Ian D. Davis, MBBS, PhD, FRACP, FAChPM
As reported inThe New England Journal of Medicine by Ian D. Davis, MBBS, PhD, FRACP, FAChPM, of Monash University and Eastern Health in Melbourne, and colleagues, the phase III ENZAMET trial has shown that the androgen receptor inhibitor enzalutamide improved progression-free and overall survival vs standard nonsteroidal antiandrogen therapy when added to testosterone suppression.1
In the open-label trial, 1,125 men from 83 sites in Australia, Canada, Ireland, New Zealand, the United Kingdom, and the United States were randomly assigned between March 2014 and March 2017 to receive enzalutamide at 160 mg daily (n= 563) or treatment with bicalutamide, nilutamide, or flutamide (n = 562); all patients received continuous testosterone suppression. After enrollment of 88 patients, a protocol revision added administration of early docetaxel as a stratification factor, with docetaxel use (75 mg/m2 every 3 weeks for a maximum of six cycles) occurring at the discretion of patient and investigator. Treatment continued until disease progression or unacceptable toxicity. Stratification factors in addition to planned use of early docetaxel included disease volume, planned use of bone antiresorptive therapy, Adult Comorbidity Evaluation 27 (ACE-27) score (with coexisting conditions rated as 0 = none; 1 = mild; 2 = moderate; 3 = severe or multiple conditions), and study site. The primary endpoint was overall survival. Secondary endpoints included prostate-specific antigen (PSA) progression-free survival and clinical progression-free survival.
“Enzalutamide was associated with significantly longer progression-free and overall survival than standard care....”— Ian D. Davis, MBBS, PhD, FRACP, FAChPM
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For the enzalutamide vs standard-care groups, the median age of patients was 69 years in both; most patients were from Australia (58% vs 57%); use of docetaxel was planned for 45% vs 44% (docetaxel was not received by 11 of these patients in each group); disease volume was high in 52% vs 53%; Gleason score was up to 7 in 27% vs 29% and 8 to 10 in 60% vs 57%; and previous therapy included antiandrogen therapy in 51% vs 56% and luteinizing hormone–releasing hormone agonists or antagonists in 73% vs 74%.
The first interim analysis of overall survival was performed after reporting of 235 deaths, with the risk of death being lower in the enzalutamide group (P = .0016). The current report includes data after 245 deaths had been observed at a median follow-up of 34 months. A total of 102 deaths occurred in the enzalutamide group vs 143 deaths in the standard-care group (hazard ratio [HR] = 0.67, P = .002). Kaplan-Meier estimate of overall survival at 3 years was 80% in the enzalutamide group vs 72% in the standard-care group.
The beneficial effect of enzalutamide on overall survival appeared to be smaller among stratified subgroups who received bone antiresorptive therapy (n = 113, HR = 1.77, 95% confidence interval [CI] = 0.83–3.77; HR = 0.59, 95% CI = 0.45–0.77 for no antiresorptive therapy), those with planned early docetaxel treatment (HR = 0.90, 95% CI = 0.62–1.31; HR = 0.53, 95% CI = 0.37–0.75, for no early docetaxel), and high disease volume (HR = 0.80, 95% CI = 0.59–1.07; HR = 0.43, 95% CI = 0.26–0.72, for low disease volume). After adjustment for multiple comparisons, the P values for heterogeneity were 0.06 for the use of antiresorptive therapy, 0.14 for early docetaxel, and 0.14 for disease volume.
PSA progression-free survival at 3 years was 67% in the enzalutamide group vs 37% in the standard-care group (HR = 0.39, P < .001). Clinical progression-free survival at 3 years was 68% vs 41% (HR = 0.40, P < .001).
At 3 years, 62% of the enzalutamide group and 34% of the standard-care group were still receiving trial treatment. Among patients with clinical disease progression, 67% of those in the enzalutamide group and 85% of those in the standard-care group received one or more subsequent therapies.
Outcomes for the subgroup treated with docetaxel were prespecified to be of particular interest. Use of docetaxel was not mandated or randomized, but it was a stratification factor, and usage was similar in each treatment group. The effect of enzalutamide on overall survival appeared in this interim analysis to be smaller in the group of participants planned to receive early docetaxel (HR = 0.90, 95% CI = 0.62–1.31 with docetaxel; HR = 0.53, 95% CI = 0.37–0.75 without docetaxel). However, benefits in clinical progression-free survival were seen with the addition of enzalutamide to testosterone suppression and docetaxel (HR = 0.48, 95% CI = 0.37–0.62 with docetaxel; HR = 0.34, 95% CI = 0.26–0.44 without docetaxel).
Fatigue of any grade occurred in 83% of the enzalutamide group vs 65% of the standard-care group. Grade ≥ 3 adverse events occurred in 57% of the enzalutamide group vs 43% of the standard-care group, with the most common events in the enzalutamide group including hypertension, febrile neutropenia, decreased neutrophils, and fatigue. Grade 5 events occurred in six vs seven patients. Serious adverse events occurred in 42% vs 34% of patients. Adverse events led to discontinuation of treatment in 33 patients (6%) vs 14 patients (3%).
The investigators concluded: “Enzalutamide was associated with significantly longer progression-free and overall survival than standard care in men with metastatic, hormone-sensitive prostate cancer receiving testosterone suppression. However, enzalutamide was associated with some additional toxic effects, including fatigue and a small risk of seizures. Among the patients who also received early docetaxel treatment, the addition of enzalutamide was associated with additional toxic effects and longer progression-free survival but not longer overall survival. Future studies of health-related quality of life will help inform whether the delay in progression results in a meaningful clinical benefit that can offset the increase in toxicity. At present, ENZAMET results do not support the use of triplet therapy with testosterone suppression, docetaxel, and enzalutamide.”
DISCLOSURE: The study was led by ANZUP Cancer Trials Group, sponsored by the University of Sydney, and funded by Astellas Scientific, Medical Affairs, and others including Cancer Australia. Dr. Davis has received institutional research funding from Amgen, Astellas Pharma, AstraZeneca, Bayer, Bristol Myers Squibb, Eisai, Janssen Oncology, MSD Oncology, Pfizer, and Roche/Genentech.
1. Davis ID, Martin AJ, Stockler MR, et al: Enzalutamide with standard first-line therapy in metastatic prostate cancer. N Engl J Med 381:121-131, 2019.