Denosumab Use for the Practicing Oncologist
By William B. Ershler, MD
The U.S. Food and Drug Administration (FDA) has recently approved denosumab for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Earlier this year, denosumab also was approved for use in women with osteoporosis who had a high risk for fracture. The drug is marketed by Amgen as Prolia® (for the osteoporosis indication) and as XGEVA® (for the cancer indication).
Denosumab is a full-length human monoclonal IgG2 that targets receptor activator of nuclear factor kappa B ligand (RANKL). RANKL exists in both transmembrane and soluble forms, and denosumab is fully capable of binding to either form. The antibody blocks the binding of RANKL to its receptor (RANK) and, thus, inhibits its downstream signaling. Of the myriad of consequences of RANKL-RANK signaling, are the formation, function, and survival of mature osteoclasts, the cells responsible for bone resorption.1 The resulting decrease in bone resorption leads to an increase in bone mass.
In early pharmacokinetic studies, it became apparent that a single 60 mg subcutaneous dose had sustained activity. Following a 60 mg single subcutaneous (SC) dose, the maximum serum denosumab concentration is typically observed from 1 to 4 weeks later and, thereafter, levels decline over a period of 4 to 5 months, with a mean half-life of approximately 25 to 30 days. No accumulation in serum denosumab concentrations was observed with repeated doses of 60 mg once every 6 months (Q6M), and denosumab pharmacokinetics do not appear to change with time (up to 4 years exposure).
Denosumab administration resulted in significant inhibition of bone resorption, as assessed by reductions in serum levels of Type 1 C-telopeptide (CTX1). In clinical studies, treatment with 60 mg of denosumab resulted in rapid reduction in serum CTX1 within 6 hours of SC administration by approximately 70%, and approximately 85% by 3 days. Serum CTX1 reductions reflecting reduced bone turnover were maintained throughout the dosing interval (6 months). Notably, bone mineral density (BMD) continuously increased during treatment.2-4
There were two pivotal trials for women with postmenopausal osteoporosis. The first was an international, multicenter, randomized, double-blind, placebo-controlled, 3-year study in which 7,868 subjects who had bone mineral density T scores below -2.5 were enrolled and a reduction in both vertebral and hip fractures was observed.5 In the second, also a randomized, double-blind study included 332 women with BMD T scores from -1.5 to -2.5, and once again denosumab proved superior to placebo by significantly increasing total BMD, bone-mineral content, and bone strength.6
The pivotal trial supporting the treatment and prevention of bone loss associated with hormone-ablation therapy for breast cancer was a 4-year, randomized, double-blind, placebo-controlled study in women with non-metastatic breast cancer undergoing aromatase-inhibitor therapy. In this trial, denosumab, administered at a subcutaneous 60 mg dose every 6 months, resulted in suppression of bone turnover and increased bone-mineral density.7
More recently, Stopeck and colleagues reported on the use of denosumab in breast-cancer patients with known osseous metastases.8 In this trial, 2,046 patients were randomized to treatment with either denosumab (120 mg, subcutaneously each month) or zoledronic acid (4 mg, intravenously each month), and the primary endpoint was time to first skeletal-related event, defined as fracture, radiation treatment, or bone surgery or spinal-cord compression. In general, both treatments were tolerated well. Those receiving zoledronic acid had more renal adverse events, whereas hypocalcemia occurred more frequently with denosumab. Bone turnover markers improved to a greater extent, and the time to skeletal-related event was significantly delayed in those who had received denosumab.
Finally, with regard to prostate cancer, a randomized, double-blind, placebo-controlled study to evaluate denosumab in the treatment of bone loss in subjects undergoing androgen-deprivation therapy for non-metastatic prostate cancer also has been reported.9 This 5-year study enrolled 1,468 subjects (734 denosumab, 734 placebo). Subjects received therapy for 36 months and were monitored for an additional 24 months. At 24 months, bone-mineral density of the lumbar spine had increased by 5.6% in the denosumab group, as compared with a loss of 1.0% in the placebo group (p < 0.001). In fact, significant differences between the two groups were seen at as early as one month and sustained through 36 months. Denosumab therapy also was associated with significant increases in bone-mineral density at the hip, femoral neck, and distal third of the radius at all time points. Patients who received denosumab had a decreased incidence of new vertebral fractures at 36 months (1.5%, vs. 3.9% with placebo) (relative risk, 0.38; 95% confidence interval, 0.19 to 0.78; p = 0.006). Rates of adverse events were similar between the two groups.
With the results of these and other research findings, the FDA recently (November 18, 2010) approved denosumab for the prevention of skeletal-related events in patients with bone metastases from solid tumors.
For the practicing oncologist, this is good news. Denosumab is a safe and well-tolerated alternative to zoledronic acid for the prevention of skeletal events in patients with breast and prostate cancer. Although bisphosphonates, such as zoledronic acid, also have been shown to decrease skeletal events, the risks over the long term have become apparent and are not insubstantial.10 Yet, there remains a lot to learn about denosumab, including the long-term effect of RANK inhibition on other facets of human physiology, including inflammation and immunity. Furthermore, with regard to breast and prostate cancer, we need to learn what effect, if any, such treatment will have on systemic treatment, and in what setting would treatment be optimally introduced (i.e., adjuvant therapy to prevent osteoporosis or even the development of osseous metastases, or in the metastatic setting to protect against skeletal events).
1. Lacey DL, Timms E, Tan HL, et al. Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell. 1998;93: 165-176.
2. Burkiewicz JS, Scarpace SL, Bruce SP. Denosumab in osteoporosis and oncology. Ann Pharmacother. 2009;43:1445-1455.
3. Fizazi K, Lipton A, Mariette X, et al. Randomized phase II trial of denosumab in patients with bone metastases from prostate cancer, breast cancer, or other neoplasms after intravenous bisphosphonates. J Clin Oncol. 2009;27:1564-1571.
4. Yonemori K, Fujiwara Y, Minami H, et al. Phase 1 trial of denosumab safety, pharmacokinetics, and pharmacodynamics in Japanese women with breast cancer-related bone metastases. Cancer Sci. 2008;99:1237-1242.
5. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756-765.
6. Genant HK, Engelke K, Hanley DA, et al. Denosumab improves density and strength parameters as measured by QCT of the radius in postmenopausal women with low bone mineral density. Bone. 2010;47:131-139.
7. Ellis GK, Bone HG, Chlebowski R, et al. Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer. J Clin Oncol. 2008;26:4875-4882.
8. Stopeck AT, Lipton A, Body JJ, et al. Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastases in Patients With Advanced Breast Cancer: A Randomized, Double-Blind Study. J Clin Oncol. 2010;28:5132.
9. Smith MR, Egerdie B, Toriz NHn, et al. Denosumab in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer. N Engl J Med. 2009;361:745-755.
10. Fornier MN. Denosumab: Second Chapter in Controlling Bone Metastases or a New Book? J Clin Oncol. 2010;28:5127-5131.