prostate-specific antigen response rate with ipilimumab (23%) than with placebo (8%). Diarrhea (15%) was the only grade 3 to 4 treatment-related adverse event (AE) reported in ≥ 10% of ipilimumab-treated patients. Nine (2%) deaths occurred in the ipilimumab arm due to treatment-related AEs; no deaths occurred in the placebo arm. Immune-related grade 3 to 4 AEs occurred in 31% and 2% of patients, respectively. Conclusion Ipilimumab did not improve OS in patients with metastatic castration-resistant prostate cancer. The observed increases in progression-free survival and prostate-specific antigen response rates suggest antitumor activity in a patient subset.

AB - Purpose Ipilimumab increases antitumor T-cell responses by binding to cytotoxic T-lymphocyte antigen 4. We evaluated treatment with ipilimumab in asymptomatic or minimally symptomatic patients with chemotherapy-naive metastatic castration-resistant prostate cancer without visceral metastases. Patients and Methods In this multicenter, double-blind, phase III trial, patients were randomly assigned (2:1) to ipilimumab 10 mg/kg or placebo every 3 weeks for up to four doses. Ipilimumab 10 mg/kg or placebo maintenance therapy was administered to nonprogressing patients every 3 months. The primary end point was overall survival (OS). Results Four hundred patients were randomly assigned to ipilimumab and 202 to placebo; 399 were treated with ipilimumab and 199 with placebo. Median OS was 28.7 months (95% CI, 24.5 to 32.5 months) in the ipilimumab arm versus 29.7 months (95% CI, 26.1 to 34.2 months) in the placebo arm (hazard ratio, 1.11; 95.87% CI, 0.88 to 1.39; P = .3667). Median progression-free survival was 5.6 months in the ipilimumab arm versus 3.8 with placebo arm (hazard ratio, 0.67; 95.87% CI, 0.55 to 0.81). Exploratory analyses showed a higher prostate-specific antigen response rate with ipilimumab (23%) than with placebo (8%). Diarrhea (15%) was the only grade 3 to 4 treatment-related adverse event (AE) reported in ≥ 10% of ipilimumab-treated patients. Nine (2%) deaths occurred in the ipilimumab arm due to treatment-related AEs; no deaths occurred in the placebo arm. Immune-related grade 3 to 4 AEs occurred in 31% and 2% of patients, respectively. Conclusion Ipilimumab did not improve OS in patients with metastatic castration-resistant prostate cancer. The observed increases in progression-free survival and prostate-specific antigen response rates suggest antitumor activity in a patient subset.

KW - Adult

KW - Aged

KW - Aged, 80 and over

KW - Antibodies, Monoclonal

KW - Antineoplastic Agents

KW - Asymptomatic Diseases

KW - Bone Neoplasms

KW - Diarrhea

KW - Disease-Free Survival

KW - Double-Blind Method

KW - Humans

KW - Ipilimumab

KW - Male

KW - Middle Aged

KW - Prostate-Specific Antigen

KW - Prostatic Neoplasms, Castration-Resistant

KW - Survival Rate

KW - Clinical Trial, Phase III

KW - Journal Article

KW - Multicenter Study

KW - Randomized Controlled Trial

U2 - 10.1200/JCO.2016.69.1584

DO - 10.1200/JCO.2016.69.1584

M3 - Article

C2 - 28034081

VL - 35

SP - 40

EP - 47

JO - Journal of Clinical Oncology

JF - Journal of Clinical Oncology

SN - 0732-183X

IS - 1

ER -