July 30, 2007

When prostate cancer no longer responds to hormone therapy - - a very beneficial "whole-body" or systemic treatment - - men with this disease face a difficult future. Few proven therapies have long-term benefits for men with hormone resistant prostate cancer, and their prognosis is often poor, even when medical teams use all the tools available.

Yes, hormone resistant (or refractory) prostate cancer is still a thorny problem, but researchers continue to develop and test new medicines and approaches to treatment, offering hope of expanded and improved therapies in the future.

Two promising drugs developed for the treatment of hormone refractory prostate cancer are ZD4054, currently entering phase III of its clinical trial, and Provenge.

ZD4054, developed by AstraZeneca, is an endothelin receptor antagonist. It works by interfering with endothelin's ability to bind to and affect cells, in other words, by blocking endothelin receptors. (Simply put, receptors are structures on the surface of a cell, or inside it, that selectively receive and bind to specific substances.)

"Endothelin is a peptide," explains Marc Zarenda, Scientific Director of Oncology for AstraZeneca Canada Inc. "Once it binds to receptors, it can encourage prostate cancer cells to grow and metastasize, but the exact mechanisms of its influence are complex."

There are two endothelin receptors, labelled A (ETA) and B (ETB). When endothelin binds to ETA, it appears to encourage cell proliferation and the development of new blood vessels (called angiogenesis); these new blood vessels "feed" the cells. It also inhibits the death of unhealthy cells (called apoptosis) and affects bone remodelling, apparently by stimulating bone metastases characterized by increased bone formation (osteoblastic bone metastases). None of these are positive effects for those battling prostate cancer. To complicate things, however, when endothelin binds to the ETB receptor, it seems to encourage apoptosis (cell death) in human cancer cells and decrease the overall concentration of endothelin in the blood - - beneficial effects.

"The benefit of ZD4054," reports Marc Zarenda, "is that it blocks the ETA receptor without blocking the ETB receptor."

ZD4054, which is taken orally, showed "promising survival data" in the randomised phase II study of the drug. Specifics of this EPOC (Endothelin A Proof Of Concept) study will be presented at the 14th European Congress of Clinical Oncology this September. The study, which involved 6 Canadian centres as well as researchers from Australia, the UK, the USA, Indonesia, France, and other European countries, randomly placed prostate cancer patients who had bone metastases and a rising PSA level into one of three groups: one taking 10 mg of ZD4054 orally once daily, a second taking 15 mg of ZD4054 orally once daily, and a third taking a placebo orally once daily.

Phase III of the ZD4054 trial, which is to begin before the end of 2007, will involve patients with both non-metastatic and metastatic hormone resistant prostate cancer. The trial will look at the effects of using ZD4054 alone, as a monotherapy, and of using it in combination with docetaxel (Taxotere™), a chemotherapy drug that does extend survival for men battling hormone refractory prostate cancer.

Provenge, a vaccine developed by the Dendreon Corporation, also targets the problem of hormone refractory prostate cancer. "The concept behind the vaccine is to try to stimulate the patient's own immune system to recognize the prostate cancer cells and keep them in check," reports Dr. Simon Hall from Mount Sinai Medical Center in New York City. Unfortunately, controversy now surrounds this vaccine. Data submitted to the US Food and Drug Administration advisory panel this spring "tend to support a finding of clinically meaningful increased survival," according to one FDA official. One small study of men with advanced metastatic prostate cancer, released in 2005, found that those who used Provenge experienced an average increase in survival time (about 4.5 months) when compared to those given a placebo. Still, there are concerns about "the persuasiveness of the efficacy data," and, although the FDA advisory panel voted 13-to-4 to say that the vaccine was a useful treatment for hormone refractory prostate cancer, the FDA itself, which does not need to follow the advice of its advisory panels, delayed approval of Provenge until Dendreon completes more research. About 100 prostate cancer activists rallied in Washington this June to protest the delay.

An important lesson can be learned here. Evaluating the effectiveness of novel approaches to treating hormone refractory prostate cancer is very challenging. Often, these treatments must be tested when all other proven therapies have been exhausted. Also, the microscopic, cellular-level chain of cause and effect is frequently obscure. Let's give Marc Zarenda of AstraZeneca the final word: "It is essential to have many researchers and companies, using multiple approaches, working toward a solution.”