Date: 2014-06-01
Type of information: Publication of results in a medical journal
phase: 3
Announcement: publication of results in The New English Journal of Medicine
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: prostate cancer
Therapeutic area:
Country: Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Israel, Italy, Japan, Republic of Korea, Lithuania, The Netherlands, Poland, Russian Federation, Singapore, Slovakia, Spain, Sweden, UK, USA
Trial
details: The Phase 3 PREVAIL trial is a randomized, double-blind, placebo-controlled, multi-national trial that enrolled more than 1,700 patients at sites in the United States, Canada, Europe, Australia, Russia, Israel and Asian countries including Japan. The trial enrolled patients with metastatic prostate cancer whose disease progressed despite treatment with androgen deprivation therapy and had not yet received chemotherapy. The co-primary endpoints of the trial are overall survival and radiographic progression-free survival. The trial was designed to evaluate enzalutamide at a dose of 160 mg taken orally once daily versus placebo. Targeted enrollment was completed in May 2012 and the interim analysis was pre-specified after 516 events (patient deaths). (NCT01212991)
Latest
news: * On March 24, 2015, Medivation and Astellas Pharma announced an updated overall survival analysis from the placebo-controlled Phase 3 PREVAIL trial of enzalutamide in chemotherapy-naive metastatic CRPC. The data were presented during a plenary session at the 2015 European Association of Urology (EAU) Congress in Madrid, Spain. * On June 1, 2014, Medivation and Astellas Pharma announced the online publication in the New England Journal of Medicine of the results from the Phase 3 PREVAIL trial, an international, randomized, double-blind, placebo-controlled clinical study of enzalutamide. The study evaluated the benefit and safety of enzalutamide in men with metastatic prostate cancer, who had few or no symptoms, that had progressed on luteinizing hormone-releasing hormone (LHRH) therapy or after bilateral orchiectomy. The paper, "Enzalutamide in Men with Metastatic Prostate Cancer Before Chemotherapy," appears in the June 1 online issue and the companies anticipate publication in a future print issue of the Journal. * On January 28, 2014, Medivation and Astellas Pharma announced final results on the primary and secondary efficacy endpoints from the Phase 3 PREVAIL trial of enzalutamide in patients with chemotherapy-naïve metastatic prostate cancer who have failed androgen deprivation therapy and have few or no symptoms. Data will be shared in a late-breaking oral presentation at the upcoming American Society of Clinical Oncology (ASCO) 2014 Genitourinary (GU) Cancers Symposium in San Francisco on Thursday, January 30, 2014. The PREVAIL study results in men with metastatic prostate cancer who have progressed on androgen deprivation therapy are as follows: Treatment with enzalutamide demonstrated a statistically significant overall survival benefit compared with placebo treatment. Enzalutamide reduced the risk of death by 29% (HR=0.71; p < 0.0001), compared with placebo. This benefit was observed despite substantial use of subsequent therapies (40% in the enzalutamide and 70% in the placebo groups). Treatment with enzalutamide significantly reduced the risk of radiographic progression or death by 81% compared with placebo treatment (HR=0.19; p < 0.0001). Consistent benefits on these co-primary endpoints of overall survival and radiographic progression-free survival were observed across patient subgroups. Men taking enzalutamide experienced a 17-month delay in the time to initiation of chemotherapy compared with men taking placebo (28.0 months versus 10.8 months; HR=0.35; p < 0.0001). The majority of men (58.8%) with soft tissue metastatic disease treated with enzalutamide versus 5% of patients treated with placebo had objective responses (complete responses or partial responses) including complete responses in 19.7% of enzalutamide patients compared with 1% of placebo patients. Enzalutamide extended the median time to PSA progression from 2.8 months (placebo) to 11.2 months (HR= 0.169; p < 0.0001). Nearly 4 out of 5 patients in the enzalutamide group experienced a PSA decline of 50% or more, compared to less than 4% in the placebo group (78% vs. 3.5%; p < 0.0001). The median times to deterioration in a measure of prostate cancer-specific quality of life, the Functional Assessment of Cancer Therapy-Prostate or FACT-P, were 11.3 months for the enzalutamide-treated patients and 5.6 months for the placebo patients (HR=0.625, p < 0.0001). The median treatment duration for enzalutamide was more than 3 times longer than for placebo (16.6 versus 4.6 months). Common side effects occurring during treatment and more common in the enzalutamide treated men included fatigue, back pain, constipation and arthralgia. Hypertension was observed in 13.4% of enzalutamide versus 4.1% of placebo-treated patients. Grade 3 or higher cardiac adverse events were reported in 2.8% of enzalutamide versus 2.1% of placebo-treated patients. Investigators reported zero seizures in the enzalutamide-treated group and one in the placebo group prior to the data cutoff date. One seizure was reported in the enzalutamide group after the data cutoff date. * On December 19, 2013, Medivation and Astellas Pharma announced that additional data from the Phase 3 PREVAIL trial evaluating enzalutamide in patients with chemotherapy-naïve metastatic prostate cancer will be highlighted in a late-breaking oral presentation at the upcoming American Society of Clinical Oncology (ASCO) 2014 Genitourinary (GU) Cancers Symposium in San Francisco. Details of the oral presentation are as follows:Title: Enzalutamide in men with chemotherapy-naïve metastatic prostate cancer (mCRPC): Results of Phase 3 PREVAIL Study (Presenter: Tomasz M. Beer, OHSU Knight Cancer Institute, Oregon Health & Science University). Two additional enzalutamide abstracts will be presented during General Poster Sessions: (Abstract #62) Enzalutamide monotherapy: Phase 2 study results in hormone-naïve prostate cancer patients. Presenter: Bertrand Tombal, Université Catholique de Louvain, Cliniques Universitaires Saint-Luc (11:30 a.m. - 1:00 p.m., Thursday, January 30, 2014) * On October 22, 2013, Medivation and Astellas Pharma announced that the Independent Data Monitoring Committee (IDMC) has informed the companies of positive results from a planned interim analysis of the global Phase 3 PREVAIL trial of enzalutamide in more than 1,700 men with metastatic prostate cancer that has progressed despite androgen deprivation therapy and who have not yet received chemotherapy. Given the observed benefits in the trial's co-primary endpoints of overall survival and radiographic progression-free survival, and considering the observed safety profile, the IDMC concluded enzalutamide demonstrated a favorable benefit-risk ratio. The IDMC recommended the study be stopped and patients treated with placebo be offered enzalutamide. Additional data from the Phase 3 PREVAIL results, including safety data, will be submitted for presentation at an upcoming medical conference. The IDMC informed the companies of the following results: Patients treated with enzalutamide demonstrated a statistically significant overall survival advantage compared with patients receiving placebo (p < 0.0001). Enzalutamide provided a 30% reduction in risk of death compared with placebo (Hazard Ratio=0.70; 95% confidence interval, 0.59-0.83).
(Title: Enzalutamide in men with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC): Final overall survival analysis of the phase 3 PREVAIL study). An updated overall survival analysis was conducted at 784 deaths and found a statistically significant overall survival benefit with a 23% reduction in risk of death (OS: HR 0.77; 95% CI 0.67-0.88; p=0.0002) and a 4-month improvement in median survival with enzalutamide (35.3 months [95% CI 32.2 - not yet reached]) over placebo (31.3 months [95% CI 28.8 - 34.2]). As of the June 2014 cut-off date with a median follow-up duration of 31 months: 52% of enzalutamide and 81% of placebo patients received ?1 subsequent life-extending prostate cancer therapy.
(Abstract #247) Enzalutamide in men with prostate cancer resistant to docetaxel and abiraterone. Presenter: Mark Creamer Scholz, Prostate Oncology Specialists (12:00 - 1:30 p.m., Friday, January 31, 2014)
Patients treated with enzalutamide demonstrated a statistically significant radiographic progression-free survival advantage compared with patients receiving placebo (p < 0.0001). Enzalutamide provided an 81% reduction in risk of radiographic progression or death compared with placebo (Hazard Ratio=0.19; 95% confidence interval, 0.15-0.23).
The percentage of patients alive in the enzalutamide arm was 72% as compared with 65% in the placebo arm at the time of the interim analysis data cut-off date. Treatment with enzalutamide resulted in a calculated point estimate for median overall survival of 32.4 months (95% confidence interval, 31.5 months-upper limit not yet reached) versus 30.2 months (95% confidence interval, 28.0 months-upper limit not yet reached) for patients receiving placebo. Because the trial will be stopped early with the majority of patients still alive, the estimated median survivals are not as precise as the hazard ratio. The hazard ratio takes into account available information about the trial endpoint from all patients whereas the median is a single point estimate of a much smaller number of patients at risk.
The median radiographic progression-free survival was not yet reached (95% confidence interval, 13.8 months-upper limit not yet reached) in the enzalutamide arm and was 3.9 months (95% confidence interval, 3.7-5.4) in the placebo arm.
Given the overall survival benefit and the observed safety profile, the IDMC considered the overall benefit-risk ratio to favor the enzalutamide arm and recommended unequivocally that patients receiving placebo be offered treatment with enzalutamide.
Of the 1,715 patients treated in the blinded PREVAIL study, two patients were reported by investigators to have had a seizure event. The full analysis of the safety data will become available upon final database lock and unblinding. Medivation and Astellas will initiate meetings with and submissions to regulatory agencies beginning in early 2014.
