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.
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.


RESULTS
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.


CONCLUSIONS
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.


BACKGROUND
Bristol-Myers Squibb.
Departments of Urology and Immunology and Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA. Electronic address: kwon.eugene@mayo.edu.
Eugene D
ED
Kwon
Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and Brady Urological Institute, Baltimore, MD, USA.
Charles G
CG
Drake
Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA.
Howard I
HI
Scher
Institut Gustave Roussy, University of Paris-Sud, Villejuif, France.
Karim
K
Fizazi
Institut Gustave Roussy, Villejuif, France.
Alberto
A
Bossi
VU University Medical Centre, Amsterdam, Netherlands.
Alfons J M
AJ
van den Eertwegh
Vienna General Hospital, Medical University Vienna, Vienna, Austria.
Michael
M
Krainer
Institut Bergonié, Bordeaux, France; CHU Caremeau, Nimes, France.
Nadine
N
Houede
Centro Médico Austral, Buenos Aires, Argentina.
Ricardo
R
Santos
Centre Jean Perrin, Clermont-Ferrand, France.
Hakim
H
Mahammedi
St John of God Hospital, Subiaco, WA, Australia.
Siobhan
S
Ng
University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy.
Michele
M
Maio
Hospital de Caridade de Ijuí, Ijuí, Brazil.
Fabio A
FA
Franke
Nottingham University Hospital, Nottingham, UK.
Santhanam
S
Sundar
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
Neeraj
N
Agarwal
Netherlands Cancer Institute and Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands.
Andries M
AM
Bergman
Institute of Oncology Ion Chiricuta and University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania.
Tudor E
TE
Ciuleanu
Hospital Británico de Buenos Aires, Buenos Aires, Argentina.
Ernesto
E
Korbenfeld
Herlev Hospital, Herlev, Denmark.
Lisa
L
Sengeløv
Odense University Hospital, Odense, Denmark.
Steinbjorn
S
Hansen
University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Christopher
C
Logothetis
Oregon Health & Science University Knight Cancer Institute, Portland, OR, USA.
Tomasz M
TM
Beer
Bristol-Myers Squibb, Wallingford, CT, USA.
M Brent
MB
McHenry
Bristol-Myers Squibb, Wallingford, CT, USA.
Paul
P
Gagnier
Bristol-Myers Squibb, Wallingford, CT, USA.
David
D
Liu
Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands.
Winald R
WR
Gerritsen
D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003131:Combined Modality Therapy; D018450:Disease Progression; D000077143:Docetaxel; D004311:Double-Blind Method; D006801:Humans; D000074324:Ipilimumab; D008297:Male; D008875:Middle Aged; D064129:Prostatic Neoplasms, Castration-Resistant / Q000401:mortality / Q000628:therapy*; D043823:Taxoids / Q000627:therapeutic use*
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000074324:Ipilimumab; D043823:Taxoids; D000077143:Docetaxel