Atrasentan/Xinlay™ Update:
"Meta-analysis" says patients had less disease progression and less pain
May 26, 2005 /PSA RISING/ -- Findings from clinical trials of Abbott's oral agent Xinlay™ (atrasentan) were presented at the annual American Society of Clinical Oncology (ASCO) conference earlier this month. A team from Johns Hopkins said patients with advanced prostate cancer who received Xinlay experienced less disease progression and less pain than patients receiving placebo.
In a meta-analysis of one dose level, 10 mg, of the two earlier trials, Michael Carducci M.D. and his team say the evidence shows statistically significant evidence for benefit from Xinlay. Earlier, a "pivotal" trial failed to reach statistical significance.
Xinlay™(atrasentan) has fast track review status at the U.S. Food and Drug Administration (FDA). In February 2005 FDA agreed to file Abbott's New Drug Application (NDA) for Xinlay for the treatment of metastatic hormoneÂrefractory prostate cancer. Abbott expected a response from FDA regarding its application in the fourth quarter of 2005.
Atrasentan (Xinlay), a selective endothelin-A receptor antagonist, has been studied in 2 randomized placebo controlled studies of men with metastatic hormone-refractory prostate cancer (HRPC) using time to disease progression as the primary endpoint. Carducci and team performed a meta-analysis of these studies " to more precisely define the clinical benefit of atrasentan 10 mg in this patient population."
The researchers took patient data from the "intent-to-treat populations" of both studies. Time to disease progression (TTP), time to bone pain (TTBP), as well as time to prostate specific antigen (TTPSA) and bone alkaline phosphatase (TTBALP) progression were analyzed by accepted statistical methods (Kaplan-Meier methodology and Cox proportional hazards modeling).
The two studies randomized 1002 men with hormone refractory prostate cancer to take either atrasentan 10 mg or placebo. Atrasentan 10 mg, according to the researchers, resulted in a statistically significant delay in time to progression and time to bone pain, as well as time to prostate specific antigen and bone alkaline phosphatase progression.
Compared with patients receiving placebo, patients treated with atrasentan 10 mg were 14% less likely to experience disease progression, had an 18% less likelihood of experiencing bone pain, had a 22% less chance of experiencing PSA progression, and were 46% less likely to experience bone alkaline phosphatase progression (a forerunner of symptomatic advanced prostate cancer).
"The relative probability of remaining progression-free was 10% greater at 3 months and 22% greater at 6 months for patients treated with atrasentan 10 mg compared with those treated with placebo, where the probability of remaining progression-free on placebo was 49% and 27% at 3 and 6 months respectively," the study says.
"The results of this analysis demonstrate that atrasentan 10 mg, a novel cytostatic agent, provides significant clinical benefit to patients with metastatic HRPC and indicate that atrasentan would be a valuable addition to the limited treatment options available for these men.
Earlier reports mention that Xinlay (10mg) was generally well tolerated in both studies among all patients. Comparing adverse events for atrasentan vs. placebo showed headache (21 percent vs. 13 percent), peripheral edema (39 percent vs. 13 percent), and rhinitis (34 vs. 14 percent) respectively.
Links
ASCO Abstracts #4563 and #269: Meta-analysis of clinical trials of atrasentan 10 mg in metastatic hormone-refractory prostate cancer N. J. Vogelzang, J. B. Nelson, C. C. Schulman, D. P. Dearnaley, F. Saad, D. J. Sleep, J. D. Isaacson, M. A. Carducci
FDA Agrees to File Abbott's New Drug Application for Xinlay  Feb 11, 2005
Atrasentan/ Xinlay™: Abbott seeks FDA Approval, Phase III results show "delay in time to disease progression" for advanced prostate cancer patients with bone disease Dec 2005
FDA Agrees to File Abbott's New Drug Application for Xinlay  Feb 11, 2005
Atrasentan clinical trials Abbott Labs site
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Review: Endothelin receptors as novel targets in tumor therapy Anna Bagnato and Pier Giorgio Natali
Journal of Translational Medicine 2004, 2 : 16 May 24, 2004 Full free text (open access)
Phase I Dose-Escalation Study of the Safety and Pharmacokinetics of Atrasentan An Endothelin Receptor Antagonist for Refractory Prostate Cancer Bernard A. Zonnenberg , Gerard Groenewegen , Todd J. Janus , Terri W. Leahy , Rod A. Humerickhouse , Jeffrey D. Isaacson , Robert A. Carr and Emile Voest
Department of Internal Medicine, University Hospital, 3584 CX Utrecht, the Netherlands [B. A. Z., G. G., E. V.], and Abbott Laboratories, Abbott Park, Illinois
This page reported by J. Strax, last updated May 26, 2005
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