In the phase III CA184-095trial reported in the Journal of Clinical Oncology, Tomasz M. Beer, MD, FACP, of the Knight Cancer Institute, Oregon Health and Science University, and colleagues found that ipilimumab (Yervoy) did not increase overall survival vs placebo in men with asymptomatic or minimally symptomatic chemotherapy-naive metastatic castration-resistant prostate cancer without visceral metastases.1 Ipilimumab was associated with prolonged progression-free survival and a higher prostate-specific antigen (PSA) response rate.
In this double-blind trial, 598 patients from sites in Europe, North and South America, and Australia were randomized 2:1 beginning in July 2010 to receive ipilimumab at 10 mg/kg (n = 399) or placebo (n = 199) every 3 weeks for up to 4 doses, with ipilimumab at 10 mg/kg or placebo maintenance given to nonprogressing patients every 3 months. The primary endpoint was overall survival in the intent-to-treat population.
Patients had a median age of approximately 69 years (68%–74% ≥ 65 years), and most were white (90%–92%, 5% in each were black), had an Eastern Cooperative Oncology Group performance status of 0 (75% in both groups), and bone metastases (78%–79%). Gleason score was ≥ 8 in 45% to 48% of patients, measurable disease was present in 42% to 48%, and median PSA levels were 41.2 mg/L in the ipilimumab group and 49.5 mg/L in the placebo group.
Overall and Progression-Free Survival
The median number of study drug doses was 4.0 in both groups; treatment was stopped before the fourth dose in 37% of the ipilimumab group and 12% of the placebo group. The trial database was locked in August 2015, with a total of 380 overall survival events reported. At the time of the primary overall survival analysis, all patients had been followed for at least 2 years, 85% for 3 years, and 26% for 4 years.
Ipilimumab did not improve overall survival in patients with metastatic castration-resistant prostate cancer. The observed increases in progression-free survival and prostate-specific antigen response rates suggest antitumor activity in a patient subset.— Tomasz M. Beer, MD, FACP, and colleagues
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Median overall survival was 28.7 months (95% confidence interval [CI] = 24.5–32.5 months) in the ipilimumab group vs 29.7 months (95% CI = 26.1–34.2 months) in the placebo group (hazard ratio [HR] = 1.11, P = .3667). The investigators noted: “Median overall survival observed in patients in the placebo arm was longer than expected at study design (21.7 months). This outcome likely reflects improvements in the standard of care and a survival benefit provided by subsequent therapies.”
Overall survival was 78% vs 85% at 1 year, 56% vs 61% at 2 years, and 41% vs 40% at 3 years. In a subgroup analysis, hazard ratios favored placebo in all patient subsets except for black patients, patients with measurable disease, and patients without bone metastases.
Median progression-free survival was 5.6 months vs 3.8 months (HR = 0.67, 95.87% CI = 0.55–0.81), with an early separation of the progression-free survival curves being sustained over time. Subsequent systemic treatment with chemotherapy, hormonal therapy, or immunotherapy was received by 67% of ipilimumab patients and 79% of placebo patients; subsequent therapies consisted of nonhormonal systemic therapy only in 17% vs 17% (including docetaxel in 16% vs 15%), hormonal therapy only in 15% vs 14%, and nonhormonal systemic therapy and hormonal therapy in 32% vs 43%. Ipilimumab patients had a longer time to systemic nonhormonal cytotoxic therapy (HR = 0.65, 95.87% CI = 0.52–0.83) and to docetaxel therapy (HR = 0.70, 95% CI = 0.55–0.88). An exploratory analysis showed a higher PSA response rate with ipilimumab (23% vs 8%).
The most common treatment-related adverse events of any grade in the ipilimumab group were diarrhea (43%), rash (33%), pruritus (27%), and fatigue (24%). Grade 3 or 4 treatment-related adverse events occurred in 40% vs 6% of patients, with diarrhea (15%) being the only event occurring in > 3% of the ipilimumab group. Immune-related events of any grade occurred in 77% vs 29% of patients and were of grade 3 or 4 in 31% vs 2%. Treatment discontinuation due to treatment-related adverse events occurred in 29% vs 3%. Death due to treatment-related events occurred in nine ipilimumab patients (2%), with causes consisting of cardiac arrest (n = 2), gastrointestinal perforation, renal failure, hepatitis, pneumonitis, as well as multiorgan lymphatic infiltration resulting in cardiac arrest, pneumonia, and hepatotoxicity.
The investigators concluded: “Ipilimumab did not improve overall survival in patients with metastatic castration-resistant prostate cancer. The observed increases in progression-free survival and prostate-specific antigen response rates suggest antitumor activity in a patient subset.”
They noted: “Two large randomized trials [the other being CA184-043] have now conclusively demonstrated that treatment with ipilimumab does not extend overall survival in unselected populations of patients with metastatic castration-resistant prostate cancer but does result in measurable antitumor activity. Future work should be directed at determining how to harness such antitumor activity, potentially through identification of biomarkers that may enable prediction of benefit from treatment with ipilimumab. Based on current evidence, a potential role for newer immune checkpoint inhibitors, such as nivolumab and pembrolizumab, and other immunostimulatory strategies, either as single agents or in combination therapy, remains to be defined in patients with metastatic castration-resistant prostate cancer.” ■
Disclosure: The study was supported by Bristol-Myers Squibb. For full disclosures of the study authors, visit www.jco.ascopubs.org.
1. Beer TM, Kwon ED, Drake CG, et al: Randomized, double-blind, phase III trial of ipilimumab versus placebo in asymptomatic or minimally symptomatic patients with metastatic chemotherapy-naive castration-resistant prostate cancer. J Clin Oncol 35:40-47, 2017.