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 - PubMed (original) (raw)
Clinical Trial
doi: 10.1016/S1470-2045(14)70189-5. Epub 2014 May 13.
Charles G Drake 2, Howard I Scher 3, Karim Fizazi 4, Alberto Bossi 5, Alfons J M van den Eertwegh 6, Michael Krainer 7, Nadine Houede 8, Ricardo Santos 9, Hakim Mahammedi 10, Siobhan Ng 11, Michele Maio 12, Fabio A Franke 13, Santhanam Sundar 14, Neeraj Agarwal 15, Andries M Bergman 16, Tudor E Ciuleanu 17, Ernesto Korbenfeld 18, Lisa Sengeløv 19, Steinbjorn Hansen 20, Christopher Logothetis 21, Tomasz M Beer 22, M Brent McHenry 23, Paul Gagnier 23, David Liu 23, Winald R Gerritsen 24; CA184-043 Investigators
Affiliations
- PMID: 24831977
- PMCID: PMC4418935
- DOI: 10.1016/S1470-2045(14)70189-5
Clinical Trial
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 et al. Lancet Oncol. 2014 Jun.
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.
Copyright © 2014 Elsevier Ltd. All rights reserved.
Figures
Figure 1. Trial profile
*Excluded from safety analyses. †Included in safety analyses.
Figure 2. Overall survival in the intention-to-treat population (A) and by patient subgroup (B)
ECOG=Eastern Cooperative Oncology Group. ULN=upper limit of normal.
Figure 3. Post-hoc subgroup analyses of overall survival in patients with good (A) and poor prognostic features (B)
(A) Overall survival in patients with alkaline phosphatase concentration less than 1·5 times the upper limit of normal (ULN), haemoglobin concentration of 110 g/L or more, and no visceral metastases (ipilimumab, n=146; placebo, n=142). (B) Overall survival in patients with at least one adverse prognostic feature— ie, alkaline phosphatase concentration of 1·5 times ULN or higher, haemoglobin concentration less than 110 g/L, or presence of visceral metastases (ipilimumab, n=253; placebo, n=258).
Figure 4. Progression-free survival in the intention-to-treat population
Comment in
- A near miss for prostate cancer immunotherapy.
Parker C. Parker C. Lancet Oncol. 2014 Jun;15(7):669-71. doi: 10.1016/S1470-2045(14)70220-7. Epub 2014 May 13. Lancet Oncol. 2014. PMID: 24831980 No abstract available. - Prostate cancer: mixed responses to ipilimumab.
Killock D. Killock D. Nat Rev Urol. 2014 Jun;11(6):305. doi: 10.1038/nrurol.2014.121. Epub 2014 May 27. Nat Rev Urol. 2014. PMID: 24861332 No abstract available. - Radiation therapy and immunotherapy: growing pains.
Golden EB, Formenti SC. Golden EB, et al. Int J Radiat Oncol Biol Phys. 2015 Feb 1;91(2):252-4. doi: 10.1016/j.ijrobp.2014.09.018. Int J Radiat Oncol Biol Phys. 2015. PMID: 25636751 No abstract available. - Commentary on: "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 ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, 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 TM, McHenry MB, Gagnier P, Liu D, Gerritsen WR, CA184-043 Investigators. Departments of Urology and Immunology and Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA, Electronic address: kwon.eugene@mayo.edu; Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and Brady Urological Institute, Baltimore, MD, USA; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA; Institut Gustave Roussy, University of Paris-Sud, Villejuif, France; Institut Gustave Roussy, Villejuif, France; VU University Medical Centre, Amsterdam, Netherlands; Vienna General Hospital, Medical University Vienna, Vienna, Austria; Institut Bergonié, Bordeaux, France; CHU Caremeau, Nimes, France; Centro Médico Austral, Buenos Aires, Argentina; Centre Jean Perrin, Clermont-Ferrand, France; St John of God Hospital, Subiaco, WA, Australia; University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; Hospital de Caridade de Ijuí, Ijuí, Brazil; Nottingham University Hospital, Nottingham, UK; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Netherlands Cancer Institute and Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Institute of Oncology Ion Chiricuta and University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania; Hospital Británico de Buenos Aires, Buenos Aires, Argentina; Herlev Hospital, Herlev, Denmark; Odense University Hospital, Odense, Denmark; University of Texas MD Anderson Cancer Center, Houston,
Trump D. Trump D. Urol Oncol. 2016 May;34(5):249-50. doi: 10.1016/j.urolonc.2015.03.013. Epub 2015 Apr 20. Urol Oncol. 2016. PMID: 25907621
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- Commentary on: "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 ED, Drake CG, Scher HI, Fizazi K, Bossi A, van den Eertwegh AJ, 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 TM, McHenry MB, Gagnier P, Liu D, Gerritsen WR, CA184-043 Investigators. Departments of Urology and Immunology and Mayo Clinic Comprehensive Cancer Center, Mayo Clinic, Rochester, MN, USA, Electronic address: kwon.eugene@mayo.edu; Johns Hopkins Sidney Kimmel Comprehensive Cancer Center and Brady Urological Institute, Baltimore, MD, USA; Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, NY, USA; Institut Gustave Roussy, University of Paris-Sud, Villejuif, France; Institut Gustave Roussy, Villejuif, France; VU University Medical Centre, Amsterdam, Netherlands; Vienna General Hospital, Medical University Vienna, Vienna, Austria; Institut Bergonié, Bordeaux, France; CHU Caremeau, Nimes, France; Centro Médico Austral, Buenos Aires, Argentina; Centre Jean Perrin, Clermont-Ferrand, France; St John of God Hospital, Subiaco, WA, Australia; University Hospital of Siena, Istituto Toscano Tumori, Siena, Italy; Hospital de Caridade de Ijuí, Ijuí, Brazil; Nottingham University Hospital, Nottingham, UK; Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA; Netherlands Cancer Institute and Antoni van Leeuwenhoek Hospital, Amsterdam, Netherlands; Institute of Oncology Ion Chiricuta and University of Medicine and Pharmacy Iuliu Hatieganu, Cluj-Napoca, Romania; Hospital Británico de Buenos Aires, Buenos Aires, Argentina; Herlev Hospital, Herlev, Denmark; Odense University Hospital, Odense, Denmark; University of Texas MD Anderson Cancer Center, Houston,
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References
- Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90. - PubMed
- Horwich A, Hugosson J, de Reijke T, et al. Prostate cancer: ESMO Consensus Conference guidelines 2012. Ann Oncol. 2013;24:1141–1162. - PubMed
- de Bono JS, Oudard S, Ozguroglu M, et al. , for the TROPIC Investigators. Prednisone plus cabazitaxel or mitoxantrone for metastatic castration-resistant prostate cancer progressing after docetaxel treatment: a randomised open-label trial. Lancet. 2010;376:1147–1154. - PubMed
- Fizazi K, Scher HI, Molina A, et al. , for the COU-AA-301 Investigators. Abiraterone acetate for treatment of metastatic castration-resistant prostate cancer: final overall survival analysis of the COU-AA-301 randomised, double-blind, placebo-controlled phase 3 study. Lancet Oncol. 2012;13:983–992. - PubMed
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