Exelixis initiates cabozantinib and abiraterone phase 1 combination trial in CRPC

Exelixis Inc. (NASDAQ:EXEL) today announced the initiation of a phase 1 dose-finding trial of cabozantinib in combination with abiraterone in men with metastatic castration-resistant prostate cancer (CRPC) who have disease progression following treatment with up to two prior chemotherapy regimens. The study is designed to define the maximum tolerated dose (MTD) of cabozantinib in combination with abiraterone and prednisone. Abiraterone was approved by the FDA in April 2011 and is indicated in combination with prednisone for the second-line treatment of CRPC in men who have received prior chemotherapy containing docetaxel. The study is being led by Dr. Chris Sweeney at the Dana-Farber Cancer Institute. The Massachusetts General Hospital and Beth Israel Deaconess Medical Center will also participate in accrual to the study.

"The Exelixis clinical development strategy for cabozantinib in CRPC is designed to rationally exploit the compound's unique activity profile as both a single-agent and in combination with other therapies," said Michael M. Morrissey, Ph.D., president and chief executive officer of Exelixis. "This investigator-sponsored trial is designed to provide important insight into the potential clinical utility of a combination of cabozantinib and abiraterone as a second-line regimen. Based on the extensive preclinical and clinical data generated to date for both compounds, we believe that a combination regimen of cabozantinib and abiraterone may provide CRPC patients with improved outcomes. Additional cabozantinib combination studies with other therapies are planned for the near future."

Rationale for Combination Approach

Clinical and preclinical evidence suggest that inhibition of androgen receptor signaling (a consequence of treatment with androgen synthesis inhibitors such as abiraterone) leads to upregulation of MET signaling, which may contribute to the survival and invasiveness of prostate cancer cells. Cabozantinib is a potent inhibitor of MET, and may therefore enhance the activity of abiraterone by blocking this putative resistance mechanism. Additionally, the high level of activity that cabozantinib has demonstrated against both soft tissue and bone lesions in men with CRPC may complement the clinical activity of abiraterone.

"Based on our increasing understanding of the biology and pathogenesis of CRPC, we now have the opportunity to impact the course of disease in this debilitating and deadly cancer. We are hopeful that the combination of two active agents with different mechanisms of action may meaningfully improve the outcome for men with metastatic prostate cancer," said Philip Kantoff, M.D., Chief Clinical Research Officer and Director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute and Professor of Medicine, Harvard Medical School.

"Although the recent approval of several new agents for the treatment of metastatic CRPC has helped to improve the treatment and outcomes for men with this disease, this is an indication that still has significant unmet medical need," said Christopher Sweeney, M.D., Clinical Director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute and Associate Professor of Medicine, Harvard Medical School, and principal investigator of the trial. "Bone metastases occur in approximately 90% of CRPC patients, and these lesions are the primary cause of morbidity and mortality in this patient population. The combination of cabozantinib and abiraterone may improve control of both soft tissue and bone lesions. Data from this study will provide a foundation on which to explore the clinical benefit this combination regimen may provide to men with CRPC."