A new randomized, controlled phase III trial reported at Tuesday’s Plenary Session found that denosumab, a novel RANK ligand inhibitor, significantly improved bone metastasis-free survival in men with castrate resistant prostate cancer (CRPC).
“This is the first large, randomized trial to demonstrate that targeting the bone microenvironment prevents bone metastasis in men with prostate cancer,” said Matthew R. Smith, M.D., PhD, Associate Professor of Medicine at Harvard Medical School and Director of the Genitourinary Malignancies Program at the Massachusetts General Hospital Cancer Center, Boston.
“Compared to placebo, denosumab significantly increased bone metastasis-free survival, time to first bone metastasis, and time to symptomatic bone metastasis. Overall rates of adverse events were similar between the groups. Hypocalcemia and osteonecrosis of the jaw, the known adverse effects of denosumab, were frequently observed,” Dr. Smith said.
“Based on the results of this global randomized, controlled trial, we conclude that denosumab is a potentially new and important treatment option for men with castrate resistant prostate cancer,” he added.
The study, known as Dmab ‘147, compared the treatment effect of denosumab with placebo on prolonging bone metastasis free survival in 1,432 men with hormonerefractory, or castrate resistant, prostate cancer and rapidly rising PSA levels who had no bone metastases at baseline. The primary end point of the trial was time to first occurrence of bone metastasis or death from any cause, with secondary end points including time to first occurrence of bone metastasis (excluding death) and overall survival.
“Bone metastases are common in men with advanced prostate cancer and represent a major cause of morbidity and mortality. Bone metastases result in significant health and economic burdens,” Dr. Smith said.
“There have been meaningful advances in the management of metastatic, castrate resistant prostate cancer, including new chemotherapy, immunotherapy, and androgen inhibitors. To date, however, no therapy has been shown to be effective in delaying the development of bone metastases in men with non-metastatic CRPC. Prevention of bone metastasis, therefore, represents an important unmet medical need,” he added.
“The development of bone metastasis involves reciprocal interactions between tumor cells and bone, the so-called vicious cycle of bone metastasis. Denosumab is a human monoclonal antibody that binds and activates the RANK ligand, a key mediator of osteoclast differentiation and survival,” Dr. Smith explained.
“Denosumab is superior to zoledronic acid for the prevention of skeletal negative events in men with CRPC and bone metastasis, and is approved for use in this setting,” he said.
The Dmab ‘147 study included castrate resistant men with prostate cancer who were at high risk for bone metastasis based on a serum prostate specific antigen (PSA) concentration less than 50 ng/ml and/or a doubling time of less than 10 months. The median age of the patients was 74 years, and the median time from prostate cancer diagnosis to study entry was 6.1 years.
Denosumab treatment was discontinued if bone metastases developed. About 42 percent of the patients in the placebo group and 35 percent of patients in the denosumab group developed bone metastases.
“The median bone metastasis-free survival was 25.2 months in the placebo group and 29.5 months in the denosumab group,” Dr. Smith said. “The difference in median bone metastasis-free survival between the groups was 4.2 months.”
The median time to first bone metastasis was 29.5 months in the placebo group and 33.2 months in the denosumab group. Overall survival was similar between the denosumab and placebo groups. The median overall survival time in both groups was approximately 44 months.
The study investigators defined progression-free survival as freedom from bone metastasis and investigator determined progression. “Compared with placebo, denosumab tended to improve the overall progression-free survival, with a hazard ratio of 0.89 and a p value of 0.93,” Dr. Smith said.
“The most common adverse events were distributed equally between the placebo and denosumab groups,” he continued. “Hypocalcemia and osteonecrosis of the jaw are recognized adverse events with denosumab and other osteoclast targeted therapies, and as expected, we observed higher rates of these conditions in the denosumab treated subjects. Among men who received denosumab, 12 (1.7 percent) had hypocalcemia and 33 (4.6 percent) experienced osteonecrosis of the jaw.”
The risk factors for osteonecrosis of the jaw include prior tooth extraction and poor dental hygiene. “Most of these cases were managed conservatively, and only two subjects required bone resection. As of February 2011, 13 cases (39 percent) had resolved,” Dr. Smith said.
The RANK ligand pathway, first discovered in the mid 1990s, is believed to play a central role in cancer-induced bone destruction, regardless of cancer type. Data suggest that in bone metastasis, cancer invasion is facilitated by bone destruction. Hence, increased bone resorption due to increased RANK ligand expression appears to augment bone metastasis.
Denosumab prevents the RANK ligand from activating its receptor, RANK, on the surface of osteoclasts, thereby decreasing bone destruction and halting the release of growth factors, making the environment less conducive to tumor growth, according to the drug’s manufacturer.