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ZD4054 Improves Overall Survival in Patients With Hormone-Resistant, Metastatic Prostate Cancer: Presented at CURy

By Chris Berrie

BARCELONA, SPAIN -- February 5, 2008 -- The specific endothelin A (ETA) receptor antagonist ZD4054 is associated with manageable adverse effects and increases overall survival (OS) for men with asymptomatic or mildly symptomatic, metastatic, hormone-resistant prostate cancer (HRPC), according to a multicentre, double-blind phase 2 study.

The findings were presented here on February 4 at the World Congress on Controversies in Urology (CURy).

With endothelin-1 (ET-1) implicated in prostate cancer progression via its effects on the ETA receptor, the targeting of ET-1 promotion of angiogenesis and tumour cell proliferation, migration, and invasion appears to be an attractive strategy for treatment of prostate cancer.

Heather Payne, MD, Consultant in Clinical Oncology, University College Hospital, London, England, United Kingdom, said this study was designed to test the safety and efficacy of ZD4054 in patients with HRPC and bone metastases who were free from or mildly symptomatic for pain and who had not received prior chemotherapy.

The primary endpoint was progression-free survival (PFS), with secondary endpoints of OS and rate of development of new bone lesions. PFS was a composite endpoint comprising clinical progression requiring surgery or radiotherapy, pain requiring opiates, soft tissue metastasis, or death in the absence of progression. Of note, prostate-specific antigen (PSA) or bone scan worsening were not included as progression events.

Patients with HRPC were randomised to placebo (n = 107), or ZD4054 at 10 mg (n = 107; ZD-10) or 15 mg (n = 98; ZD-15), with treatment groups similar across their measured demographics and baseline characteristics; median PSA levels at baseline were 64.0, 54.9, and 68.9 ng/mL, respectively. However, there were a greater number of bone metastases at baseline in the ZD-15 group.

First analysis was after 165 progression events (April 2006). There were, however, no significant differences versus placebo seen for PFS in the intention-to-treat population for both ZD-10 (hazard ratio [HR], 0.90; 80% confidence interval [CI], 0.73-1.11; P =.51) and ZD-15 (HR, 0.83; 80% CI, 0.66-1.04; P =.28).

Although based on only 40 deaths, OS did show promising treatment improvements versus placebo for ZD-10 (HR, 0.38; 80% CI, 0.22-0.64) and ZD-15 (HR, 0.62; 80% CI, 0.38-0.99).

The survival analysis in February 2007 showed no significant differences for PFS, while suggesting better OS versus placebo for both ZD-10 (HR, 0.55; 80% CI, 0.41-0.73) and ZD-15 (HR, 0.65; 80% CI, 0.49-0.86), with median OS of 17.3, 24.5, and 23.5 months for the placebo, ZD-10, and ZD-15 groups, respectively.

Common adverse events (AEs) were as might be predicted for the pharmacologic actions of ZD4054 as an ETA receptor antagonist: headaches, peripheral oedema, and nasal congestion (>30% of patients for each). There were few AEs of grade 3 or above.

While the number of bone metastases increased in all patient groups, ZD4054 again showed favourable effects as the HR of the increase compared with placebo: ZD-10, 0.86 (80% CI, 0.72-1.03); ZD-15, 0.95 (80% CI, 0.79-1.14).

Dr. Payne indicated that the combined form of the PFS definition may have had a role in the absence of significant benefit of ZD4054 for PFS; this led to a large number of patients progressing very quickly, thus reducing the ability to discriminate among the treatment groups. While this definition of PFS is consistent with that used in previous clinical trials in this setting, this discordance between PFS and OS does suggest that this definition of PFS may need to be refined, he said.

Finally, Dr. Payne stressed again that ZD4054 at 10 mg does indeed have the potential to increase the median OS for these men with asymptomatic or mildly symptomatic metastatic HRPC, while showing a manageable AE profile.

This presentation took place during a symposium sponsored by AstraZeneca, which provided funding for this study.


[Presentation title: Progress-Free Survival, Overall Survival and Bone Metastasis in a Phase 2 Trial of the Specific Endothelin A Receptor Antagonist ZD4054 in Patients With Hormone-Resistant Prostate Cancer. Session 5: New Targeted Therapy for Urological Cancer]

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