Study Examines Immunotherapy in Metastatic Castration-Resistant Prostate Cancer
In the randomized, phase III CA184-043 trial, ipilimumab (Yervoy) improved progression-free survival and prostate-specific antigen (PSA) response compared with placebo, but failed to improve overall survival significantly in postdocetaxel metastatic castration-resistant prostate cancer. Prespecified subset analyses suggested that ipilimumab improves survival in patients with more favorable prognostic factors (ie, no visceral metastasis, lower levels of alkaline phosphatase, and elevated hemoglobin).
“Although the primary endpoint of this trial was not met, antitumor activity [of ipilimumab] is suggested by other efficacy endpoints. It appears that patients with more favorable prognostic factors may be more likely to benefit from ipilimumab treatment,” said lead author Charles Drake, MD, of The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore. Dr. Drake presented the results of the subset analyses of overall survival at the 2014 Genitourinary Cancers Symposium (Abstract 2).
“There are several new therapies in metastatic castration-resistant prostate cancer,” Dr. Drake noted, “but few with long-term responses.” The rationale for studying this new approach in castration-resistant prostate cancer was based on ipilimumab’s mechanism of action and success of this immunotherapy in metastatic melanoma, with about 25% of patients alive at 5 years, he said.
Study Details
The study included 799 patients with metastatic castration-resistant prostate cancer who had received prior treatment with docetaxel. All patients received at least one dose of radiotherapy to bone-directed sites and were randomly assigned in a 1:1 ratio to ipilimumab vs placebo.
Patients in the ipilimumab arm received maintenance ipilimumab every 12 weeks, and those in the placebo arm received maintenance placebo every 12 weeks.
Median overall survival was 11.2 months for ipilimumab vs 10 months for placebo (hazard ratio [HR] = 0.85, 95% confidence interval [CI] = 0.72–1.00, P = .0530). The secondary endpoint of progression-free survival was met, with a median progression-free survival of 4 months in the ipilimumab group and 3 months in placebo group.
Effect of Visceral Metastases on Survival
The investigators went back and analyzed subgroups to determine if any subgroups had a survival benefit from ipilimumab. The only factor that appeared to be of importance was the presence of visceral metastases. Median overall survival was 14.4 months with ipilimumab in patients with no visceral metastases vs 5.7 months in the presence of visceral metastases.
Dr. Drake acknowledged that the trial was underpowered to show an interaction between ipilimumab and visceral metastases, “but the hazard ratio [HR = 1.644, 95% CI = 1.157–2.336, P = .0056] is clearly in the wrong direction.”
He stated, “The bottom line is that visceral metastases interfere with the treatment effect.”
Multivariate analysis identified the following favorable prognostic factors for overall survival: age under 70 years, alkaline phosphatase < 1.5 times the upper limit of normal, hemoglobin ≥ 11 g.dL, and the absence of visceral metastases.
The safety of ipilimumab was consistent with that of other trials with this agent.
Another phase III trial of ipilimumab has been launched (CA184-095) in chemotherapy-naive castration-resistant prostate cancer, and it excludes patients with visceral metastases.
The study was funded by Bristol Myers Squibb. For full disclosures of the study authors, view the study abstract at www.gucasym.org.
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