Astellas Pharma Inc. (TSE: 4503, President and CEO: Naoki Okamura, “Astellas”) and Pfizer Inc. (NYSE: PFE) announced that the companies received an approval by the U.S. Food and Drug Administration (FDA) of a supplemental New Drug Application for XTANDI® (enzalutamide), following FDA expedited development and review programs (Priority Review designation, Fast Track designation, Real-time Oncology Review), based on results from the Phase 3 EMBARK trial. With this approval, XTANDI becomes the first and only androgen receptor signaling inhibitor approved by the FDA for the treatment of patients with nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR). Patients with nmCSPC with high-risk BCR may be treated with XTANDI with or without a gonadotropin-releasing hormone (GnRH) analog therapy.
Of men who have undergone definitive prostate cancer treatment, including radical prostatectomy, radiotherapy, or both, an estimated 20-40% will experience biochemical recurrence (BCR) within 10 years.(1) 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.(2)
"For patients who were previously treated for prostate cancer and had achieved remission, only to later receive the distressing news of disease recurrence with a risk of metastasis, the emotional toll can be profound," said Courtney Bugler, President and CEO of ZERO Prostate Cancer. "This approval of XTANDI is a promising treatment option for the community, offering a ray of hope to patients and their caregivers during these challenging times."
"Having had the privilege of taking care of patients with prostate cancer for nearly 40 years, I have been fortunate to have participated in many of the prostate cancer landscape changing trials; notably, we have not progressed our evidenced-based care for patients with biochemical recurrence (BCR), also known as nmCSPC, until the completion of the EMBARK trial," said Neal Shore, MD, FACS, Chief Medical Officer of Strategic Innovation and Pharmacy, GenesisCare USA, Director, CPI, Carolina Urologic Research Center, and Primary Investigator for the EMBARK trial. "Previously, treatment options for these BCR patients, especially those who have a high likelihood of developing metastases were limited. The FDA approval of XTANDI for patients with nmCSPC with BCR at high risk of metastasis represents an important advancement whereby an androgen deprivation signaling inhibitor, enzalutamide, has achieved standard of care discussion for patient-physician decision-making."
The approval is based on results from the Phase 3 EMBARK trial, which evaluated XTANDI plus leuprolide, placebo plus leuprolide, and XTANDI (single agent) in patients with nonmetastatic hormone- (or castration-) sensitive prostate cancer (nmHSPC or nmCSPC) with high-risk BCR. Detailed results from the trial were presented as a plenary session during the 2023 American Urological Association Annual Meeting and subsequently published in the New England Journal of Medicine.
"Today's FDA approval is the culmination of over a decade of research and development as we’ve worked to bring XTANDI forward for as many patients with prostate cancer as possible who may benefit," said Ahsan Arozullah, M.D., MPH, Senior Vice President and Head of Oncology Development, Astellas. “With every milestone, our clinical development program has played an instrumental role in changing the course of patients’ lives. We are proud that XTANDI can now be offered to a subset of men with nonmetastatic castration-sensitive prostate cancer with biochemical recurrence and at high risk for metastases.” “More than 300,000 men in the U.S. have been prescribed XTANDI, and we are excited to have this approval expand the indication for the first time into an earlier setting of the disease,” said Chris Boshoff, M.D., Ph.D., Chief Oncology Research and Development Officer and Executive Vice President at Pfizer. "This milestone is a testament to XTANDI’s legacy and robust clinical profile, with overall survival demonstrated for patients with metastatic castration-resistant prostate cancer, nonmetastatic castration-resistant prostate cancer, and metastatic castration-sensitive prostate cancer. With today's approval, we look forward to bringing this therapy to even more patients who have nonmetastatic castration-sensitive prostate cancer at high risk for their cancer metastasizing."
XTANDI is currently under review with other regulatory authorities around the world, including the European Medicines Agency, to support an expanded indication in nmHSPC (or nmCSPC) with high-risk BCR based on the results of EMBARK.
About EMBARK
The Astellas- and Pfizer-led Phase 3, randomized, double-blind, placebo-controlled, multi-national trial enrolled 1,068 patients with nonmetastatic hormone- (or castration-) sensitive prostate cancer (nmHSPC or nmCSPC) with high-risk BCR at sites in the U.S., Canada, Europe, South America, and the Asia-Pacific region. Patients who were considered to experience high-risk BCR had a prostate-specific antigen doubling time (PSA-DT) ≤ 9 months; serum testosterone ≥ 150 ng/dL (5.2 nmol/L); and screening PSA by the central laboratory ≥ 1 ng/mL if they 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 (n=355), enzalutamide 160 mg as a single agent (n=355), or placebo plus leuprolide (n=358). Leuprolide 22.5 mg was administered every 12 weeks.EMBARK met its primary endpoint of metastasis-free survival (MFS) for the XTANDI plus leuprolide arm, demonstrating a statistically significant reduction in the risk of metastasis or death over placebo plus leuprolide. MFS is defined as the duration of time in months between randomization and the earliest objective evidence of radiographic progression by central imaging or death due to any cause, whichever occurred first.
The study also met a key secondary endpoint, by demonstrating that patients treated with XTANDI (single agent) had a statistically significant reduction in the risk of metastasis or death versus placebo plus leuprolide, meeting its MFS endpoint.
In EMBARK, Grade 3 or higher adverse events (AEs) were reported in 46% of XTANDI plus leuprolide patients, 50% of patients treated with XTANDI (single agent), and 43% of patients receiving placebo plus leuprolide. Permanent discontinuation due to AEs as the primary reason was reported in 21% of XTANDI plus leuprolide patients, 18% in XTANDI (single agent) patients, and 10% in placebo plus leuprolide patients.
For more information on the EMBARK trial (NCT02319837) go to www.clinicaltrials.gov.
About Nonmetastatic Castration-Sensitive Prostate Cancer with High-Risk Biochemical Recurrence
In nonmetastatic castration- (or hormone-) sensitive prostate cancer (nmCSPC or nmHSPC), no evidence of the cancer spreading to distant parts of the body (metastases) is detectable with conventional radiological methods (CT/MRI), and the cancer still responds to medical or surgical treatment designed to lower testosterone levels.(3,4) Of men who have undergone definitive prostate cancer treatment, including radical prostatectomy, radiotherapy, or both, an estimated 20-40% will experience a BCR within 10 years.(1) About 9 out of 10 men with high-risk BCR will develop metastatic disease, and 1 in 3 will die as a result of their metastatic prostate cancer.(2) The EMBARK trial focused on men with high-risk BCR. Per the EMBARK protocol, patients with nmCSPC and high-risk BCR are those initially treated by radical prostatectomy or radiotherapy, or both, with a PSA-DT ≤ 9 months. High-risk BCR patients with a PSA-DT of ≤ 9 months have a higher risk of metastases and death.(5) In the U.S., it is estimated that 12,000-16,000 patients are diagnosed with nmCSPC with high-risk BCR annually.(6)
About XTANDI® (enzalutamide)
XTANDI® (enzalutamide) is an androgen receptor signaling inhibitor. XTANDI is a standard of care and has received regulatory approvals in one or more countries around the world for use in men with metastatic castration-sensitive prostate cancer (mCSPC; also known as metastatic hormone-sensitive prostate cancer or mHSPC), metastatic castration-resistant prostate cancer (mCRPC), non-metastatic castration-resistant prostate cancer (nmCRPC) and nonmetastatic castration-sensitive prostate cancer (nmCSPC) with biochemical recurrence at high risk for metastasis (high-risk BCR). XTANDI is currently approved for one or more of these indications in more than 90 countries, including in the U.S., European Union and Japan. Over one million patients have been treated with XTANDI globally.(6)Please see Full Prescribing Information for additional safety information.
About Astellas
Astellas Pharma Inc. is a pharmaceutical company conducting business in more than 70 countries around the world. We are promoting the Focus Area Approach that is designed to identify opportunities for the continuous creation of new drugs to address diseases with high unmet medical needs by focusing on Biology and Modality. Furthermore, we are also looking beyond our foundational Rx focus to create Rx+® healthcare solutions that combine our expertise and knowledge with cutting-edge technology in different fields of external partners. Through these efforts, Astellas stands on the forefront of healthcare change to turn innovative science into VALUE for patients.
About Pfizer Oncology
At Pfizer Oncology, we are committed to advancing medicines wherever we believe we can make a meaningful difference in the lives of people living with cancer. Today, we have an industry-leading portfolio of 24 approved innovative cancer medicines and biosimilars across more than 30 indications, including breast, genitourinary, colorectal, blood and lung cancers, as well as melanoma.
About the Pfizer/Astellas Collaboration
In October 2009, Medivation, Inc., which is now part of Pfizer (NYSE:PFE), and Astellas (TSE: 4503) entered into a commercial agreement to jointly develop and commercialize XTANDI® (enzalutamide) in the United States, while Astellas has responsibility for manufacturing and all additional regulatory filings globally, as well as commercializing the product outside the United States. Pfizer receives alliance revenues as a share of U.S. profits and receives royalties on sales outside the U.S.
1. Ward JF, Moul JW. Rising prostate-specific antigen after primary prostate cancer therapy. Nat Clin Pract Urol. 2005 Apr;2(4):174-82. doi: 10.1038/ncpuro0145. PMID: 16474760.
2. Antonarakis, Emmanuel S et al. “The natural history of metastatic progression in men with prostate-specific antigen recurrence after radical prostatectomy: long-term follow-up.” BJU international vol. 109,1 (2012): 32-9. doi:10.1111/j.1464-410X.2011.10422.
3. Cancer.net. Prostate Cancer: Types of Treatment (12-2022). https://www.cancer.net/cancer-types/prostate-cancer/types-treatment. Accessed March 16, 2023.
4. American Society of Clinical Oncology. ASCO Answers: Prostate Cancer (2021). http://www.cancer.net/sites/cancer.net/files/asco_answers_guide_prostate.pdf. Accessed March 16, 2023.
5. Paller, Channing J et al. “Management of patients with biochemical recurrence after local therapy for prostate cancer.” Hematology/oncology clinics of North America vol. 27,6 (2013): 1205-19, viii. doi:10.1016/j.hoc.2013.08.005
6. Astellas. Data on File. XTANDI patient. January 2023.