Date: 2016-01-13
Type of information: Publication of results in a medical journal
phase: 2
Announcement: publication of results in The Lancet Oncology
Company: Medivation (USA - CA) Astellas (Japan)
Product: Xtandi® (enzalutamide)
Action
mechanism: Xtandi® (enzalutamide) is an androgen receptor inhibitor that acts on different steps in the androgen receptor signaling pathway. It has been shown to competitively inhibit androgen binding to androgen receptors and inhibit androgen receptor nuclear translocation and interaction with DNA. A major metabolite, N-desmethyl enzalutamide, exhibited similar in vitro activity to Xtandi®. Xtandi® decreased proliferation and induced cell death of prostate cancer cells in vitro, and decreased tumor volume in a mouse prostate cancer xenograft model.
Disease: metastatic castration-resistant prostate cancer (mCRPC)
Therapeutic area: Cancer - Oncology
Country:
Trial
details: The Phase 2 TERRAIN trial enrolled 375 patients in North America and Europe. The trial involved patients with metastatic prostate cancer whose disease progressed despite treatment with a luteinizing hormone-releasing hormone (LHRH) analogue therapy or following surgical castration. The primary endpoint of the trial was progression-free survival, defined as time from randomization to centrally confirmed radiographic progression, skeletal related event, initiation of new anti-neoplastic therapy or death, whichever occurs first. The trial was designed to evaluate enzalutamide at a dose of 160 mg taken once daily versus bicalutamide at a dose of 50 mg taken once daily, the approved dose in combination with a LHRH analogue. Targeted enrollment was completed in July 2013.
Latest
news: * On January 13, 2016, Medivation and Astellas announced that results from the Phase 2 TERRAIN trial of enzalutamide compared to bicalutamide in metastatic castration-resistant prostate cancer (CRPC) were published in The Lancet Oncology. The article is titled, "Efficacy and Safety of enzalutamide Versus bicalutamide for Patients with Metastatic Prostate Cancer (TERRAIN)". The TERRAIN study achieved its primary endpoint demonstrating a statistically significant increase in progression-free survival (PFS) for enzalutamide compared to bicalutamide (Hazard Ratio = 0.44; 95% Confidence Interval, 0.34-0.57; p < 0.0001). Median PFS, defined as time from randomization to centrally confirmed radiographic progression, skeletal-related event, initiation of new anti-neoplastic therapy or death, whichever occurred first, was 15.7 months in the enzalutamide group compared to 5.8 months in the bicalutamide group. The observed adverse event profile of enzalutamide in TERRAIN appeared consistent with that from Phase 3 enzalutamide trials. The median time on treatment in TERRAIN was 11.7 months in the enzalutamide group versus 5.8 months in the bicalutamide group. Serious adverse events were reported in 31.1% of enzalutamide-treated patients and 23.3% of bicalutamide-treated patients. Individual Grade 3 or higher adverse events largely occurred at a similar rate ( < 1% difference) between treatment groups, with the exception of hypertension (7.1% vs. 4.2%) and back pain (2.7% vs. 1.6%), which occurred more frequently in the enzalutamide treatment group. Grade 3 or higher cardiac events were reported in 5.5% of enzalutamide-treated patients versus 2.1% of bicalutamide-treated patients. Two seizures were reported in the enzalutamide group and one in the bicalutamide group. The most common side effects occurring during treatment and more common in the enzalutamide-treated versus bicalutamide-treated patients included fatigue, back pain, hot flush, hypertension, diarrhea, weight decreased and pain in extremity. * On March 24, 2015, Medivation and Astellas Pharma announced new data from the Phase 2 TERRAIN trial of enzalutamide compared to bicalutamide in metastatic castration-resistant prostate cancer (CRPC). The data were presented during a plenary session at the 2015 European Association of Urology (EAU) Congress in Madrid, Spain. Title: A randomized, double-blind, phase 2, efficacy and safety study of enzalutamide vs. bicalutamide in metastatic castrate resistant prostate cancer: TERRAIN trial : The Phase 2 TERRAIN trial enrolled 375 patients in North America and Europe. The trial enrolled patients with metastatic prostate cancer whose disease progressed despite treatment with a luteinizing hormone-releasing hormone (LHRH) analogue therapy or following surgical castration. The primary endpoint of the trial was progression-free survival (PFS), defined as time from randomization to centrally confirmed radiographic progression, skeletal-related event, initiation of new anti-neoplastic therapy or death, whichever occurred first. The trial was designed to evaluate enzalutamide at a dose of 160 mg taken orally once daily versus bicalutamide at a dose of 50 mg taken once daily, the approved dose in combination with an LHRH analogue. The study achieved its primary objective of a statistically significant increase in PFS for enzalutamide compared to bicalutamide. The median PFS in the enzalutamide arm was 9.9 months longer compared to that in the bicalutamide arm (15.7 vs. 5.8 months, respectively) with a Hazard Ratio (HR) of 0.44 (95% confidence interval [CI], 0.34-0.57; p < 0.0001); * On January 22, 2015, Medivation and Astellas Pharma announced topline results from the Phase 2 TERRAIN trial comparing enzalutamide with bicalutamide in men with metastatic castration-resistant prostate cancer. The study achieved its primary endpoint demonstrating a statistically significant increase in progression-free survival (PFS) for enzalutamide compared to bicalutamide (Hazard Ratio = 0.44; 95% Confidence Interval, 0.34-0.57; p < 0.0001). Median PFS was 15.7 months in the enzalutamide group compared to 5.8 months in the bicalutamide group. The median time on treatment in TERRAIN was 11.7 months in the enzalutamide group versus 5.8 months in the bicalutamide group. Serious adverse events were reported in 31.1% of enzalutamide-treated patients and 23.3% of bicalutamide-treated patients. Grade 3 or higher cardiac adverse events were reported in 5.5% of enzalutamide-treated patients versus 2.1% of bicalutamide-treated patients. Two seizures were reported in the enzalutamide group and one in the bicalutamide group. The most common side effects occurring during treatment and more common in the enzalutamide-treated versus bicalutamide-treated patients included fatigue, hot flush, hypertension, diarrhea, weight decreased and pain in extremity. Additional data from the Phase 2 TERRAIN trial, including the secondary endpoints and further safety data, will be submitted for presentation at an upcoming medical conference.
The median time to PSA progression was 13.6 months longer with enzalutamide (19.4 months) relative to bicalutamide treatment (5.8 months) with an HR of 0.28 (p < 0.0001);
82% of enzalutamide-treated patients achieved ? 50% PSA reduction from baseline by week 13 vs. 21% of bicalutamide-treated patients;
The median time on enzalutamide treatment was 11.7 months compared to 5.8 months on bicalutamide;
The safety profile of the enzalutamide-treated patients in TERRAIN is consistent with the known safety profile of enzalutamide.
Serious adverse events (AEs) were reported in 31.1% of enzalutamide vs. 23.3% of bicalutamide patients and Grade 3 or higher cardiac AEs were observed in 5.5% of enzalutamide vs. 2.1% of bicalutamide patients. Two seizures were reported with enzalutamide and one with bicalutamide;
The common AEs reported more frequently with enzalutamide vs. bicalutamide were fatigue (27.9% vs. 20.1%), back pain (19.1% vs. 18.0%), hot flush (14.8% vs. 11.1%), hypertension (14.2% vs. 7.4%), diarrhea (11.5% vs. 9.0%), weight decreased (10.9% vs. 7.9%) and pain in extremities (10.9% vs. 5.3%).
