• Research & Development
Enzalutamide

Overview

Enzalutamide is an androgen receptor inhibitor that blocks multiple steps in the androgen receptor signaling pathway within the tumor cell.1 Enzalutamide currently is approved in the United States, Europe and numerous other countries worldwide for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC), and is being further developed* for earlier stages of prostate cancer, advanced breast cancer and hepatocellular carcinoma.

Prostate Cancer

AFFIRM
Our FDA approval in post-chemotherapy mCRPC was based on the results of the AFFIRM trial, a randomized, double-blind Phase 3 trial evaluating enzalutamide (160 mg once daily) as compared to placebo in 1,199 post-chemotherapy mCRPC patients. The primary endpoint of the enzalutamide trial was overall survival. Data from the AFFIRM trial were first reported in November 2011 and were published in The New England Journal of Medicine in August 2012. The AFFIRM trial also led to the initial marketing approvals of enzalutamide by regulatory authorities in Europe, Japan and numerous other countries worldwide. The open-label extension of this trial is ongoing.

PREVAIL
Our FDA approval in pre-chemotherapy mCRPC was based on the results of the PREVAIL trial, a randomized, double-blind, placebo controlled Phase 3 trial, evaluating enzalutamide (160 mg once daily) as compared to placebo in 1,717 patients with pre-chemotherapy mCRPC. The co-primary endpoints were radiographic PFS and overall survival. Positive results from the PREVAIL trial were first reported in October 2013 and were published in The New England Journal of Medicine in June 2014. The PREVAIL trial also led to expanded marketing approvals by regulatory authorities in Europe, Japan, and numerous other countries worldwide. In July 2015, the FDA approved a label update for XTANDI based on an updated overall survival analysis of the Phase 3 PREVAIL trial. This analysis was conducted when 784 deaths were observed and found an overall survival benefit with a 23% reduction in risk of death (Hazard ratio = 0.77; 95% CI: 0.67, 0.88) 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]). The open-label extension of this trial is ongoing.

TERRAIN
The Phase 2 TERRAIN trial was initiated in March 2011 and completed enrollment in July 2013. The trial evaluated enzalutamide head-to-head versus bicalutamide, the leading marketed anti-androgen drug, in 375 pre-chemotherapy mCRPC patients. The primary endpoint of the trial was progression-free survival, or PFS, defined as time from randomization to centrally determined radiographic progression, skeletal-related event, initiation of new anti-neoplastic therapy or death, whichever occurred first. In January 2015, we and Astellas reported top-line results from the Phase 2 TERRAIN trial. The trial achieved its primary endpoint demonstrating a statistically significant increase in PFS for patients with mCRPC for enzalutamide compared to bicalutamide (Hazard Ratio = 0.44; 95% Confidence Interval (CI): 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 the TERRAIN trial 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. Results from the TERRAIN trial were published in an online issue of Lancet Oncology in January 2016.

STRIVE
The Phase 2 STRIVE trial was initiated in August 2012 and completed enrollment in March 2014. The trial evaluated enzalutamide head-to-head versus bicalutamide, the leading marketed anti-androgen drug, in 396 pre-chemotherapy CRPC patients. The randomized, double-blind trial enrolled both metastatic and non-metastatic patients. The primary endpoint of the trial was PFS defined as time from randomization to radiographic (bone or soft tissue) progression, PSA progression (defined by Prostate Cancer Working Group 2 criteria), or death due to any cause, whichever occurs first. In April 2015, we and Astellas reported top-line results from the Phase 2 STRIVE trial. The trial achieved its primary endpoint demonstrating a statistically significant prolongation of PFS for patients with CRPC for enzalutamide compared with bicalutamide (Hazard Ratio = 0.24; 95% CI: 0.18, 0.32; p < 0.0001). Median PFS was 19.4 months in the enzalutamide group compared with 5.7 months in the bicalutamide group. The median time on treatment in the STRIVE trial was 14.7 months in the enzalutamide group versus 8.4 months in the bicalutamide group. Serious adverse events were reported in 29.4% of enzalutamide-treated patients and 28.3% of bicalutamide-treated patients. Grade 3 or higher cardiac adverse events were reported in 5.1% of enzalutamide-treated patients versus 4.0% of bicalutamide-treated patients. One seizure was reported in the trial in the enzalutamide-treated group and none in the bicalutamide-treated group. Results from the STRIVE trial were published in an online issue of Journal of Clinical Oncology in January 2016.

PROSPER
The first patient was enrolled in the Phase 3 PROSPER trial in December 2013. The trial is evaluating the safety and efficacy of enzalutamide in patients with non-metastatic CRPC. The PROSPER trial is intended to enroll a high-risk subgroup of patients with prostate cancer who are progressing despite androgen deprivation therapy, but who are asymptomatic with no prior or present evidence of metastatic disease. The Phase 3 randomized, double-blind, placebo-controlled, multi-national trial is designed to enroll approximately 1,560 patients with non-metastatic CRPC. The primary endpoint of the trial is metastasis-free survival.

EMBARK
The first patient was enrolled in the Phase 3 EMBARK trial in January 2015. The trial is intended to evaluate the efficacy and safety of enzalutamide alone or in combination with androgen deprivation therapy compared with androgen deprivation therapy alone in patients with high risk, hormone-sensitive, non-metastatic prostate cancer that has biochemically recurred (rising PSA level) following definitive local therapy with radical prostatectomy and/or radiation. The purpose of the trial is to help determine if enzalutamide can delay or prevent the development of metastatic prostate cancer in high-risk men with a rapidly rising PSA. The trial is designed to enroll approximately 1,860 patients. The primary endpoint of the trial is metastasis-free survival.

PLATO
The Phase 4 PLATO trial was initiated in November 2013 and completed enrollment in September 2014. The trial is evaluating the efficacy and safety of continued treatment with enzalutamide plus abiraterone acetate and prednisone as compared to abiraterone acetate and prednisone alone in patients with chemotherapy-naive mCRPC whose disease has progressed following enzalutamide therapy. The purpose of the trial is to help determine the potential clinical benefit of continued enzalutamide treatment after progression on enzalutamide therapy. The global randomized, double-blind, placebo-controlled trial has enrolled 509 chemotherapy-naive patients with mCRPC. The primary endpoint of the trial is PFS defined as time from randomization to radiographic progress ion, unequivocal clinical progression, or death, whichever occurs first. Top-line results from PLATO may be available as early as the second half of 2016.

ARCHES
In January 2016, Astellas initiated start-up activities for the Phase 3 ARCHES trial in patients with metastatic hormone-sensitive prostate cancer, or mHSPC. The trial is intended to evaluate the efficacy and safety of enzalutamide in combination with androgen deprivation therapy compared with androgen deprivation therapy alone in approximately 1,100 patients. The primary endpoint of the trial is radiographic PFS.

Breast Cancer

In April 2012, we and Astellas expanded the clinical development of enzalutamide to include breast cancer. We currently have three Phase 2 clinical trials evaluating enzalutamide in three subsets of breast cancer:

AR+, TNBC
This Phase 2 open-label, single arm, multicenter clinical trial evaluated enzalutamide as a single agent for the treatment of advanced androgen receptor positive, or AR+, TNBC. 118 women with advanced TNBC were enrolled in this Simon 2 stage study at sites in the United States, Canada, and Europe. The objective of the study was to evaluate the safety and clinical benefit of enzalutamide, 160 mg/day orally, for advanced TNBC and to identify a biomarker to better select those women more likely to respond to enzalutamide. The primary endpoint of the trial was the clinical benefit rate at 16 weeks, or CBR16, defined as the proportion of evaluable patients with a complete response, or CR, partial response, or PR, or stable disease for at least 16 weeks. Secondary endpoints of the trial included clinical benefit rate at 24 weeks, or CBR24, and PFS, defined as time from the date of first dose of study drug until documented disease progression or death due to any cause, overall survival, and safety. The primary endpoint analysis was pre-specified to be conducted in the evaluable patient population, defined as all patients who had at least one follow-up tumor assessment after starting enzalutamide and whose TNBC had at least 10% of the tumor cells stain positive for AR using a central immunohistochemistry, or IHC, assay. The evaluable population was pre-specified based on the hypothesis that patients whose tumor tissue expressed higher levels of AR protein may be more likely to receive benefit from enzalutamide than those whose tumors had less than 10% cells with AR expression. Of the 118 patients enrolled into the study, 75 were evaluable. Analyses for clinical benefit and safety were also conducted in all 118 patients enrolled.

The study met its primary endpoint, achieving a CBR16 of 35% (95% CI: 24, 46), including six CRs or PRs (8%) in the evaluable population based on results as of March 25, 2015. The secondary endpoint of CBR24 was 29% (95% CI: 20, 41), and the median PFS on enzalutamide therapy was 14.7 weeks (95% CI: 8.1, 19.3) in the evaluable population. Using the total intent-to-treat, or ITT, population, CBR16 was achieved in 25% (95% CI: 17, 33) including seven CRs or PRs (6%), CBR24 was achieved in 20% (95% CI: 14, 29), and the median PFS was 12.6 weeks (95% CI: 8.1, 15.7). Nearly half of the enrolled patients (47%) tested positive for a novel gene expression profile. Of these 56 diagnostic positive women with advanced TNBC, 39% achieved CBR16 (95% CI: 27, 53) and 36% achieved CBR24 (95% CI: 24, 49). Of the 62 women who were diagnostic negative for the novel gene expression profile, 11% achieved a CBR16 (95% CI: 5, 21) and 6% achieved CBR24 (95% CI: 2, 16). Median PFS in the diagnostic positive group was 16.1 weeks (95% CI: 13.3, 27.4) compared with 8.1 weeks in the diagnostic negative group (95% CI: 7.4, 12.6). Over half (n=62) of the ITT patients enrolled received enzalutamide as their first- or second-line treatment and median PFS on enzalutamide in diagnostic positive patients was 40.4 weeks (95% CI: 16.1, not yet reached) whereas it was 9 weeks (95% CI: 7.3, 15.7) in the diagnostic negative group. An exploratory analysis of overall survival data collected as of September 15, 2015 demonstrated that patients treated with enzalutamide whose tumors tested positive according to the novel diagnostic assay experienced a 13.8-month longer median overall survival duration compared to those patients whose tumors tested negative for the novel gene expression profile. Median overall survival in the diagnostic positive group treated with enzalutamide was 21.3 months (95% CI: 12.9, 21.3) compared with 7.5 (95% CI: 4.8, 11.2) months for the diagnostic negative group treated with enzalutamide. Multicovariate analyses demonstrated that only diagnostic status (positive) and number of prior lines of therapy (0-1) were statistically significantly and independently associated with both improved PFS and overall survival outcomes. The most common (reported in ≥10% of patients) adverse events reported as related to enzalutamide treatment in the ITT population were fatigue (35%), nausea (26%), decreased appetite (13%), diarrhea (10%), and hot flush (10%).

ER+ or PgR+ and HER2 Normal
The Phase 2 trial was initiated in December 2013 and completed enrollment of 247 patients in March 2015. The trial is evaluating exemestane in combination with enzalutamide and exemestane in combination with placebo in women with advanced breast cancer that is estrogen receptor positive, or ER+, or progesterone receptor positive, or PgR+, and HER2 normal. The Phase 2 randomized, double-blind, placebo-controlled, multicenter trial will assess outcomes in two parallel enrolled cohorts. The first cohort enrolled patients who had not previously received hormonal treatment for advanced breast cancer. The second cohort enrolled patients who had previously progressed following one hormonal treatment for advanced disease. The primary endpoint of the trial is PFS in all patients and by cohort and PFS in the subset of patients whose tumors test positive for a diagnostic assay.

AR+ HER2 Amplified
In August 2014, Astellas initiated a Simon 2 stage Phase 2 clinical trial evaluating the safety and efficacy of adding enzalutamide to trastuzumab in approximately 80 patients with advanced breast cancer that is AR+ and HER2 amplified. Patients must also have previously received and progressed on trastuzumab. The primary endpoint of the trial is clinical benefit rate defined as complete response or partial response or stable disease for at least 24 weeks. The trial met the criteria to proceed to stage 2 which required a minimum of three evaluable patients in the first 21 evaluable patients to achieve CBR24. Like the TNBC clinical trial, the evaluable population consists of patients with at least one follow-up tumor assessment after starting enzalutamide and whose breast cancer has AR protein expression by central IHC testing in at least 10% of tumor cells

Hepatocellular carcinoma
In January 2016, Astellas enrolled the first patient into a Phase 2 placebo-controlled trial evaluating enzalutamide in hepatocellular carcinoma. The trial will assess approximately 144 patients with advanced hepatocellular carcinoma that have failed sorafenib or other anti-vascular endothelial growth factor therapies. The primary endpoint of the trial is overall survival.

1The clinical significance of this mechanism of action is unknown.

*Enzalutamide is being developed in collaboration with Astellas.