Results from the PROSPER trial show a median metastasis-free survival (MFS) of 36.6 months for enzalutamide plus androgen deprivation therapy (ADT) vs 14.7 months for men who received placebo plus ADT(1)
TOKYO, Japan and CHERTSEY, UK I September 24, 2018 I Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., “Astellas”) announced today that The Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion to expand the indication for Xtandi (enzalutamide) to include adult men with high-risk non-metastatic castration-resistant prostate cancer (nmCRPC).2 If approved by the European Commission (EC), enzalutamide will be one of the first treatments approved for this critical stage of disease, currently associated with a significant unmet medical need. Enzalutamide was first approved by the EC in June 2013 and is currently indicated in the treatment of adult men with metastatic CRPC who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy (ADT) in whom chemotherapy is not yet clinically indicated or whose disease has progressed on or after docetaxel therapy.3
“In nmCRPC, the high risk patient is at a stage where his cancer is growing even though it’s not visible yet despite hormone therapy and will manifest itself given time. The objective of early access to enzalutamide in these patients is to delay the emergence of metastasis with the hope of improving quantity and quality of life,” said Maha Hussain, MD, FACP, FASCO, Genevieve Teuton Professor of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, United States, and lead study investigator. “The potential of an effective treatment option for this stage of disease signifies an important therapeutic advancement.”
The CHMP opinion is based on the results from the pivotal phase 3 PROSPER trial which evaluated enzalutamide plus ADT vs placebo plus ADT in patients with nmCRPC and rapidly rising prostate-specific antigen (PSA) levels.1 The trial met its primary endpoint of metastasis-free survival (MFS). The median MFS was 36.6 months for men who received enzalutamide plus ADT, compared to 14.7 months with placebo plus ADT (n=1401; HR=0.29 [95% CI: 0.24–0.35]; p<0.001).1
The PROSPER trial results indicated a 71% reduction in the risk of radiographic progression or death in men with nmCRPC and rapidly rising PSA levels, compared to placebo plus ADT (HR=0.29 [95% CI: 0.24–0.35]; p<0.001).1 The most common adverse events of any grade for patients ≥10% and higher for enzalutamide plus ADT vs placebo plus ADT were: fatigue (33% vs 14%), hot flush (13% vs 8%), hypertension (12% vs 5%), nausea (11% vs 9%), fall (11% vs 4%), dizziness (10% vs 4%) and decreased appetite (10% vs 4%).1 These results were published in the June 2018 edition of the New England Journal of Medicine.1
“This positive CHMP opinion represents an important step towards providing specialist health care professionals with a new treatment option for patients with nmCRPC and rapidly rising levels of prostate specific antigen. These patients are at higher risk of developing metastasis and death. Subject to EMA approval, we have the potential to expand the use of enzalutamide in a patient population where there is a clear unmet medical need,” said Steven Benner, M.D, Senior Vice President and Global Therapeutic Area Head, Oncology Development, Astellas.
The positive opinion from the CHMP will now be reviewed by the EC, which has the authority to approve medicines for the 28 European Union member countries plus Iceland, Norway and Liechtenstein. The EC, which generally follows the recommendation of the CHMP, is expected to make its final decision in the final quarter of 2018.
PROSPER Trial Results
PROSPER is a double-blind, placebo-controlled, pivotal phase 3 trial conducted at 300 sites in 32 countries that randomised 1,401 patients with non-metastatic castration-resistant prostate cancer (nmCRPC) and a prostate-specific antigen (PSA) doubling time of 10 months or less, 2:1 to either receive once-daily enzalutamide plus androgen deprivation hormone therapy (ADT) (n=933) or placebo plus ADT (ADT alone [n=468]), respectively.1
Secondary outcomes included a statistically significant delay in the median time to first use of new antineoplastic therapy (TTA) of 39.6 vs 17.7 months; HR=0.21 [95% CI: 0.17–0.26]; p<0.001 for patients who received enzalutamide plus ADT compared to those who received placebo plus ADT.1
About Prostate Cancer
Prostate cancer is the most common cancer diagnosis for men in the European Union (EU).4 There are 375,842 men in the EU currently diagnosed with prostate cancer, accounting for an estimated 23.2% of all cancers in men in 2018.4 Some studies estimate that, within five years of diagnosis,10–20% of men with prostate cancer will develop CRPC.5
CRPC refers to the subset of men whose prostate cancer progresses despite castrate levels of testosterone (i.e., less than 50 ng/dL).6 Non-metastatic CRPC means there is no clinically detectable evidence of the cancer spreading to other parts of the body (metastases), and there is a rising PSA level.6 Many men with non-metastatic CRPC and a rapidly rising PSA level go on to develop metastatic CRPC.7,8
About Enzalutamide
Enzalutamide is an oral, once-daily androgen receptor signaling inhibitor. Enzalutamide directly targets the androgen receptors (AR) and exerts its effects on three steps of the AR signaling pathway:3
- Inhibits androgen binding: Androgen binding induces a conformational change that triggers activation of the receptor3
- Prevents nuclear translocation: Translocation of the AR to the nucleus is an essential step in AR-mediated gene regulation3
- Impairs DNA binding: Binding of the AR to the DNA is essential for modulation of gene expression3
Enzalutamide is currently approved in Japan for castration-resistant prostate cancer9 and in July 2018 the United States Food and Drug Administration (FDA) broadened the approved indication for enzalutamide to include men with nmCRPC.10
Important Safety Information for Enzalutamide in the EU
For important Safety Information for enzalutamide please see the full Summary of Product Characteristics at: https://www.medicines.org.uk/emc/product/3203.
About XTANDI® (enzalutamide) capsules in the U.S.
XTANDI (enzalutamide) is an androgen receptor inhibitor indicated for the treatment of patients with castration-resistant prostate cancer.
About Astellas
Astellas Pharma Inc., based in Tokyo, Japan, is a company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceutical products. For more information, please visit our website at https://www.astellas.com/en.
About Astellas Pharma Europe Ltd.
Astellas Pharma Europe Ltd. operates in 40 countries across Europe, the Middle East and Africa, and is the regional business of Tokyo-based Astellas Pharma Inc. Astellas is a pharmaceutical company dedicated to improving the health of people around the world through the provision of innovative and reliable pharmaceuticals. The organization’s focus is to deliver outstanding R&D and marketing to continue growing in the world pharmaceutical market.
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 global agreement to jointly develop and commercialise enzalutamide. The companies jointly commercialise enzalutamide in the United States and Astellas has responsibility for manufacturing and all additional regulatory filings globally, as well as commercialising enzalutamide outside the United States.
References
1. Hussain M, et al. Enzalutamide in men with nonmetastatic castration-resistant prostate cancer. N Engl J Med. 2018;378:2465–74.
2. European Medicines Agency. CHMP Positive Opinion: Xtandi. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion/human/002639/WC500255611.pdf. Last accessed September 2018.
3. European Medicines Agency. Summary of Product Characteristics: Xtandi 40 mg soft capsules. Available at: https://www.medicines.org.uk/emc/product/3203/smpc. Last accessed September 2018.
4. European Union: Eurostat: Available online at: https://ecis.jrc.ec.europa.eu. Last accessed September 2018.
5. Kirby M, et al. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract. 2011;65:1180–92.
6. Luo J, et al. Treatment of nonmetastatic castration-resistant prostate cancer. Oncology. 2016;30:336–44.
7. Smith MR, et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol. 2005;23:2918–25.
8. Smith MR, et al. Disease and host characteristics as predictors of time to first bone metastasis and death in men with progressive castration-resistant nonmetastatic prostate cancer. Cancer. 2011;117:2077–85.
9. Japan pharmaceutical and medical device agency. List of approved products 2013. Available at: https://www.pmda.go.jp/files/000153463.pdf . Last accessed September 2018.
10. US Food and Drug Administration. XTANDI [Prescribing Information]. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/203415s014lbl.pdf. Last accessed September 2018.
SOURCE: Astellas Pharma US
