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Survival Data Presented From Phase II Study of Investigational Drug ZD4054 in Hormone-Resistant Prostate Cancer Patients

Wide-Ranging ZD4054 Phase III Development Program Announced

WILMINGTON, Del., Sept. 25 /PRNewswire-FirstCall/ -- The results from the randomized, double-blind, placebo-controlled, Phase II EPOC (Endothelin A Proof Of Concept) Study of ZD4054 -- a specific endothelin A (ETA) receptor antagonist -- were delivered today at the 14th European Congress of Clinical Oncology (ECCO, 23-27 September, Barcelona). The data presented today for ZD4054, an investigational compound in development for the treatment of men with hormone resistant prostate cancer (HRPC), showed no differences in progression free survival (PFS) but did report encouraging overall survival (OS) data.(1)

To further evaluate the potential of ZD4054, the Phase III trial program ENTHUSE (ENDOTHELIN A USE), consisting of three studies, will begin this year. 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 nonmetastatic HRPC patients. A third trial will study ZD4054 in combination with docetaxel (Taxotere(TM)) for the treatment of metastatic HRPC.

Nick James, Professor of Clinical Oncology, Institute for Cancer Studies, Birmingham, UK, and principal investigator of the EPOC study said: "Men with advanced prostate cancer are typically treated with hormonal therapies. Whilst these therapies can provide great benefits, most men will become resistant to them. Currently, the only licensed treatment option for metastatic patients shown to improve survival in men with HRPC is chemotherapy with docetaxel."

"The results from the EPOC study suggest that ZD4054 10 mg once daily may have the potential to increase the median overall survival time for men with asymptomatic or mildly symptomatic metastatic HRPC."

EPOC (Endothelin A Proof Of Concept) Phase II findings:

The primary endpoint of the study was progression free survival (PFS) and a secondary endpoint was Overall Survival (OS). The PFS data did not show a statistically significant difference between ZD4054 and placebo treatment arms. The updated Phase II data presented today show that, patients who received ZD4054 10 mg once daily had a median OS of 24.5 months, patients who received ZD4054 15 mg once daily had a median OS of 23.5 months and the placebo arm had a median OS of 17.3 months.

The side effect profile of ZD4054 in this study included headache, edema and nasal congestion.

The OS results were as follows:

Intent-to-treat population ZD4054 15mg ZD4054 10mg Placebo

Number of patients 98 107 107

Number of deaths 34 33 51

Median overall survival (months) 23.5 24.5 17.3

Hazard ratio versus placebo 0.65 0.55 -

80% CI 0.49, 0.86 0.41, 0.73 -

"It is usual to use PFS as an endpoint in Phase II studies, however it can be difficult to measure accurately in patients with metastatic HRPC. Overall survival is an unambiguous endpoint and clearly an important outcome for patients," commented Professor Nick James.

PFS in this study was measured through clinical 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.

The Phase II EPOC study design:

This study recruited a total of 312 asymptomatic or mildly symptomatic HRPC patients with bone metastases who were randomized into one of three treatment arms: 15 mg ZD4054 once daily; 10 mg ZD4054 once daily or a placebo tablet once daily. In addition to study treatment, all men randomized into the study received best supportive care.

Mode of action -- specific ETA receptor antagonism:

ZD4054 targets the ETA receptor. Inhibition of this receptor is thought to be related to multiple processes that drive tumour growth and spread, including tumour cell proliferation, tumour cell survival, angiogenesis, and the formation of bone metastases.(2)

Notes to Editors

About Prostate Cancer

Prostate cancer primarily affects men over the age of 50.(3) It is the most commonly diagnosed male cancer in many western countries and its incidence is increasing. Worldwide, more than 670,000 men are diagnosed with prostate cancer every year, accounting for one in nine of all new cancers in men. Prostate cancer is the second most common cancer in men after lung cancer.(4) HRPC affects approximately 60,000 new patients in the US alone each year.(5)

About AstraZeneca

AstraZeneca is a major international health care business engaged in the research, development, manufacture and marketing of prescription pharmaceuticals and the supply of health care services. It is one of the world's leading pharmaceutical companies with health care 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.

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(1) James, M.D. ZD4054, a potent, specific endothelin A receptor antagonist, improves overall survival in pain-free or mildly symptomatic patients with hormone-resistant prostate cancer (HRPC) and bone metastases.

(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) Kirby RS et al. Prostate cancer and sexual function. Prostate Cancer and Prostatic Diseases 1998:1:179-184.

(4) Cancer Research UK, Prostate Cancer Incidence statistics

(5) DaVinci Cancer!MPact 2006.

SOURCE AstraZeneca
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