A novel compound in development by AstraZeneca as an oral tablet for hormone resistant prostate cancer (HRPC), ZD4054, could improve overall survival (OS) in men with metastatic HRPC, according to Phase II data published today in European Urology.[1]

Men with advanced prostate cancer may receive initially effective treatment with hormonal therapies to which the majority of prostate cancers can later become resistant. This is known as hormone refractory, androgen resistant or castration (medical or surgical) resistant prostate cancer. The Phase II EPOC (Endothelin A Proof Of Concept) data published today show that HRPC patients who were asymptomatic or mildly symptomatic for pain and received ZD4054 10mg once-daily experienced a 45% reduction in the risk of death compared to placebo (HR 0.55; 80% CI 0.41, 0.73). [1]

The Phase II EPOC data show an increase in overall survival (OS) (the secondary endpoint of the study) though they do not show a statistically significant difference in Progression-Free Survival (PFS) between ZD4054 and placebo treatment arms (the primary endpoint of the study). [1]

Nick James, Professor of Clinical Oncology, Institute for Cancer Studies, Birmingham, UK, and principal investigator of the EPOC study said: "Currently, the only licensed treatment option for metastatic patients shown to improve survival in men with HRPC is docetaxel chemotherapy. These data demonstrate that ZD4054 may offer hope to men with the most severe form of prostate cancer who no longer respond to hormone therapies."

To further evaluate the potential of ZD4054 in men with HRPC, a Phase III trial programme ENTHUSE (ENDOTHELIN A USE) is underway. The ENTHUSE programme consists of three studies. The first of these trials is aimed at investigating the efficacy of ZD4054 in metastatic HRPC, while the second will look at its role in non-metastatic HRPC patients. A third trial will study ZD4054 in combination with docetaxel chemotherapy (Taxotere TM) for the treatment of metastatic HRPC.

EPOC Phase II Clinical findings

Results from the EPOC study, which originally presented at the 14th European Congress of Clinical Oncology (ECCO, 23-27 September, Barcelona) in which all men received study treatment in addition to best supportive care (palliative measures that help control cancer symptoms and treatment side effects), suggest that patients who received ZD4054 10mg once-daily experienced a 45 per cent reduction in the risk of death compared to placebo (HR 0.55; 80% CI 0.41, 0.73). Patients who received ZD4054 15mg once-daily experienced a 35% reduction in risk of death (HR 0.65; 80% CI 0.49, 0.86), translating into an improved median OS of 23.5 months compared with 17.3 months in the placebo arm. [1]

The primary endpoint of PFS data did not show a statistically significant difference between ZD4054 and placebo treatment arms. PFS in this study was measured through clinical progression or radiological evidence of disease worsening, or worsening of disease-related pain. However, patients with metastatic HRPC can typically have multiple bone metastases, making assessments of further changes in bone metastases difficult.

Professor Nick James commented: "There is no established definition for progression in HRPC and as such it can be difficult to measure accurately; however, overall survival represents a clear endpoint in this disease stage."

ZD4054 taken as an oral tablet was seen to be convenient and well tolerated, with a side-effect profile consistent with that seen in previous ZD4054 studies, which included headache, oedema and nasal congestion. [1] Further assessment of the safety of ZD4054 will continue throughout the ENTHUSE clinical trials.

More information on the ZD4054 ENTHUSE programme in the UK can be found on . astrazenecaclinicaltrials/ and astrazeneca.citeline.

Mode of action - specific ETA receptor antagonism

ZD4054 works by specifically blocking the ETA receptor. This may lead to the inhibition of multiple processes that drive tumour growth and spread, including tumour cell proliferation, tumour cell survival, angiogenesis and the formation of bone metastases. It does so without blocking the ETB receptor, which may provide beneficial biological effects in terms of encouraging apoptosis, the death of unhealthy cells.[2]

About the EPOC study

-The EPOC study is a Phase II, randomised, double-blind, placebo-controlled study of ZD4054

-A total of 312 pain-free or mildly symptomatic patients with metastatic hormone-resistant prostate cancer were enrolled in the study

-Participants were from Australia, Belgium, Canada, Denmark, Finland, France, Indonesia, Netherlands, Norway, Poland, Sweden, Switzerland, UK and the USA

About Prostate Cancer in the UK

Prostate cancer is the most common cancer to be found in elderly men in the UK. Over 34,000 men in the UK alone are diagnosed with prostate cancer each year and prostate cancer has overtaken lung cancer to become the most common cancer for men in the UK. Prostate cancer is the second biggest cause of death from cancer in men in the UK with around 10,000 deaths each year. More than 60 percent of cases occur in men over 70 years old and the largest number of cases is diagnosed in those aged 70-79. [3]

About AstraZeneca

AstraZeneca is a major international healthcare business engaged in the research, development, manufacture and marketing of prescription pharmaceuticals and the supply of healthcare services. It is one of the world's leading pharmaceutical companies with healthcare sales of $26.475 billion and leading positions in sales of gastrointestinal, cardiovascular, neuroscience, respiratory, oncology and infection products. AstraZeneca is listed in the Dow Jones Sustainability Index (Global) as well as the FTSE4 Good Index.

References

[1] James ND, et al. Safety and Efficacy of the Specific Endothelin-A Receptor Antagonist ZD4054 in Patients with Hormone-Resistant Prostate Cancer, Eur Urol (2008), doi:10.1016/j.eururo.2008.11.002

[2] Morris, C.D. et al. Specific inhibition of the endothelin A receptor with ZD4054: clinical and pre-clinical evidence. British Journal of Cancer. 2005: 92

[3] Cancer Research UK. infoncerresearchuk/cancerstats/types/prostate/ accessed November 2008

AstraZeneca

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