New Phase II data suggests 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.
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 ZD4054's 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 (Taxotere) 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 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.”
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.