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Abbott Laboratories announced on Friday, February 11, 2005 that the U.S. Food and Drug Administration (FDA) has agreed to file the New Drug Application (NDA) for its Selective Endothelin A Receptor Antagonist (SERA™), Xinlay™ (atrasentan) for the treatment of metastatic hormone-refractory prostate cancer. This decision indicates the NDA is sufficiently complete to permit a substantive FDA review of the data supporting the safety and effectiveness of Xinlay™. Abbott expects a response from the FDA regarding its application in the fourth quarter of 2005.

SERA™: Endothelins are peptides produced by the body that are comprised of 21 amino acids, the building blocks of protein. When bound to endothelin receptor A, endothelins are known to constrict blood vessels, stimulate cell growth, and increase cell survival. Prostate cancer cells have high levels of endothelins and endothelin receptor A expressed on their cell surface, particularly on high-grade cancer cells. As a result, the endothelin binds with the receptor, stimulating growth and increasing survival of the cancer cells.

Phase III Xinlay™: The recent phase III clinical trial of Xinlay™ involved 809 patients with metastatic prostate cancer that has become resistant to hormonal therapy.[1] Patients received Xinlay™ or placebo (inactive substitute) and the two groups were compared for clinical and x-ray indications of cancer progression and change from baseline in bio-markers of progression, including prostate specific antigen (PSA), bone alkaline phosphatase (BAP), and total alkaline phosphatase (ALP). Alkaline phosphatase is an enzyme that is involved in bone formation and other processes. Blood levels of alkaline phosphatase are increased in patients with bone metastases.

Xinlay™ significantly delayed cancer progression in patients with bone metastases.[2] Results suggest that Xinlay™ appears to delay progression of bone metastases, as it was shown to delay BAP progression. Compared to patients that received placebo, patients treated with Xinlay™ experienced a 2-fold longer period (a total of 505 days, 251 days more than placebo) before measures of their BAP increased 50% or more from the low point (nadir).

Researchers have also determined that treatment with Xinlay™ provided a small improved quality of life over placebo.[3] Quality of life was evaluated using two questionnaires that measure symptoms related to prostate cancer, including pain, fatigue, weight loss, and urinary problems. Higher scores indicate better quality of life and fewer symptoms. The questionnaires were filled out before and after treatment. Scores for the patients treated with placebo went down more between baseline (initial) measurement and post-treatment, indicating a greater reduction in quality of life and increase in symptoms, compared to patients treated with Xinlay™. The benefit with Xinlay™ was most apparent with patients who had cancer that had spread (metastasized) only to bone.

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[1] Carducci M, Nelson JB, Saad F, et al. Effects of atrasentan on disease progression and biological markers in men with metastatic hormone-refractory prostate cancer: Phase 3 study. Journal of Clinical Oncology, 2004 Annual Meeting Proceedings (Post-meeting edition);22(14S), Abstract #4508.

[2] Lipton A, Sleep DJ, Hulting SM, et al. Benefit of atrasentan in men with hormone refractory prostate cancer metastatic to bone. Journal of Clinical Oncology , 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition);22(14S), Abstract #4687.

[3] Yount S, Cella D, Mulani P, et al. Impact of atrasentan on prostate-specific outcomes with hormone refractory prostate cancer patients. Journal of Clinical Oncology , 2004 ASCO Annual Meeting Proceedings (Post-Meeting Edition);22(14S), Abstract #4582.

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