No Overall Survival Improvement With Ipilimumab After Radiotherapy in Metastatic Castration-Resistant Prostate Cancer Progressing After Docetaxel
In a phase III trial (CA184-043) reported in The Lancet Oncology, Kwon et al assessed the effects of adding ipilimumab (Yervoy) after radiotherapy in patients with metastatic castration-resistant prostate cancer progressing after docetaxel chemotherapy. The investigators found no improvement in overall survival vs placebo but did see significant improvement in progression-free survival. Moreover, the hazard ratio for overall survival for ipilimumab vs placebo decreased over time and was significant in favor of ipilimumab at later time points.
Ipilimumab is a fully human monoclonal antibody that binds cytotoxic T-lymphocyte antigen, enhancing antitumor immunity by preventing CTLA-4-mediated downregulation of T-lymphocyte activity. The prospect of activity of such treatment in metastatic castration-resistant prostate cancer was raised by early-phase clinical trial data.
Study Details
This double-blind trial included 799 patients with at least one bone metastasis from castration-resistant prostate cancer that had progressed after docetaxel treatment from 191 centers in 26 countries. Patients were randomly assigned between May 2009 and February 2012 to receive bone-directed radiotherapy (8 Gy in one fraction) followed by either ipilimumab at 10 mg/kg or placebo every 3 weeks for up to four doses. Patients not showing disease progression could continue to receive ipilimumab at 10 mg/kg or placebo as maintenance therapy every 3 months.
Patients were stratified by Eastern Cooperative Oncology Group (ECOG) performance status, alkaline phosphatase concentration, hemoglobin concentration, and study site. The primary endpoint was overall survival assessed in the intention-to-treat population.
The ipilimumab and placebo groups were generally balanced for age (median, 69 and 68 years), alkaline phosphatase level (56% and 58% < 1.5 times upper limit of normal), Gleason score (> 7 in 48% and 47%), hemoglobin (≥ 110 g/L in 67% in both), ECOG performance status (0 in 42% and 43%, 1 in 54% and 55%), number of bone metastases (up to five in 69% and 63%), visceral metastases (none in 70% and 69%), lactate dehydrogenase level (≤ 2 times upper limit of normal in 82% and 81%), prostate-specific antigen (PSA) level (median, 139 and 177 µg/L), and pretreatment prednisone use (17% and 16%).
Overall Survival Findings
After median follow-up of 9.9 months in the ipilimumab group and 9.3 months in the placebo group, median overall survival was 11.2 vs 10.0 months (hazard ratio [HR] = 0.85, P = .053). Proportional-hazards assumptions were assessed by testing the period-by-treatment interaction term in a time-dependent Cox model, with period (before or after the time point at which obvious separation of survival curves began) as a binary variable.
Crossover of Kaplan-Meier survival curves occurred at 7 to 8 months, with survival being greater in the ipilimumab group after crossover. The assessment of the proportional hazards assumption showed that it was violated (P = .0031). An exploratory piecewise hazard model showed that the hazard ratio for ipilimumab vs placebo decreased over time, from 1.46 (95% confidence interval [CI] = 1.10–1.95) at < 5 months to 0.65 (95% CI = 0.50–0.85) between 5 and 12 months and 0.60 (95% CI = 0.43–0.86) at > 12 months.
Ipilimumab treatment was associated with significantly prolonged progression-free survival (median, 4.0 vs 3.1 months, HR = 0.70, P < .0001). Reduction in prostate-specific antigen (PSA) of ≥ 50% was more common with ipilimumab (13% vs 5%).
Adverse Events
Drug-related adverse events of any grade were more common in the ipilimumab group (75% vs 45%). The most common adverse events of any grade were total immune-related events (63% vs 22%), with the most common individual events being diarrhea (38% vs 31%), nausea (32% and 27%), and decreased appetite (31% vs 25%).
Grade 3 or 4 adverse events occurred in 59% vs 41% of patients, with the most common being total immune-related events (26% vs 3%) and the individual events of diarrhea (16% vs 2%), fatigue (11% vs 9%), and anemia (10% vs 11%). Adverse events led to discontinuation of treatment in 35% vs 16% of patients and resulted in death in 17% vs 11%. Four deaths in the ipilimumab group (1%) were considered related to study drug toxicity.
The investigators concluded, “[T]his study did not meet its primary endpoint of improved overall survival in a population with advanced metastatic castration-resistant prostate cancer. However, we did identify some evidence of antitumour activity with ipilimumab treatment as assessed by prespecified secondary and exploratory endpoints, including reductions in PSA concentration and improved progression-free survival…. [T]he signs of activity with the drug … warrant further investigation.”
Eugene D. Kwon, MD, of the Mayo Clinic, is the corresponding author for The Lancet Oncology article.
The study was funded by Bristol-Myers Squibb. For full disclosures of the study authors, visit www.thelancet.com.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
