The monoclonal antibody denosumab extended bone metastasis–free survival in an international, placebo-controlled phase III study involving 1,432 men with castration-resistant prostate cancer published online Nov. 16 in the Lancet Oncology.
Denosumab also prolonged the time to first bone metastasis and was associated with fewer symptomatic bone metastases in these high-risk patients, said Dr. Matthew R. Smith of the cancer center at the Massachusetts General Hospital, Boston, and his associates.
However, the agent did not improve overall survival, they noted.
The researchers assessed denosumab in a randomized, double-blind clinical trial conducted at 319 medical centers in 30 countries. Study subjects were men with castration-resistant prostate cancer who had no evidence of metastasis on radioisotope bone scanning, which was confirmed with subsequent imaging by CT, MRI, or plain radiography. All subjects were at high risk for disease progression based on elevated prostate-specific antigen results or short PSA doubling times.
The study subjects were randomly assigned to receive either subcutaneous denosumab 120 mg (716 patients) or placebo (716 patients) every 4 weeks until a study event (bone metastasis or death) was reached. All were strongly advised to take daily calcium and vitamin D supplements. They underwent further bone scans every 4 months to detect bone metastases.
Patients who developed a bone metastasis were discontinued from study treatment so that they could receive standard therapy, but were followed for up to an additional 3 years.
There were 605 bone metastases and 100 deaths during a median follow-up of 20 months.
The primary efficacy end point was bone metastasis–free survival. Compared with placebo, denosumab extended this end point by 4.2 months. Median bone metastasis–free survival was 29.5 months with denosumab and 25.2 months with placebo, "representing a decrease in risk of 15%," Dr. Smith and his colleagues said (Lancet Oncol. 2011 Nov. 16 [doi:10.1016/S0140-6736(11)61226-9]).
The median time to bone metastasis was 33.2 months with denosumab, compared with 29.5 months with placebo. And the rate of symptomatic bone metastasis was 10% with denosumab, compared with 13% with placebo; the investigators reported a 33% reduction in the risk of symptomatic bone metastasis.
The median overall survival was similar between the two groups, however, at 43.9 months in the denosumab group and 44.8 months in the placebo group. Similarly, median progression-free survival was 21.7 months with denosumab and 19.3 months with placebo.
The investigators noted that their ability to assess survival was hampered by the requirement that patients who developed bone metastasis discontinue denosumab and undergo standard treatment to prevent bone-related events. "This requirement restricted our ability to evaluate overall survival with denosumab, since about 80% of the deaths occurred in patients who had discontinued the investigational product," they said.
"This same requirement also limited our ability to establish when asymptomatic bone metastases became symptomatic, since patients were removed from the study once a bone metastasis was detected and symptoms might not yet have occurred," they added.
The most common adverse events (back pain, constipation, arthralgia, diarrhea, and urinary tract infections) developed in a similar number of patients in both groups. Adverse events leading to withdrawal from the study developed in 11% of patients receiving denosumab and in 10% of those receiving placebo, a nonsignificant difference. And the rate of serious adverse events was 46% in both groups.
Denosumab was associated with an increased incidence of jaw osteonecrosis (5% vs. 0% with placebo), however, and an elevated rate of hypocalcemia (2% vs. less than 1% with placebo). Of note, the incidence of jaw necrosis increased over time from 1% in year 1 to 4% at the end of year 3, and 31 of 33 patients who developed this side effect had oral risk factors. A total of 64% of men who developed jaw necrosis required curettage and debridement, 6% required bone resection, and the remaining 30% were managed with oral rinses or antibiotics.
Denosumab specifically binds and inactivates RANK ligand, "an essential mediator of osteoclast formation, function, and survival." Activation of osteoclasts by RANK ligand is thought to promote the establishment of prostate cancer in the skeleton, and the expression of RANK ligand on prostate cancer cells may enhance the metastatic behavior of tumor cells, "with RANK ligand serving as a homing signal to bone marrow," Dr. Smith and his associates said.
Thus, "our finding that denosumab increases bone metastasis–free survival provides clinical evidence for the important role of the bone microenvironment and RANK ligand signaling in the development of bone metastases in men with prostate cancer," they noted.
Denosumab is approved as Xgeva for bone problems caused by solid tumors that have metastasized and as Prolia for osteoporosis in postmenopausal women at risk of breaking bones.