PROSPER: Enzalutamide Prolongs Metastasis-Free Survival in Nonmetastatic Castration-Resistant Prostate Cancer
As reported in The New England Journal of Medicine by Hussain et al, the phase III PROSPER trial has shown a 71% reduction in risk of metastasis or death with enzalutamide (Xtandi) vs placebo in men with nonmetastatic castration-resistant prostate cancer.
Study Details
In the double-blind trial, 2,874 patients from more than 300 sites in 31 countries underwent screening between November 2013 and June 2017. A total of 1,401 eligible patients with prostate-specific antigen (PSA) doubling time of ≤ 10 months who were continuing on androgen-deprivation therapy (ADT) were randomized 2:1 to receive enzalutamide 160 mg (n = 933) or placebo (n = 468) once daily. Patients had to have been receiving ADT with a gonadotropin-releasing hormone agonist or antagonist or to have undergone bilateral orchiectomy. Randomization was stratified by PSA doubling time (< 6 months vs ≥ 6 months) and previous or current use of a bone-targeting agent at baseline. The primary endpoint was metastasis-free survival.
For the enzalutamide vs placebo groups, median age was 74 years (range = 50–95 years) vs 73 years (range = 53–92 years), Eastern Cooperative Oncology Group performance status was 0 in 80% vs 82% and 1 in 20% vs 18%; median serum PSA was 11.1 ng/mL vs 10.2 ng/mL; median PSA doubling time was 3.8 months (77% < 6 months) vs 3.6 months (77% < 6 months); and 11% vs 10% of patients had received bone-targeting agents.
Metastasis-Free Survival
At data cutoff, 219 patients (23%) in the enzalutamide group vs 228 (49%) in the placebo group had experienced a primary endpoint event. Median metastasis-free survival was 36.6 months in the enzalutamide group vs 14.7 months in the placebo group (hazard ratio [HR] = 0.29, P < .001). Among the 219 patients in the enzalutamide group with an endpoint event, 187 (85%) had radiographic progression and 32 (15%) died without radiographic progression. Of the 228 patients in the placebo group with an endpoint event, 224 (98%) had radiographic progression and 4 (2%) died without radiographic progression.
Subsequent antineoplastic treatment was used by 15% vs 48% of patients, with median time to first use being 39.6 vs 17.7 months (HR = 0.21, P < .001). PSA progression occurred in 22% vs 69% of patients, with median time to progression of 37.2 vs 3.9 months (HR = 0.07, P < .001).
At the first interim analysis of overall survival, death had occurred in 11% of the enzalutamide group vs 13% of the placebo group (HR = 0.80, 95% confidence interval = 0.58–1.09).
Adverse Events
The only adverse event of any grade occurring in > 20% of the enzalutamide group was fatigue (33% vs 14% in placebo group). Adverse events of grade ≥ 3 occurred in 31% of the enzalutamide group vs 23% of the placebo group, with the most common in the enzalutamide group being hypertension (5% vs 2%). Serious adverse events occurred in 24% vs 18%. Adverse events led to study drug discontinuation in 9% vs 6%. Adverse events led to death in 3% vs 1%.
Adverse events of special interest of any grade that occurred with ≥ 2% greater frequency in the enzalutamide group were hypertension (12% vs 5%), major cardiovascular events (in 5% vs 3%), and mental impairment disorders (5% vs 2%). No episodes of posterior reversible encephalopathy syndrome were reported; however, five patients in the enzalutamide group were reported to have “noninfectious encephalopathy or delirium” (three with delirium, one with encephalopathy, and one with leukoencephalopathy). Three patients in the enzalutamide group had convulsions, all of which were considered to be serious and drug-related; one patient discontinued enzalutamide and another had complications that led to death. Falls and nonpathologic fractures occurred in 17% vs 8% of patients.
The most common adverse events leading to death were cardiac events, in nine patients (1%) receiving enzalutamide and two (< 1%) receiving placebo. In the enzalutamide group, acute myocardial infarction occurred in six patients, and cardiac failure, cardiorespiratory arrest, and ventricular arrhythmia respectively occurred in one each. In the placebo group, cardiac arrest and left ventricular failure occurred in one patient each. In both groups, major cardiac events were more common among patients with history of cardiovascular disease, hypertension, diabetes, or hyperlipidemia, or who were aged ≥ 75 years.
The investigators concluded, “Among men with nonmetastatic, castration-resistant prostate cancer with a rapidly rising PSA level, enzalutamide treatment led to a clinically meaningful and significant 71% lower risk of metastasis or death than placebo. Adverse events were consistent with the established safety profile of enzalutamide.”
The study was funded by Pfizer and Astellas Pharma.
Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, and Cora N. Sternberg, MD, of the San Camillo Forlanini Hospital, Rome, contributed equally to the The New England Journal of Medicine article.
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