Astellas Pharma Europe Limited

Results From Pivotal Phase 3 PROSPER Trial of XTANDI[TM] (enzalutamide) in Men With Non-Metastatic Castration-Resistant Prostate Cancer Published in New England Journal of Medicine

Tokyo (ots/PRNewswire) - Results show enzalutamide plus androgen deprivation therapy significantly reduced the risk of developing metastases or death by 71 percent compared to placebo plus androgen deprivation therapy[i]

FOR EMEA MEDICAL MEDIA ONLY - Astellas Pharma Inc. (TSE: 4503, President and CEO: Kenji Yasukawa, Ph.D., "Astellas") today announced that results from the pivotal Phase 3 PROSPER trial, which evaluated enzalutamide plus androgen deprivation therapy (ADT) versus placebo plus ADT in patients with non-metastatic castration-resistant prostate cancer (CRPC), were published in the New England Journal of Medicine. The paper, "Enzalutamide in Men with Nonmetastatic, Castration-Resistant Prostate Cancer", appears in the 28 June print edition of the Journal.[i]

In the study, enzalutamide plus ADT significantly reduced the risk of developing metastases or death compared to ADT alone: 23% of patients in the enzalutamide and ADT arm had metastasis or had died, vs 49% in the ADT alone arm. The primary endpoint of median metastasis-free survival (MFS) was 36.6 months for men who received enzalutamide compared to 14.7 months with ADT alone (n=1401; HR=0.29 [95% CI: 0.24-0.35]; p<0.001).[i]

"I'm pleased with the PROSPER trial results, which confirm that men with non-metastatic CRPC receiving enzalutamide plus androgen deprivation therapy (ADT) had an almost two year delay in appearance of prostate cancer metastasis or death as compared to those taking ADT," said Maha Hussain, MD, FACP, FASCO, Genevieve Teuton Professor of Medicine, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, and lead study investigator.

Based on the results of the PROSPER study, Astellas submitted a Type II Variation to the European Medicines Agency (EMA) in January 2018 to extend the overall indication for enzalutamide to include patients with non-metastatic CRPC. Enzalutamide was first approved by the European Commission in June 2013 for the treatment of adult men with metastatic CRPC who are asymptomatic or mildly symptomatic after failure of androgen deprivation therapy in whom chemotherapy is not yet clinically indicated or whose disease has progressed on or after docetaxel therapy.[ii] Enzalutamide is not currently licensed in the European Union for treatment of men with non-metastatic CRPC.

PROSPER Trial Results[i]

PROSPER is a double-blind, placebo-controlled, pivotal phase 3 trial conducted at 300 sites in 32 countries that randomized 1,401 patients with non-metastatic CRPC and a PSA doubling time of 10 months or less, 2:1 to either receive once-daily enzalutamide plus ADT (n=993) or placebo plus ADT (ADT alone [n=468]), respectively.

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 ADT alone. At the first interim analysis of overall survival, 103 patients (11%) in the enzalutamide group and 62 (13%) in the placebo group had died. The median overall survival was not reached in either group. There was no decrease in quality of life associated with enzalutamide treatment.

The most common adverse events of any grade for patients >=10% and higher for enzalutamide plus ADT vs ADT alone were: fatigue 33% vs 14%, hot flush 13% vs 8%, nausea 11% vs 9%, hypertension 12% vs 5%, dizziness 10% vs 4%, fall 11% vs 4% and decreased appetite 10% vs 4%. The adverse events in this trial were consistent with the established safety profile of enzalutamide.

About Prostate Cancer

Prostate cancer is the second most common cancer in men worldwide.[iii] In the European Union, the estimated number of new prostate cancer cases in 2015 was 365,000.[iv] More than 164,000 men in the United States are estimated to be newly diagnosed with prostate cancer in 2018.[v]

Castration-resistant prostate cancer (CRPC) refers to the subset of men whose prostate cancer progresses despite castrate levels of testosterone (i.e., less than 50 ng/dL).[vi] 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 prostate-specific antigen (PSA) level.[vii] Many men with non-metastatic CRPC and a rapidly rising PSA level go on to develop metastatic CRPC.[viii],[ix]

About Enzalutamide

Enzalutamide is an oral, once-daily androgen receptor signaling inhibitor. Enzalutamide directly targets the androgen receptors (AR) and exerts its effects on all three steps of the AR signaling pathway:

- Blocks androgen binding: Androgen binding induces a conformational 
  change that triggers activation of the receptor[x],[xi]
- Prevents nuclear translocation: Translocation of the AR to the 
  nucleus is an essential step in AR-mediated gene regulation[x],[xi]
- Impairs DNA binding: Binding of the AR to the DNA is essential for 
  modulation of gene expression[x],[xi] 

Important Safety Information for Enzalutamide

For important Safety Information for enzalutamide please see the full Summary of Product Characteristics at: https://www.medicines.org.uk/emc/product/3203

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 commercialize enzalutamide. The companies jointly commercialize enzalutamide in the United States and Astellas has responsibility for manufacturing and all additional regulatory filings globally, as well as commercializing enzalutamide outside the United States.

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.

Astellas Forward-Looking Statement

In this press release, statements made with respect to current plans, estimates, strategies and beliefs and other statements that are not historical facts are forward-looking statements about the future performance of Astellas. These statements are based on management's current assumptions and beliefs in light of the information currently available to it and involve known and unknown risks and uncertainties. A number of factors could cause actual results to differ materially from those discussed in the forward-looking statements. Such factors include, but are not limited to: (i) changes in general economic conditions and in laws and regulations, relating to pharmaceutical markets, (ii) currency exchange rate fluctuations, (iii) delays in new product launches, (iv) the inability of Astellas to market existing and new products effectively, (v) the inability of Astellas to continue to effectively research and develop products accepted by customers in highly competitive markets, and (vi) infringements of Astellas' intellectual property rights by third parties.

Information about pharmaceutical products (including products currently in development), which is included in this press release is not intended to constitute an advertisement or medical advice.

i. Hussain, Maha, et al. Enzalutamide in Men with Nonmetastatic Castration-Resistant Prostate Cancer. N Engl J Med 2018; 378:2465-74

ii. European Medicines Authority. Summary of Product Characteristics: Xtandi 40 mg soft capsules. Accessed 22-06-18 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002639/WC500144996.pdf

iii. Torre L. et al. Global Cancer Incidence and Mortality Rates and Trends - an Update. Cancer Epidemiol Biomarkers Prev; 25(1):pp16-27 January 2016

iv. European Commission. Epidemiology of prostate cancer in Europe (03-17-2017). https://ec.europa.eu/jrc/en/publication/epidemiology-prostate-cancer-europe . Accessed 22-06-2018.

v. American Cancer Society. Key Statistics for Prostate Cancer. https://www.cancer.org/cancer/prostate-cancer/about/key-statistics.html . Accessed 06-13-2018.

vi. Kirby M, Hirst C, Crawford ED. Characterising the castration-resistant prostate cancer population: a systematic review. Int J Clin Pract 2011;65(11):1180-92.

vii. Luo J, Beer T, Graff J. Treatment of nonmetastatic castration-resistant prostate cancer. Oncology 2016;30(4):336-44.

viii. Smith MR, Kabbinavar F, Saad F, et al. Natural history of rising serum prostate-specific antigen in men with castrate nonmetastatic prostate cancer. J Clin Oncol 2005;23(13):2918-25.

ix. 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: 2077-2085

x. Tran C, et al. Development of a second-generation antiandrogen for treatment of advanced prostate cancer. Science 2009; 324:787-790

xi. Hu R, Denmeade SR and Luo J. Molecular processes leading to aberrant androgen receptor signaling and castration resistance in prostate cancer. Expert Rev Endocrinol Metab 2010; 5 (5): 753-764

Contact:

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