Dovitinib Reduces Prostate Cancer Bone Metastases

Treatment with the FGFR tyrosine kinase inhibitor dovitinib (TKI258; Novartis) may benefit a subset of men with castration-resistant prostate cancer (CRPC) and bone metastases, researchers have found.

The study, published in Science Translational Medicine, integrated data from mouse models and men with prostate cancer that had metastasized to bone despite androgen-deprivation therapy.

“Other malignancies produce bone-forming metastases, but not as frequently or as consistently as prostate cancer does,” says senior author Nora Navone, MD, PhD, an associate professor in the Department of Genitourinary Medical Oncology at The University of Texas MD Anderson Cancer Center in Houston. “That tells us there is communication between prostate cancer cells and bone that is unique and encourages cancer progression, and that dovitinib appears to block that particular communication in some patients.”

Previously, the group conducted studies in mice that suggested prostate cancer cells can alter the bone microenvironment by triggering the expression of FGFs, which are critical to bone development and have been associated with cancer cell proliferation and survival.

During their latest investigation, Navone, first author Xinhai Wan, PhD, and colleagues also found that activation of FGFR-mediated signaling in CRPC appears to determine the effectiveness of dovitinib treatment. The team compared subsets of xenografted mice and found that those with prostate cancer cells expressing higher levels of FGFR1 experienced an 80% reduction in tumor volume after 3 weeks of dovitinib treatment.

“We observed death of tumor cells, but we also saw improvements in bone mass in the mice,” says Navone, who explains that blocking FGFR1 in osteoblasts appears to increase the antitumor activity of dovitinib by both improving bone quality and blocking the interaction of cancer and bone cells.

The investigators then conducted a proof-of-principle study, evaluating 23 patients with CRPC and bone metastases who were treated with dovitinib. Six of the patients experienced improvements in bone scans and reported fewer skeletal symptoms, 13 patients showed no disease progression, and four progressed despite treatment. “We've shown blocking the FGF axis has clinical benefits,” says Navone. “The challenge is to find markers to better determine which patients will respond to therapy.”

Philip W. Kantoff, MD, director of the Lank Center for Genitourinary Oncology at Dana-Farber Cancer Institute in Boston, MA, who was not involved in the study, is optimistic about the role of dovitinib in CRPC. “The study provides convincing preclinical data of the importance of FGF signaling in the bone microenvironment in the context of bone metastases from prostate cancer, and it provides early evidence of the activity of an FGFR inhibitor in interfering with bone remodeling,” he notes.

In addition to searching for predictive markers, Navone and colleagues aim to identify beneficial drug combinations. “There are broadly two types of drugs that we view as effective: those that directly affect the tumor cells and those that affect the stromal cells, such as dovitinib,” she says. “We expect the combination will prolong survival in prostate cancer patients.”