Study Finds Enzalutamide Increases Progression-Free Survival vs Bicalutamide in Metastatic Prostate Cancer
Use of the androgen receptor–inhibitor enzalutamide (Xtandi) more than doubled progression-free survival vs the nonsteroidal antiandrogen bicalutamide in patients with metastatic prostate cancer progressing on androgen-deprivation therapy, according to the randomized phase II TERRAIN trial reported in The Lancet Oncology by Shore et al.
Enzalutamide is currently indicated for treatment of castration-resistant metastatic prostate cancer on the basis of improved survival in placebo-controlled trials. The agent targets a number of steps in the androgen receptor–signaling pathway, exhibiting a mechanism of action distinct from that of antiandrogens; unlike bicalutamide, it does not exert agonist activity at the wild-type androgen receptor. Bicalutamide is approved for use in combination with luteinizing hormone–releasing hormone analog treatment in hormone treatment–naive prostate cancer and has been recommended as second-line therapy in castration-resistant disease.
Study 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 randomized 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. 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 enzalutamide and bicalutamide groups were generally balanced for age (median, 71 years in both; 29% and 34% >75 years), race/ethnicity (93% and 92% white), region (Europe for 59% in both), Eastern Cooperative Oncology Group performance status (0 for 71% and 76%, 1 for 29% and 24%), pain score (0–1 in 55% and 61%, 2–3 in 38% and 35%, > 3 in 5% and 2%), localization (bone only in 45% and 48%, soft tissue only in 20% and 15%, both in 35% and 36%), previous antiandrogen use (54% and 51%), luteinizing hormone–releasing hormone analog or orchiectomy (before metastasis in 47% and 40%, after in 53% and 60%), Gleason score ≥ 8 (55% and 58%), and metastatic disease (M0 in 36% and 34%, M1 in 35% and 39%, Mx or unknown in 29% and 28%). In addition, 43% of both groups had previous radiotherapy, about 25% of both groups had had prostatectomy, and between 6% and 7% of both groups had had orchiectomy. 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
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 progression was 19.4 vs 5.8 months (HR = 0.28, P < .0001). Median time to ≥ 50% prostate-specific antigen 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 patients in the enzalutamide group vs 5 (7%) of 71 patients in the bicalutamide group had an objective response (P < .0001). Of patients with circulating tumor cell counts ≥ 5 cells per 7.5 mL blood at baseline, conversion to < 5 cells per 7.5 mL occurred in 60 (80%) of 75 enzalutamide patients vs 45 (58%) of 77 bicalutamide patients (P = .004).
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 flush (15% vs 11%), and those occurring more frequently with bicalutamide were nausea (14% vs 17%) and arthralgia (10% vs16%). 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, at least three cardiac adverse events 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.”
The study was funded by Astellas Pharma, Inc, and Medivation, Inc.
Neal D. Shore, MD, of Carolina Urologic Research Center, Myrtle Beach, South Carolina, is the corresponding author of The Lancet Oncology article.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
