Winald R. Gerritsen, MD
A phase III trial examining the anti-CTLA-4 immune checkpoint inhibitor ipilimumab (Yervoy) in men with metastatic castration-resistant prostate cancer (mCRPC) failed to meet its primary endpoint of prolongation in overall survival (OS), according to a statement issued by the manufacturer, Bristol-Myers Squibb.
Despite the lack of an OS benefit, progression-free survival (PFS) and a marked reduction in PSA were observed with the immunotherapy. A subgroup analysis suggests that patients with less advanced disease could still benefit from treatment with ipilimumab. The announcement of these findings comes in advance of the presentation of the full results at the 2013 European Cancer Congress on September 28, 2013.
“Although the study did not meet its primary endpoint, clinical activity was observed in this Phase III trial with a suggestion of greater activity in those with less advanced castration-resistant prostate cancer,” said Winald R. Gerritsen, MD, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands. “These results offer important insights for ongoing and future studies of Yervoy in prostate cancer, including a second large trial of Yervoy in patients with less advanced disease.”
The phase III CA-184-043 trial (Study 043) enrolled 799 patients with mCRPC who had received prior docetaxel. In the trial, patients were randomized in a 1:1 ratio to receive bone-directed radiation therapy at 8 Gy followed by ipilimumab at 10 mg/kg (n=399) or placebo (n=400). Treatment was administered every 3 weeks for 4 cycles and eligible patients received maintenance therapy every 3 months. Baseline characteristics were balanced across both arms and were representative of advanced CRPC. In all, 48% of patients had baseline pain of ≥4 per Brief Pain Inventory.
The ipilimumab arm demonstrated a median OS of 11.2 months compared with 10 months with placebo (HR=0.85; 95% CI, 0.72–1.00; P
= 0.053), which did not meet the predetermined criteria for statistical significance. The 1-year OS rate was 47% compared with 40% and the 2-year OS rate was 26% versus 15%, for ipilimumab and placebo, respectively.
The secondary endpoint of PFS favored treatment with ipilimumab over placebo, with a HR of 0.70. Additionally, a reduction in PSA of greater than or equal to 50% was experienced by 13.1% of patients receiving ipilimumab compared with 5.3% for placebo.
A pre-specified subset analysis suggests that patients with lower disease burden experience the most benefit with ipilimumab. In general, the greatest benefit was observed for patients without visceral disease and favorable laboratory prognostic factors, such as decreased alkaline phosphatase and elevated hemoglobin.
The most common ipilimumab-related grade 3/4 immune-related adverse events were gastrointestinal (18%), liver (5%), endocrine (2%), and dermatologic (1%). However, most of these events were consistent with expectations and manageable using standard protocols included in the risk management evaluation and mitigation strategy (REMS) for the treatment.
“While we are disappointed that the primary endpoint of overall survival was not met, we remain encouraged that results in this advanced population support the potential role of immunotherapies for prostate cancer. We are committed to continuing our development of Yervoy in prostate cancer,” said Brian Daniels the senior vice president of Global Development and Medical Affairs at Bristol-Myers Squibb. “Immuno-oncology is a rapidly evolving treatment modality and findings from this study provide important scientific insights that can be applied to current and future studies of Yervoy as well as our broad pipeline of immunotherapies in development.”
The current development program for ipilimumab includes a second phase III trial (Study 095) for patients with mCRPC. In this trial, ipilimumab at 10 mg/kg is being compared to placebo for patients with mCRPC who have not yet received prior chemotherapy.
Ipilimumab was initially approved in March 2011 as a 3 mg/kg monotherapy for patients with unresectable or metastatic melanoma. In addition to mCRPC, the immunotherapy will continue to be researched in adjuvant melanoma and non-small cell lung cancer.