Enzalutamide Prolongs Survival in Treatment-resistant Prostate Cancer Patients
August 16, 2012 -- Results of the Phase III clinical trial drug enzalutamide, (formerly MDV3100) presented earlier at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago, and published today in the New England Journal of Medicine show that the once-daily androgen receptor signaling inhibitor is well tolerated and significantly prolongs overall survival (OS) in men with progressive treatment-resistant prostate cancer, after chemotherapy.
Androgen (male hormone) signaling remains a major driver of prostate cancer growth and spread, its activity mediated by the Androgen Receptor (AR). Androgen receptor plays an important role in the development of treatment-resistance by traveling to the cellular nucleus, binding to DNA and increasing pro-cancer gene expression.
Enzalutamide is an AR–signaling inhibitor chosen for clinical development on the basis of activity in preclinical models (PCF-funded discovery research at the University of California, Los Angeles that resulted in the synthesis of the compound) and promising Phase I/II clinical trial data (conducted through the PCF-funded Prostate Cancer Clinical Trials Consortium). It is distinct from the currently available anti-androgens in that it targets multiple steps in the AR–signaling pathway; enzalutamide inhibits the androgen receptor’s nuclear translocation, DNA binding, and coactivator recruitment for regulating gene expression. Enzalutamide also has a greater affinity for AR, and has been shown to induce tumor shrinkage in xenograft models in which conventional agents typically only retard growth.
The international, double-blind, placebo-controlled Phase III AFFIRM trial studied 1,199 patients with prostate cancer that had progressed, despite hormonal and chemotherapy treatments. The investigators randomly assigned 800 patients to the enzalutamide arm and 399 patients to the placebo arm.
Enzalutamide significantly prolonged the survival of men with metastatic treatment-resistant prostate cancer after chemotherapy by a median of 4.8 months and reduced the risk of death by 37 percent versus placebo. This survival benefit was seen in all patient subgroups, including those stratified according to age, the geographic location of the study center, the extent of disease on diagnostic imaging, and biochemical measurements that included PSA and lactate dehydrogenase, even after adjustment for baseline factors.
During the planned interim analysis the Independent Data Monitoring Committee concluded that there was a statistically and clinically meaningful overall survival benefit with enzalutamide and determined that the AFFIRM study should be halted and unblinded, with eligible patients in the placebo arm offered enzalutamide therapy.
PCF-funded scientist and co-investigator of the AFFIRM data, Dr. Johann S. de Bono, of the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust, United Kingdom, said that the survival data “are the best we’ve seen in the post-chemotherapy setting.” Overall survival rates were about five months longer among treated patients, with a 37 percent reduction in risk of death.
On all of the trial’s secondary endpoints: the response indicators (which include prostate- specific antigen response, soft tissue objective response, and Functional Assessment of Cancer Therapy-Prostate quality of life) and the progression indicators (which include time to PSA progression, radiographic progression-free survival (rPFS), and time to first skeletal related event), enzalutamide was superior to placebo.
AFFIRM demonstrated a very high PSA response rate with enzalutamide. “I never thought I would see a 50 percent and 90 percent fall in PSA in this population of patients, with 54 percent having a more than 50 percent fall in PSA,” Dr. de Bono said. Quality-of-life responses were significantly higher with enzalutamide on all measures.
Enzalutamide was generally well tolerated, Dr. de Bono said, with little difference in toxicity with placebo. There was, however, a higher and non-significant risk of fatigue and a small risk of seizures with enzalutamide.
Enzalutamide is being developed by Medivation and Astellas Pharma, who submitted a New Drug Application (NDA) to the US Food and Drug Administration (FDA) for approval to market the drug for “the treatment of treatment-resistant prostate cancer in patients previously treated with chemotherapy” on May 21, 2012. Based on the promising clinical trial data, FDA approval is expected around the end of this year.
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