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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,

Lancet Oncol 2014 Jun;15(7):700-12.

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.

Comment from Henk van der Poel:
Being breakthrough of the year in 2013 as announced by the journal Science certainly holds some promise for immunotherapy and cancer. Earlier studies on immunomodulators in prostate cancer management revealed improved overall survival despite absence of clear benefits for progression-free survival. Ipilimumab, an inhibitor of CTLA4, combined with 1x8Gy radiotherapy to bone metastases, however, failed to improve overall survival in this trial. Subgroup analysis, however, clearly showed benefit and unlike earlier immunotherapy trials in prostate cancer, ipilimumab and radiotherapy significantly delayed clinical progression by almost a month. What can we learn from this trial? Patients with visceral metastases were unlikely to response favorably to ipilimumab. Even worse, death was 46% more likely after 5 months in the ipilimumab group compared to placebo. Then again, in men with low alkaline phosphatase levels, no anemia and no visceral metastases at entry, median overall survival gain in the ipilimumab was an impressive 6.9 months and comparable to figures from the sipuleucel-T trial (IMPACT trial). Interestingly, in the sipuleucel-T trial where CRPC patients were treated with sipuleucel-T vaccination therapy, median overall survival in the control population was 21.7months that is more than twice the median survival in the ipilimumab trial. Likewise, whereas prior docetaxel was given in only 15% of men in the sipuleucel-T trial all men in the ipilimumab trial had prior docetaxel treatment at entry. These observations suggest that if used in CRPC, immunotherapy seems most effective when given early. With a mild toxicity profile (5% diarrhea as most frequent toxicity) ipilimumab may certainly have a role in prostate cancer management despite this negative trial. Men with castration resistant prostate cancer, no prior docetaxel, no visceral metastases and good performance status are currently studied in the CA184-095 trial comparing ipilimumab to placebo. The trial completed accrual. In this trial no radiotherapy is applied but the inclusion criteria remarkably resemble those of the men that were most likely to benefit in the CA184-043.

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