In the randomized phase II TERRAIN trial reported in The Lancet Oncology, Neal D. Shore, MD, of Carolina Urologic Research Center, Myrtle Beach, and colleagues found that use of the androgen receptor inhibitor enzalutamide (Xtandi) more than doubled median progression-free survival vs bicalutamide in patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer.1 In the randomized phase II STRIVE trial reported in the Journal of Clinical Oncology, David F. Penson, MD, MPH, of Vanderbilt University Medical Center, Nashville, and colleagues found that enzalutamide tripled median progression-free survival in patients with nonmetastatic or metastatic castration-resistant disease.2
TERRAIN Details
In this double-blind trial, 375 asymptomatic or minimally symptomatic men with prostate cancer progressing on androgen-deprivation therapy from 84 sites in North America and Europe were randomly assigned between March 2011 and July 2013 to receive enzalutamide at 160 mg/d (n = 184) or bicalutamide at 50 mg/d (n = 191) in addition to androgen-deprivation therapy until disease progression.1 The primary endpoint was progression-free survival on independent central review. An open-label period of the trial is in progress, in which patients remaining on treatment at the end of the double-blind treatment period were offered open-label enzalutamide at patient and investigator discretion.
The data from the TERRAIN trial support the use of enzalutamide rather than bicalutamide in patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer.— Neal D. Shore, MD, and colleagues
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The enzalutamide and bicalutamide groups were generally balanced for most baseline characteristics. Somewhat more enzalutamide patients had cardiac disorders (atrial fibrillation in 9% and 5%, coronary artery disease in 8% and 5%, myocardial infarction in 5% and 7%, cardiac heart failure in 2% in both).
Progression-Free Survival in TERRAIN
Median follow-up was 20.0 months in the enzalutamide group and 16.7 months in the bicalutamide group. Median progression-free survival was 15.7 months (95% confidence interval [CI] = 11.5–19.4 months) vs 5.8 months (95% CI = 4.8–8.1 months; hazard ratio [HR] = 0.44, P < .0001). On investigator review, median progression-free survival was 15.3 vs 5.7 months (HR = 0.42, P < .0001). Hazard ratios significantly favored enzalutamide in all subgroups examined.
Median time to radiographic progression was not reached vs 16.4 months (HR = 0.51, P = .0002), and median time to prostate-specific antigen (PSA) progression was 19.4 vs 5.8 months (HR = 0.28, P < .0001). Median time to ≥ 50% PSA decline was 2.8 months vs not reached (HR = 7.01, P < .0001).
Among patients with measurable soft-tissue disease at baseline, 26 (37%) of 70 in the enzalutamide group vs 5 (7%) of 71 in the bicalutamide group had an objective response (P < .0001). Of patients with circulating tumor cell counts ≥ 5 cells/7.5 mL blood at baseline, conversion to < 5 cells/7.5 mL occurred in 60 (80%) of 75 enzalutamide patients vs 45 (58%) of 77 bicalutamide patients (P = .004).
Role of Enzalutamide in Prostate Cancer
In the TERRAIN study, enzalutamide was associated with significantly prolonged progression-free survival vs bicalutamide in patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer. In the STRIVE study, enzalutamide was associated with significantly prolonged progression-free survival in patients with nonmetastatic and metastatic castration-resistant prostate cancer.Adverse Events
Of the most common adverse events of any grade, those occurring more frequently with enzalutamide were fatigue (28% vs 20%), back pain (19% vs 18%), and hot flushes (15% vs 11%), and those occurring more frequently with bicalutamide were nausea (14% vs 17%) and arthralgia (10% vs 16%). Adverse events of grade ≥ 3 occurred in 40% vs 38% of patients, with the most common being hypertension (7% vs 4%), hydronephrosis (2% vs 4%), back pain (3% vs 2%), pathologic fracture (3% vs 1%), dyspnea (2% vs 1%), bone pain (1% vs 2%), congestive heart failure (2% vs 1%), myocardial infarction (3% vs 0%), and anemia (2% vs 0%). Overall, cardiac adverse events of grade ≥ 3 occurred in 5% vs 2% of patients.
Serious adverse events occurred in 31% vs 23% of patients. Adverse events led to discontinuation of study treatment in 28% vs 23%. One of nine deaths in the enzalutamide group (due to systemic inflammatory response syndrome) was considered possibly related to study treatment, compared with none of three deaths in the bicalutamide group.
The investigators concluded: “The data from the TERRAIN trial support the use of enzalutamide rather than bicalutamide in patients with asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer.”
STRIVE Details
In this double-blind trial, 396 patients with nonmetastatic (n = 139) or metastatic disease (n = 257) from 62 U.S. sites were randomized between August 2012 and March 2014 to receive enzalutamide at 160 mg/d (n = 198) or bicalutamide at 50 mg/d (n = 198), with androgen-deprivation therapy continued in both groups.2 The primary endpoint was progression-free survival.
The enzalutamide and bicalutamide groups were generally balanced for all baseline characteristics.
Progression-Free Survival in STRIVE
Median time on treatment was 14.7 months in the enzalutamide group vs 8.4 months in the bicalutamide group. Median progression-free survival was 19.4 months (95% CI = 16.5 months to not reached) in the enzalutamide group vs 5.7 months (95% CI = 5.6–8.1 months in the bicalutamide group [HR = 0.24, P < .001]). Enzalutamide was associated with significant improvement in median time to PSA progression (not reached vs 8.3 months [HR = 0.19, P < .001]), proportion of patients with a ≥ 50% PSA response (81% vs 31%, P < .001), and median radiographic progression-free survival (not reached vs 11.2 months [HR = 0.30, P < .001]).
Enzalutamide significantly reduced risk of prostate cancer progression or death compared with bicalutamide in patients with nonmetastatic or metastatic [castration-resistant prostate cancer].— David F. Penson, MD, MPH
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In the 70 and 69 patients with nonmetastatic disease, median progression-free survival was not reached vs 8.6 months (HR = 0.24, P < .001), median time to PSA progression was not reached vs 11.1 months (HR = 0.18, P < .001), and median radiographic progression-free survival was not reached in either group (HR = 0.24, P < .001). In the 128 and 129 patients with metastatic disease, median progression-free survival was 16.5 vs 5.5 months (HR = 0.24, P < .001), median time to PSA progression was 24.9 vs 5.7 months (HR = 0.19, P < .001), and median radiographic progression-free survival was not reached vs 8.3 months (HR = 0.32, P < .001).
Adverse Events
Among adverse events of any grade, those reported more frequently with enzalutamide included fatigue (38% vs 28%), back pain (18% vs 16%), hot flashes (16% vs 10%), falls (14% vs 8%), hypertension (12% vs 5%), dizziness (12% vs 7%), and decreased appetite (12% vs 9%), and those reported more frequently with bicalutamide included constipation (17% vs 10%), diarrhea (14% vs 9%), anemia (11% vs 7%), and urinary tract infection (11% vs 5%).
Adverse events of grade ≥ 3 occurred in 36% of patients in both the enzalutamide and bicalutamide groups, with the most common being fatigue (5% vs 3%), hypertension (5% vs 2%), and anemia (3% vs 5%). Serious adverse events occurred in 29% vs 28%, and adverse events led to treatment discontinuation in 8% vs 6%. Adverse events led to death in 3% of patients in each group.
The investigators concluded:
Enzalutamide significantly reduced risk of prostate cancer progression or death compared with bicalutamide in patients with nonmetastatic or metastatic [castration-resistant prostate cancer]. ■
Disclosure: TERRAIN was funded by Astellas Pharma, Inc, and Medivation, Inc. STRIVE was funded by Medivation and Astellas Pharma Global Development. For full disclosures of the study authors, visit jco.ascopubs.org and www.thelancet.com.
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