ECCO: Investigational Drug Shows Survival Edge in Advanced Prostate Cancer

BARCELONA, Spain -- An investigational drug that blocks key cancer growth messages appears to give patients with metastatic hormone resistant prostate cancer an extra six months' survival.

Paradoxically, the phase II trial that compared two doses of the drug, known as ZD4054, against placebo failed to achieve its primary endpoint - progression-free survival, reported Nicholas James, BSc., Ph.D., of the Institute for Cancer Studies in Birmingham, England.

"We observed that 107 men treated with placebo survived an average of 17.5 months while 98 men who received a 15-mg dose of ZD4054 survived an average of 23.5 months (P=.052) and 107 men who received a 10-mg daily dose of ZD4054 survived an average of 24.5 months (p=.008)," Dr. James said during a presentation at the European Cancer Organization meeting here.

Dr. James said that the treatment with ZD4054, a specific endothelin A receptor antagonist, essentially gave those men an extra six months of life -- despite the fact that the drug didn't appear any more effective than placebo in stopping disease progression.

"We are not really sure how to explain this," he said. "If may be that we do not have a really good description of disease progression." In the trial, disease progression occurred if a patient required surgery or radiation therapy for symptoms, had cancer pain that required opiates, or developed soft issue metastases.

When the study met its pre-specified 165 events marking progression, 40 deaths had been recorded in the randomized, double-blind, placebo-controlled trial. The study was then extended and was re-analyzed following the deaths of 118 participants.

"These results are amazing," commented surgical oncologist Alexander Eggermont, M.D., Ph.D., of at Erasmus University Medical School in Rotterdam. "The results are extraordinary in light of the fact that you did not have any indication of disease-free progression and yet there is a significant survival benefit for these patients." Dr. Eggermont, the new president of the European Cancer Organization, moderated the session at the conference where the ZD4054 data were presented.

"It is usual to use progression-free survival as an endpoint in phase II studies," Dr. James said. "However it can be difficult to measure accurately in patients with metastatic hormone resistant prostate cancer. Overall survival is an unambiguous endpoint and clearly an important outcome for patients." He said the drug was well tolerated.

The men in the study were selected from among patients who had undergone definitive prostate cancer treatment and had rising PSAs that were relatively asymptomatic.

ZD4054, made by AstraZeneca, was designed to block the action of the endothelin A receptor which Dr. James said has been implicated in metastasis, disease progression, angiogenesis and osteoblast stimulation. On the other hand, he noted, the drug does not block the action of the endothelin B receptor, believed to be helpful in apoptosis and vasodilation.

In an AstraZeneca-sponsored press briefing following Dr. James' presentation to the congress, Tom Morris, M.D., medical science director for the company, said that three phase III studies with ZD4054 are being planned. He said accrual for the studies is expected to begin within a month or so.

"Overall survival will be the primary endpoint in these studies," Dr. Morris said. He said the company will take forward the 10-mg dose into the pivotal trials that include use of ZD4054 with docetaxel, currently the only drug approved for the treatment of men who have progressive disease after hormonal therapy has failed to control the malignancy.

"This drug gives home to the men with hormone-resistant prostate cancer," said Sandy Tyndale-Biscoe, chairman of the Prostate Cancer Network, the largest prostate cancer advocacy group in the United Kingdom. "Right now we have very limited treatments."

He said that the men who die from prostate cancer are exactly the men in the EPOC ((Endothelin A Proof Of Concept). "There is something to this drug [ZD4054] that suggests something can be done about this disease. Something that adds a six-month survival is a very exciting."