Maha Hussain, MD

AS REPORTED in The New England Journal of Medicine by Maha Hussain, MD, of the Robert H. Lurie Comprehensive Cancer Center, Northwestern University, and colleagues, the phase III PROSPER trial has shown a 71% reduction in the risk of metastasis or death with enzalutamide (Xtandi) vs placebo in men with nonmetastatic, castration-resistant prostate cancer.¹ 

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 a prostate-specific antigen (PSA) doubling time of ≤ 10 months who were continuing on androgen-deprivation therapy were randomized 2:1 to receive enzalutamide at 160 mg (n = 933) or placebo (n = 468) once daily. Patients had to have been receiving androgen-deprivation therapy with a gonadotropin-releasing hormone agonist or antagonist or had 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, the 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 measurement 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 in the enzalutamide group (23%) vs 228 in the placebo group (49%) had experienced a primary endpoint event. The 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 disease progression and 32 (15%) died without radiographic disease progression. Of the 228 patients in the placebo group with an endpoint event, 224 (98%) had radiographic disease progression and 4 (2%) died without radiographic disease progression. 

“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.”

— Maha Hussain, MD, and colleagues

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Subsequent antineoplastic treatment was used by 15% vs 48% of patients, with a median time to first use of 39.6 vs 17.7 months (HR = 0.21, P < .001). PSA progression occurred in 22% vs 69% of patients, with a median time to disease 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 the placebo group). Adverse events of grade ≥ 3 occurred in 31% of the enzalutamide group vs 23% of the placebo group, with the most common event 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 (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 related to the study drug; 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 9 patients (1%) receiving enzalutamide and 2 patients (< 1%) receiving placebo. In the enzalutamide group, acute myocardial infarction occurred in six patients; cardiac failure, cardiorespiratory arrest, and ventricular arrhythmia 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 a history of cardiovascular disease, hypertension, diabetes, or hyperlipidemia or who were 75 years of age or older. 

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.” ■

DISCLOSURE: The study was funded by Pfizer and Astellas Pharma. For full disclosures of the study authors, visit www.nejm.org. 

REFERENCE 

1. Hussain M, Fizazi K, Saad F, et al: Enzalutamide in men with nonmetastatic, castration-resistant prostate cancer. N Engl J Med 378:2465-2474, 2018.