Twice-yearly intravenous infusion with denosumab, a new targeted therapy to stop bone loss, increased bone density and prevented spinal fractures in men receiving androgen-deprivation therapy for prostate cancer. The report from an international research study, the first to document reduced fracture risk in men receiving the hormone-blocking treatment, was published today in the print edition of the New England Journal of Medicine (NEJM). Both fundamental research on rank ligand (RANKL) in prostate cancer bone metastasis and other molecular factors involved in the denosumab study were supported at Massachusetts General Hospital with funding from the Prostate Cancer Foundation (PCF).
As this study by Smith and colleagues could have an impact on the standard of care for tens of thousands of prostate cancer patients, it has received considerable interest from the medical community and media leading up to today’s publication. The study was a Phase III trial supporting the application for approval from the Food and Drug Administration (FDA) filed by Amgen Inc., the primary sponsor of the NEJM report.
“Androgen-deprivation therapy is the standard treatment for men with locally advanced, recurrent and metastatic prostate cancer; but many active men who have been successfully treated for their cancer develop debilitating bone fractures as a result,” outlines Matthew Smith, MD, PhD, of the Massachusetts General Hospital (MGH) Cancer Center, who led the study as part of the Denosumab HALT Prostate Cancer Study Group. “The results of this study should be critically important in improving the quality of life of thousands of prostate cancer survivors.”
About one third of the two million prostate cancer survivors in the U.S. currently receive androgen-deprivation therapy, which blocks the release of testosterone. Testosterone is a molecular signal for prostate cancer cells to grow. Several medications used to treat osteoporosis, including drugs called bisphosphonates, have been shown to reduce androgen-deprivation-related bone loss in men in earlier small clinical studies, but none of those trials were adequate to demonstrate reduced fracture risk. Denosumab, a fully-human monoclonal antibody that blocks the action of osteoclasts—the cells that break down bone in the normal process of bone remodeling—is also being investigated to prevent fractures in women with osteoporosis.
Denosumab works by targeting rank ligand, a protein that acts as the primary signal to promote bone removal. In many bone loss conditions, RANKL overwhelms the body's natural defense against bone destruction. Denosumab mimicks the endogenous effects of osteoprotegerin, a cytokine, which can inhibit the production of osteoclasts.
“At the PCF we led the initial research investments in targets like rank ligand blockade and other molecular factors in prostate cancer bone metastasis that are involved in death and suffering from prostate cancer. We also introduced these molecular concepts from our university funded laboratories to the biotechnology sector in the late 1990s,” commented Dr. Jonathan W. Simons, president and CEO of the PCF. “We are delighted to see the promising data come out of this denosumab study. The efforts argue for more work in creating an even more robust pipeline of new drugs that can treat the cancer and eliminate adverse side effects from treatments, increasing the wellness of every prostate cancer patient.”
Since the PCF was founded in 1993, there has been important growth in the number of new drugs and clinical trials for prostate cancer. Sixteen years ago, there were no new drugs in the development pipeline and only two clinical trials in process; in 2008 there were more than 30 drugs in development and over 60 clinical trials in process. Abiraterone, ipilimumab, MDV3100 and provenge are among several other promising new drugs that were supported by PCF funding and are now either in clinical trials or awaiting FDA approval. Ipilimumab and provenge are both immunotherapeutics that have been shown to stimulate the body’s own immune system to fight cancer.
In this latest study for denosumab, men undergoing androgen-deprivation therapy for nonmetastatic prostate cancer were enrolled at 156 centers in North America and Europe and randomly assigned to receive injections of either denosumab or a placebo every six months for three years. Participants were also instructed to take daily calcium and vitamin D supplements during the study period. Among the participants who completed the study, denosumab significantly increased bone density at all the monitored sites – including the lumbar spine, total hip and femoral neck – and reduced new vertebral fractures by 62 percent. Bone density at the radius, one of the bones in the forearm, also increased in the treatment group, an improvement not seen with other osteoporosis drugs.
“Denosumab is an important new therapy to prevent painful fractures in prostate cancer survivors,” says Smith. “An ongoing clinical trial will also evaluate whether denosumab prevents spread of prostate cancer to bone, the most common site of metastases in men with this disease.” Smith is also an associate professor of Medicine at Harvard Medical School.