medwireNews: Men with metastatic castration-resistant prostate cancer (mCRPC) who receive ipilimumab after radiotherapy to bone metastases have a significantly better long-term survival rate than those who receive placebo, study findings indicate.
Primary analysis of the phase 3 CA184-043 trial suggested that there was no significant difference in survival between the 399 men who were randomly assigned to receive ipilimumab 10 mg/kg every 3 weeks for four doses then every 3 months as maintenance until progression, and the 400 assigned to placebo.
However, with an additional 2.4 years of follow-up, in which time 90% of patients had died, Karim Fizazi (Institut Gustave Roussy, Villejuif, France) and co-investigators found this was not the case.
They report in European Urology that survival curves for the two study arms crossed at around 7 to 8 months and continued to separate thereafter, with long-term survival rates initially favoring patients who received placebo but ultimately being higher in those who received ipilimumab.
Indeed, during the first 5 months from baseline, individuals in the ipilimumab arm had a significant 49% higher risk for death than those in the placebo arm but from 5 months onward the risk was a significant 34% lower.
At a median 50 months of follow-up, median overall survival (OS) was 11.0 months with ipilimumab and 10.0 months with placebo, with disease progression the most common cause of death in both arms.
The researchers also estimated yearly OS rates using Kaplan–Meier analysis. At 1 year there was no significant difference between the patients who received ipilimumab versus placebo (47.0 vs 41.0%), but the between-group differences were significant at 2 years (25.2 vs 16.6%), 3 years (15.3 vs 7.9%), 4 years (10.1 vs 3.3%), and 5 years (7.9 vs 2.7%).
Fizazi et al note that seven (1.8%) patients in the ipilimumab arm and one (0.3%) in the placebo arm died as a result of study drug toxicity but the safety profile of ipilimumab was consistent with that reported previously.
Discussing their findings, the authors say that the failure of the primary analysis of this trial to demonstrate significantly improved OS with ipilimumab is likely due to the apparent increased risk for death during the first 7 months.
They believe this could be explained by “hyperprogression of cancer,” which has been described with this type of immunotherapy.
Fizazi and colleagues also suggest that an excess of early adverse events in the ipilimumab arm and the fact that “men with more indolent cancers and those with a lower burden of cancer may also be more sensitive to immunotherapy [...] may account for the delayed effect on survival.”
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