Pfizer Inc. (NYSE: PFE) and Astellas Pharma U.S. Inc. (Head of Commercial: Mike Petroutsas, "Astellas") today announced final overall survival (OS) results from the Phase 3 EMBARK study evaluating XTANDI® (enzalutamide), in combination with leuprolide and as monotherapy, in men with non-metastatic hormone-sensitive prostate cancer (nmHSPC; also known as nonmetastatic castration-sensitive prostate cancer or nmCSPC) with biochemical recurrence (BCR) at high risk for metastasis. For the key secondary endpoint of OS, XTANDI plus leuprolide reduced the risk of death by 40.3% compared to leuprolide alone (Hazard Ratio [HR]: 0.597; 95% Confidence Interval [CI], 0.444-0.804; p=0.0006), making this the first and only androgen receptor inhibitor-based regimen to demonstrate an OS benefit in nmHSPC with high-risk BCR.1 The 8-year overall survival was 78.9% (95% CI, 73.9% to 83.1%) among patients receiving XTANDI plus leuprolide and 69.5% (95% CI, 64.0% to 74.3%) among patients taking leuprolide alone.1 A numerical improvement in OS with XTANDI as monotherapy compared to leuprolide alone (HR: 0.83 [95% CI, 0.63-1.095; p=0.1867) did not reach statistical significance.1 These data are being presented today in an oral presentation at the European Society for Medical Oncology (ESMO) Congress in Berlin, Germany and have been simultaneously published in The New England Journal of Medicine.
"These results highlight the central role of enzalutamide in extending survival for men with conventional imaging negative HSPC with high-risk BCR," said Stephen J. Freedland, M.D., Director of the Center for Integrated Research in Cancer and Lifestyle at Cedars-Sinai and Associate Director for Training and Education at the Samuel Oschin Comprehensive Cancer Institute. "These data reinforce the benefits of earlier treatment initiation with enzalutamide."
The median follow up time was 94.2 months for XTANDI in combination with leuprolide, 94 months for leuprolide only, and 93.8 months in the monotherapy XTANDI group.1
The safety profile of XTANDI was consistent with that observed at the primary EMBARK analysis, and no new safety signals were identified. The most common adverse events (occurring in ≥10% of patients) in the XTANDI combination group were hot flashes and fatigue. The most common adverse events in the XTANDI monotherapy group were gynecomastia, hot flashes, and fatigue.1,2
"With up to 90 percent of men with high-risk BCR developing metastatic disease, early intervention with effective therapy is critical,"3 said Johanna Bendell, M.D., Chief Development Officer, Oncology, Pfizer. "The final analysis from EMBARK shows that XTANDI plus leuprolide improved outcomes and extended lives for men facing high-risk BCR after local therapy with curative intent."
Among men who have undergone definitive prostate cancer treatment, including radical prostatectomy, radiotherapy or both, an estimated 20-40% will experience BCR within 10 years.4 About nine out of 10 men with high-risk BCR will develop metastatic disease, and one in three will die as a result of their metastatic prostate cancer.3
"This marks the eighth publication of XTANDI data in The New England Journal of Medicine, further demonstrating XTANDI's profound impact on clinical outcomes in men with certain types of advanced prostate cancer," said Shontelle Dodson, Executive Vice President, Head of Medical Affairs, Astellas. "These findings reinforce XTANDI's position as a cornerstone therapy in the proactive management of these patients."
The EMBARK trial primary analysis was previously reported in The New England Journal of Medicine in 2023, demonstrating that the study met its primary endpoint with a statistically significant and clinically meaningful improvement in metastasis-free survival (MFS) for patients treated with XTANDI plus leuprolide versus leuprolide alone (HR: 0.42 [95% CI, 0.30-0.61]; p<0.001). Additionally, MFS for XTANDI monotherapy was superior to treatment with leuprolide alone (HR: 0.63 [95% CI, 0.46-0.87]; p=0.005). Of note, the MFS for XTANDI single agent was a secondary endpoint.2
XTANDI is approved for one or more indications in more than 80 countries, including the United States, European Union, and Japan. Earlier approvals were for castration-resistant prostate cancer and metastatic castration-sensitive (hormone-sensitive) prostate cancer. It was then approved for patients with nmCSPC with BCR at high risk for metastasis in 2023 based on improved metastasis-free survival comparing the combination of enzalutamide with leuprolide vs leuprolide alone, as well as enzalutamide monotherapy vs leuprolide alone.
Descriptive updates of multiple secondary and exploratory endpoints (time to new antineoplastic therapy, time to first symptomatic skeletal events, and time to progression on subsequent therapy) were consistent with the primary analyses announced based on the MFS data cutoff in 2023.1
About EMBARK2
This Phase 3, randomized, double-blind, placebo-controlled, multi-national trial enrolled 1,068 patients with non-metastatic hormone-sensitive prostate cancer (nmHSPC; also known as non-metastatic castration-sensitive prostate cancer or nmCSPC) with high-risk biochemical recurrence (BCR) at sites in the United States, Canada, Europe, South America, and the Asia-Pacific region. Patients considered to have high-risk BCR disease had a prostate-specific antigen (PSA) doubling time ≤ 9 months, serum testosterone ≥ 150 ng/dL (5.2 nmol/L), and screening PSA by the central laboratory ≥ 1 ng/mL if they had had a radical prostatectomy (with or without radiotherapy) as primary treatment for prostate cancer or at least 2 ng/mL above the nadir if they had radiotherapy only as primary treatment for prostate cancer. Patients in the EMBARK trial were randomized to receive enzalutamide 160 mg daily plus leuprolide, enzalutamide 160 mg as monotherapy, or leuprolide alone.
The primary results from the EMBARK trial were published in the New England Journal of Medicinein 2023. The primary endpoint of the trial was metastasis-free survival (MFS) for enzalutamide plus leuprolide versus leuprolide alone. MFS is defined as the duration of time between randomization and the earliest objective evidence of radiographic progression by central imaging or death.
