Effect of enzalutamide on health-related quality of life, pain, and skeletal-related events in asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer (PREVAIL): results from a randomised, phase 3 trial.

BACKGROUND: Enzalutamide significantly increased overall survival and radiographic progression-free survival compared with placebo in the PREVAIL trial of asymptomatic and minimally symptomatic, chemotherapy-naive patients with metastatic castration-resistant prostate cancer. We report the effect of enzalutamide on health-related quality of life (HRQoL), pain, and skeletal-related events observed during this trial. METHODS: In this phase 3, double-blind trial, patients were randomly assigned (1:1) to receive enzalutamide 160 mg/day (n=872) or placebo (n=845) orally. HRQoL was assessed at baseline and during treatment using the Functional Assessment of Cancer Therapy-Prostate (FACT-P) and EQ-5D questionnaires. Pain status was assessed at screening, baseline, week 13, and week 25 with the Brief Pain Inventory Short Form (BPI-SF). The primary analysis of HRQoL data used a mixed-effects model to test the difference between least square means change from baseline at week 61. We assessed change from baseline, percentage improvement, and time to deterioration in HRQoL and pain, the proportion of patients with a skeletal-related event, and time to first skeletal-related event. Analysis was done on the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01212991. FINDINGS: Median treatment duration was 16·6 months (IQR 10·1-21·1) in the enzalutamide group and 4·6 months (2·8-9·7) in the placebo group. The mixed-effects model analyses showed significant treatment differences in change from baseline to week 61 with enzalutamide compared with placebo for most FACT-P endpoints and EQ-5D visual analogue scale. Median time to deterioration in FACT-P total score was 11·3 months (95% CI 11·1-13·9) in the enzalutamide group and 5·6 months (5·5-5·6) in the placebo groups (hazard ratio [HR] 0·62 [95% CI 0·54-0·72]; p<0·0001). A significantly greater proportion of patients in the enzalutamide group than in the placebo group reported clinically meaningful improvements in FACT-P total score (327 [40%] of 826 vs 181 [23%] of 790), in EQ-5D utility index (224 [28%] of 812 vs 99 [16%] of 623), and visual analogue scale (218 [27%] of 803 vs 106 of [18%] 603; all p<0·0001). Median time to progression in BPI-SF pain at its worst was 5·7 months (95% CI 5·6-5·7) in the enzalutamide group and 5·6 months (5·4-5·6) in the placebo group (HR 0·62 [95% CI 0·53-0·74]; p<0·0001). Progression of pain at its worst was less common in the enzalutamide group than in the placebo group at week 13 (220 [29%] of 769 vs 257 [42%] of 610; p<0·0001), but not at week 25 (225 [32%] of 705 vs 135 [38%] of 360; p=0·068). 278 (32%) of 872 patients in the enzalutamide group and 309 (37%) of 845 patients in the placebo group had experienced a skeletal-related event by data cutoff. Median time to first skeletal-related events in the enzalutamide group was 31·1 months (95% CI 29·5-not reached) and 31·3 months (95% CI 23·9-not reached) in the placebo group (HR 0·72 [95% CI 0·61-0·84]; p<0·0001). INTERPRETATION: In addition to improving overall survival relative to placebo, enzalutamide significantly improves patient-related outcomes and delays occurrence of first skeletal-related event in chemotherapy-naive men with metastatic castration-resistant prostate cancer. FUNDING: Astellas Pharma and Medivation.

Enzalutamide in metastatic prostate cancer before chemotherapy.

BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy. METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival. RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment. CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).

Aspirin and urinary 11-dehydrothromboxane B(2) in African American stroke patients.

BACKGROUND AND PURPOSE: The aim of the study was to evaluate the relationship between daily aspirin use and urinary excretion of a stable thromboxane metabolite, 11-dehydrothromboxane B(2) (11-DTB2), in African American stroke patients. METHODS: Subjects were a subgroup of those screened for the African American Antiplatelet Stroke Prevention Study. Subjects were within 4 months of noncardioembolic ischemic stroke and were not being treated with anticoagulants. Antithrombotic therapy at the time of urine collection varied according to the practice patterns of various attending physicians who treated the patients during their acute strokes. 11-DTB2 was measured by enzyme immunoassay in random urine samples 1 to 4 months after the stroke. RESULTS: Eighty-seven of 92 patients enrolled were able to give a urine sample at the time of enrollment. There were 51 men and 36 women aged 36 to 87 (mean 62) years. On the basis of antithrombotic treatment before the sample collection, we divided patients into 4 groups: (1) 16 patients treated with no aspirin (no antithrombotic drugs [n=4] or ticlopidine [n=12]), (2) 21 patients treated with 81 to 325 mg aspirin per day (81 mg/d [n=2], 325 mg/d [n=19]), (3) 20 patients treated with 650 mg aspirin per day, and (4) 30 patients treated with 975 to 1300 mg aspirin per day (975 mg/d [n=2] and 1300 mg/d [n=28]). In patients taking daily aspirin at any dose, the median urinary 11-DTB2 was 783 pg/mg creatinine compared with 1386 pg/mg creatinine in patients not taking daily aspirin (P=0.01 by Wilcoxon rank sum test). In multivariate regression analysis, aspirin use remained significantly associated with lower urinary 11-DTB2 (P=0.008). There was no dose-response effect between the 3 aspirin dose groups and urinary 11-DTB2 (P=0.70). CONCLUSIONS: In African American stroke patients, aspirin use is associated with significantly lower urinary 11-DTB2 independent of other vascular factors, and there does not appear to be a dose-response effect for aspirin doses of 325 to 1300 mg daily. The clinical significance of these finding remains to be determined.