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Phase II study shows HRPC patients with bone metastases see improved survival with ZD4054

Macclesfield, UK, 25 September 2007. New Phase II data presented today suggest that ZD4054, a novel compound in development for the treatment of men with Hormone Resistant Prostate Cancer (HRPC), could offer a promising improvement in overall survival in men with metastatic HRPC who were asymptomatic or mildly symptomatic for pain.1 Patients who received ZD4054 10mg once-daily experienced a 45 percent reduction in the risk of death compared to placebo (HR 0.55; 80 percent CI 0.41, 0.73).1

To further evaluate ZD4054s potential, the Phase III trial programme 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 non-metastatic HRPC patients. A third trial will study ZD4054 in combination with docetaxel (TaxotereTM) for the treatment of metastatic HRPC.

The results from the randomised, 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).

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 promising results from the EPOC study suggest that ZD4054 10mg once-daily has the potential to increase the median overall survival time for men with asymptomatic or mildly symptomatic metastatic HRPC, with the benefit of a manageable side-effect profile and the convenience of once-daily oral dosing.

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. However, preliminary survival data suggested an improvement in overall survival. The Phase II data presented today show that, at further follow-up, patients who received ZD4054 10mg once daily experienced a 45 percent reduction in the risk of death compared to placebo (HR 0.55; 80 percent CI 0.41, 0.73), translating into an improved median OS of 24.5 months with ZD4054 10mg once-daily compared with 17.3 months in the placebo arm.

Patients who received ZD4054 15mg once-daily experienced a 35 percent reduction in risk of death (HR 0.65; 80 percent CI 0.49, 0.86), again translating into an improved median OS of 23.5 months with ZD4054 15mg once-daily compared with 17.3 months in the placebo arm.

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 percent 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 EPOC data suggest that ZD4054 once-daily could be an important treatment option for patients with HRPC. In addition, ZD4054 has a manageable side-effect profile, which included headache, oedema and nasal congestion.1

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

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.2 It does so without blocking the ETB receptor, which may provide beneficial biological effects in terms of encouraging apoptosis, the death of unhealthy cells.

The future of ZD4054:

ZD4054 has shown promising results in this Phase II study in patients with metastatic hormone resistant prostate cancer, said Alex Oldham, ZD4054 Vice President. AstraZeneca is committed to confirming these findings and further evaluating the activity of ZD4054 in HRPC through a comprehensive Phase III clinical development programme.

The three Phase III trials will investigate a 10mg once-daily dose of ZD4054.

AstraZeneca has a well-established prostate cancer franchise based on its leading hormonal treatments ZOLADEX (goserelin), first launched in 1987, and CASODEX (bicalutamide), first launched in 1995.


Contact: Aoife Gallagher
Cohn & Wolfe Healthcare, London

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