STOCKHOLM – Denosumab prolongs bone metastasis-free survival across a variety of nonmetastatic, castrate-resistant prostate cancer subgroups, according to subanalyses of a phase III study.
Denosumab (Xgeva) improved bone metastasis-free survival compared with placebo in men with dual prostate-specific antigen risk factors (hazard ratio, 0.83; P = .07), a single PSA risk factor (HR, 0.87; P = .20), a Gleason score of 2-7 (HR, 0.85, P = .12), and Gleason score of 8-10 (HR, 0.81; P = .10).
The advantage with denosumab was observed regardless of patient age, geographic region, or race, Dr. Stephane Oudard said at the European Multidisciplinary Cancer Congress.
Overall, the primary end point of bone metastasis-free survival was increased from 25.2 months with placebo to 29.5 months with denosumab. This corresponds to a relative risk reduction of 15% (hazard ratio, 0.85; P = .028).
Dr. Oudard pointed out that nearly all men with prostate cancer develop bone metastases, and that this is "the first randomized study to demonstrate that targeting bone microenvironment prevents bone metastasis in men with prostate cancer."
Denosumab is a monoclonal antibody that inhibits RANK ligand, a key mediator of bone osteoclast activity. The drug was approved in 2010 for the treatment of postmenopausal osteoporosis under the trade name Prolia, and later that year for the prevention of skeletal-related events in patients with bone metastases from solid tumors.
In September 2011, two new indications were added for denosumab: to increase bone mass in patients at high risk for fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, or adjuvant aromatase inhibitor therapy for breast cancer.
The phase III denosumab 147 study evenly randomized 1,432 men with nonmetastatic, castrate-resistant prostate cancer to monthly subcutaneous denosumab 120 mg or placebo. Bone metastases were detected by bone scan and confirmed by scintigraphy.
"[This is] the first randomized study to demonstrate that targeting bone micro-environment prevents bone metastasis in men with prostate cancer."
The men were at high risk of developing bone metastasis as defined by a PSA of 8.0 ng/mL for 3 months prior to randomization or a PSA doubling time of 10 months or less. These dual PSA risk factors were present in 48% of the men. At least one-third of the men had a Gleason score of 8 or more at diagnosis.
The median time from diagnosis was 6 years and duration of androgen-deprivation therapy 4 years, said Dr. Oudard, chief of oncology at Georges Pompidou Hospital in Paris.
Denosumab significantly delayed the time to symptomatic bone metastases (HR, 0.67; P = .01), which translates into a 33% relative risk reduction. Similar benefits were observed for this end point across all disease and patient demographic characteristics, he said.
The overall results of the trial were reported earlier this year at the American Urological Association meeting. Despite delaying bone metastases, patients taking denosumab did not live longer than did those given placebo. Median overall survival was approximately 44 months in both groups (HR, 1.01; P = .91).
Serious adverse event rates were nearly identical at 46% in each arm; hypocalcemia was higher in the denosumab group at 1.7% vs. 0.3% with placebo. Another side effect, osteonecrosis of the jaw, was also slightly increased with denosumab at a cumulative incidence of 1.1% in year 1, 2.9% in year 2, and 4.2% in year 3 vs. 0% for all three years in the placebo group, Dr. Oudard said at the meeting, a joint congress of the European Cancer Organization, the European Society for Medical Oncology, and the European Society for Radiotherapy and Oncology.
Invited discussant Dr. Joaquim Bellmunt, with Hospital Valle de Hebron in Barcelona, said delaying the development of bone metastasis in men with castrate-resistant prostate cancer represents an important unmet medical need, and that screening for bone metastasis is often inadequate in clinical practice.
He went on to say that long-term quality of life data are needed, since the study showed only that denosumab prolongs the period before metastasis, where the patients’ quality of life has not yet suffered to a great extent.
Finally, Dr. Bellmunt took issue with the lack of survival benefit with denosumab, observing that patients with bone metastases have an almost five-time higher risk of death compared with those patients without.
Prevention of skeletal-related events and pain control are important in multimodality treatment of bone metastasis, he said, but "I want to stress that survival and quality of life is critical in these patients."
The study was funded by Amgen Inc. Disclosures were not presented at the meeting.
Christine Kilgore contributed to this report.