ZD4054 and OGX-011: promise that needs to be confirmed

In the past two days, data has been made available from Phase II trials suggesting the potential of the AstraZeneca endothelin antagonist ZD4054 and Oncogenex’s resistance inhibitor OGX-011 in the treatment of hormone-refractory prostate cancer.

In the case of OGX-011, a company press release issued by Oncogenex states that, in a randomized, placebo-controlled, Phase II clinical trial, patients receiving OGX-011 in combination with docetaxel and prednisone (“the OGX-011 arm”) demonstrated a 10.6-month median overall survival benefit compared to patients receiving docetaxel and prednisone alone (“the control arm”) for first-line treatment of metastatic, castrate-resistant prostate cancer. We believe that this is the largest overall survival benefit ever documented by comparison with any standard therapy in the treatment of metastatic, hormone-resistant prostate cancer.

According to Oncogenex, “The study randomized 82 patients with metastatic or locally recurring prostate cancer refractory to hormone therapy. The median survival was 27.5 months for the patients in the OGX-011 arm and 16.9 months for those in the control arm. Results currently indicate that patients in the OGX-011 arm have a death rate approximately 40% lower than patients in the control arm. The current results are based on study data with a median follow-up of approximately 30 months for both arms. Additional survival updates are needed before a mature median survival for the OGX-011 arm can be reported. Based on the current results, OncoGenex has calculated that the final median survival for patients in the OGX-011 arm can not be lower than 22.7 months.”

The company plans to present details of these results in a presentation at the American Society of Clinical Oncology annual meeting in Chicago next May. In the meantime, we assume that the company will be planning to initiate at least one pivotal Phase III clinical trial to confirm these results and act as the basis for a potential approval of OGX-011. Such a trial might need to enroll about 300 patients, but based omn the results announced by Oncogenex yesterday, it is possible that a smaller trial might be sufficient.

With respect to ZD4054, AstraZeneca has announced publication of the results of a Phase II trial by James et al. in European Urology. It should be stated clearly that these results were previously presented at the European Congress of Clinical Oncology in late 2007.

This Phase II study was a double-blind, placebo-controlled, randomized, parallel-group, multicenter trial in patients with HRPC and bone metastases who were pain free or mildly symptomatic for pain. The patients received once-daily oral tablets of ZD4054 10 mg, or ZD4054 15 mg, or placebo. The primary end point was time to disease progression.

A total of 312 patients were randomised (ZD4054 10 mg, n = 107; ZD4054 15 mg, n = 98; placebo, n = 107). At the primary analysis, median time to progression was 3.6, 4.0, and 3.8 months in the placebo, ZD4054 10 mg, and ZD4054 15 mg groups, respectively. There was no no statistically significant difference between ZD4054 groups and placebo. However, there were suggestions of overall survival benefit in the ZD4054 treatment groups compared to 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, 24.5, and 23.5 months in the placebo group, the ZD4054 10 mg group, and the ZD4054 15 mg group, respectively.

AstraZeneca is currently enrolling patients into the “ENTHUSE” Phase III clinical trial initiative. The ENTHUSE program consists of three studies. The first trial is investigating the efficacy of ZD4054 in metastatic HRPC; the second will look at its role in non-metastatic HRPC patients; and a third trial will study ZD4054 in combination with docetaxel chemotherapy for the treatment of metastatic HRPC.

The bottom line here is that OGX-011 looks very promising as a product that can be combined with chemotherapy at least for the treatment of hormone-refractory patients. The potential of ZD4054 is less clear and will depend on the results of the Phase III trials. (It is worth bearing in mind that Abbott Laboratories first-in-class endothelin antagonist — atrasentan — performed well in  Phase II trials but failed to show any significant clinical benefit in Phase III trials.)

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