ZD4054 is a potential anti-cancer agent now in a clinical trials around the world for men with metastatic hormone refractory prostate cancer (HRPC) and for men with non-metastatic hormone refractory prostate cancer.

The trials are run by pharmaceutical company AstraZeneca, which makes ZD4054. These two distinct trials differ significantly in the level of therapy offered to men who do not receive the novel (new and not yet proven) trial drug.

The novel drug is a selective endothelin-A receptor antagonist (SERA) from the same family as atrasentan (brand name Xinlay) and YM598. Xinlay, which for a while looked quite promising, failed to prove effective in clinical trials for prostate cancer in 2005 and did not win FDA approval.

The trial for non-metastatic HRPC offers all patients standard of care. “All patients participating in this clinical trial will receive existing prostate cancer treatments in addition to trial therapy. Half the patients will receive ZD4054, and half the patients will receive placebo in addition to standard prostate cancer therapy. By participating in this trial there is a 50% chance that patients will receive an agent that may slow the progression of the tumour. No patients will be deprived of standard prostate cancer therapy.”

This should make the trial quite worthwhile for patients who are willing to take Taxotere at this relatively early stage of advanced prostate cancer.

However, the other trial, for men who do have metastatic HRPCA, offers nothing but Taxotere alone to those randomized to the placebo group.

For some men with hormone-resistant prostate cancer (HRPC) who would be willing to accept Taxotere alone as a chemotherapy, and who are interested in a chance to receive in addition a potentially potent therapy, this clinical trial might be worth considering.

The primary downside in this particular ZD4054 trial lfor metastic patients lies in the 50/50 odds of being randomized to take Taxotere on its own OR with a drug which might turn out to be less than effective. Usually, Taxotere is prescribed in combination with other chemo drugs like Carboplatin and Emcyt and/or supportive drugs like prednisone. No one knows yet whether patients who are randomized to receive Tax with ZD4054 will gain as much of a boost as patients on standard combination therapies.

Let’s look briefly at evidence for benefits, risks and side effects for ZD4054 on its own. ZD4054 is being tested in patients with prostate cancer to see if it can block the uptake of endothelin A (details below) and thereby shrink tumors or slow their progression. What effects have been seen so far?

A Phase 2 study in the UK reported in May 2009 on results in patients attending cancer centres with HRPC and bone metastases who were pain free or mildly symptomatic for pain. Patients were randomized into 3 groups to receive once-daily oral tablets of ZD4054 10 mg, or ZD4054 15 mg, or placebo:

At the primary analysis, median time to progression was 3.6 mo, 4.0 mo, and 3.8 mo in the placebo, ZD4054 10 mg, and ZD4054 15 mg groups, respectively, with no statistically significant difference between ZD4054 groups and placebo. . . . However, a signal for prolonged overall survival was observed in the ZD4054 treatment groups versus placebo, based on 40 deaths. At a subsequent analysis after 118 deaths, this survival benefit was confirmed . . . but the differences in time to progression remained nonsignificant. Median overall survival was 17.3 mo, 24.5 mo, and 23.5 mo in the placebo group, the ZD4054 10 mg group, and the ZD4054 15 mg group, respectively. Discordance between results for time to progression and overall survival may be due to the sensitivity of the definition of progression. Adverse events were in line with the expected pharmacologic effects of an ETAR antagonist. CONCLUSIONS: The primary end point of time to progression was not achieved in this study, but an improvement was seen in overall survival in both active treatment arms. ZD4054 was well tolerated.

What Type of Drug is ZD4054 and How Is it Thought to Affect Tumors?

ZD4054 (napthalene sulfonamide: see chart 2) is classified as a specific endothelin A (ETA) receptor antagonist. Endothelins are proteins involved in tissue repair. They constrict blood vessels and raise blood pressure. When these are over-expressed, they contribute to high blood pressure (hypertension) and heart disease. Evidence suggests endothelins also have a role in cancer and its spread:

The endothelins have been implicated in numerous physiological and pathological conditions, including hypertension, cardiac failure and disseminated intravascular coagulation. Interest in the role of ET-1 in cancer has grown over the last decade, following the work of Kusuhara et al (1990) that demonstrated ET-1 production by several tumour cell lines. Currently there is evidence that ET-1 may modulate mitogenesis, apoptosis, angiogenesis, tumour invasion and development of metastases. From Endothelin-1: a multifunctional molecule in cancer. British Journal of Cancer (2003)

Tumor tissues including prostate cancer tissues have more receptors for endothelin A (ETA) and fewer receptors for endothelin B (ETB). In prostate cancer tissue, levels of receptor expression for ETA “have been found to correlate with both Gleason score and presence of metastases (Gohji et al, 2001)” (BJC).

LINKS AND SOURCES

A Phase III Trial of ZD4054 (Endothelin A Antagonist) and Docetaxel in Metastatic Hormone Resistant Prostate Cancer (ENTHUSEM1C) (last verified Aug 28 2009)

A Phase III Trial of ZD4054 (Endothelin A Antagonist) in Non-metastatic Hormone Resistant Prostate Cancer (ENTHUSE M0)
“All patients participating in this clinical trial will receive existing prostate cancer treatments in addition to trial therapy. Half the patients will receive ZD4054, and half the patients will receive placebo in addition to standard prostate cancer therapy. By participating in this trial there is a 50% chance that patients will receive an agent that may slow the progression of the tumour. No patients will be deprived of standard prostate cancer therapy.”

Safety and efficacy of the specific endothelin-A receptor antagonist ZD4054 in patients with hormone-resistant prostate cancer and bone metastases who were pain free or mildly symptomatic: a double-blind, placebo-controlled, randomised, phase 2 trial. Eur Urol. 2009 May;55(5):1112-23

James ND et al, School of Cancer Sciences, University of Birmingham, Birmingham, UK. [email protected].

Profile of Past and Current Clinical Trials Involving Endothelin Receptor Antagonists: The Novel “-Sentan” Class of Drug
Bruno Battistini et al. Experimental Biology and Medicine 231:653-695 (2006)

The Specific Endothelin A Receptor Antagonist ZD4054: Preclinical and Clinical Results European Urology Supplements, Volume 8, Issue 1, Pages 29-35. N. James, J. Growcott