On November 18, 2010, the US FDA approved the use of denosumab for the prevention of SREs in patients with bone metastases from solid tumors, and on September 16, 2011, the FDA approved the use of denosumab as a treatment to increase bone mass in patients at high risk for fracture, including patients on ADT for nonmetastatic prostate cancer. Each indication requires a different dosing and frequency of denosumab administration. As a treatment for the prevention of SREs in bone metastases from solid tumors, denosumab (Xgeva®
; Amgen, Thousand Oaks, CA) is administered as a 120 mg subcutaneous injection in the upper arm, thigh, or abdomen once every four weeks. As a treatment for increasing bone mass in patients at high risk for fracture, including those undergoing ADT for nonmetastatic prostate cancer, denosumab (Prolia®
; Amgen) is administered as a 60 mg subcutaneous injection once every 6 months. The use of denosumab for the treatment of osteoporosis is reported elsewhere.54
Toxicities related to denosumab administration were of sufficient concern that the FDA requested postmarketing surveillance studies. Hypocalcemia was seen in 13% of patients (5% with grade 3 or higher), with low calcium levels occurring most frequently in the first 6 months after initiation of treatment.9
Calcium levels should be repleted prior to initiating denosumab, and patients should be monitored closely, especially during the first few months of treatment. National Osteoporosis Foundation Guidelines call for patients > 50 years of age being treated with denosumab to consume elemental calcium 1200–1500 mg/day and vitamin D 800–1000 international units/day while being treated with denosumab.57
In addition, severe hypophosphatemia was experienced by 15.4% of patients in a pooled analysis,40
and phosphate levels should be monitored and repleted as needed.
Osteonecrosis of the jaw was seen in 5% of patients on denosumab and in none on placebo in a Phase III trial with 1432 patients with nonmetastatic, castration-resistant prostate cancer.11
A second trial involving patients with metastatic disease found a nonsignificant trend toward cumulative increases in osteonecrosis of the jaw (1% in year 1 and 2% in year 2).12
The majority of patients who developed osteonecrosis of the jaw (79%) had poor oral hygiene, dental appliances, and/or a recent history of tooth extraction. The median time to development of osteonecrosis of the jaw was 14 months.40
Oral examination and preventive dentistry should be performed prior to the initiation of denosumab, and patients should be closely monitored for symptoms indicating the development of osteonecrosis of the jaw.
Other uncommon but serious toxicities, including infections, secondary malignancies, and cataracts, have been observed in selected studies. Given RANKL expression on both T and B cells, there exists a basis for concern about an increased risk of serious infections and tumor development or progression with denosumab. Several (but not all) studies have found small but significant increases in serious infections in the denosumab arm of their trials including, for example, respiratory infections and cellulitis, rarely requiring hospitalization.58
The risk of increased cataract development is being evaluated in a Phase III trial [NCT00925600].
Phase III trials of denosumab for the prevention of SREs
The safety and efficacy of denosumab were evaluated in a double-blind Phase III trial comparing denosumab with zoledronic acid – the standard of care for delaying SREs in metastatic castration-resistant prostate cancer patients. From May 2006 through October 2009, 1904 men with castration-resistant prostate cancer were enrolled from 342 centers in 39 countries, and were randomized 1:1 to receive denosumab or zoledronic acid. Eligible patients included those with prostate adenocarcinoma who had failed at least one line of hormone therapy (PSA > 0.4 μg/L and rising), and had radiographic evidence of at least one bone metastasis. Additional inclusion criteria were albumin-adjusted calcium levels of 2.0 to 2.9 mmol/L and Eastern Cooperative Oncology Group performance status < 2. Exclusion criteria included: prior intravenous treatment with bisphosphonate or current oral bisphosphonate treatment for bone metastases; planned palliative radiation or surgery to bone; a life expectancy of less than 6 months; creatinine clearance < 30 mL/min; and current or previous osteonecrosis of the jaw. The primary endpoint was time to the first on-study SRE (including spinal cord compression, pathological fracture, radiation to bone, or bone surgery). Denosumab lengthened the time to SRE by 18% with a between group difference of 3.6 months (20.7 months for those on denosumab, 17.1 months for those on zoledronic acid) (HR 0.82; 95% confidence interval [CI]: 0.71–0.95; P
= 0.0002 for noninferiority and 0.008 for superiority). At the primary analysis cut-off date, median on-study duration was 12.2 months for patients treated with denosumab and 11.2 months for patients treated with zoledronic acid.12
Subgroup analysis found that denosumab had an even greater advantage over zoledronic acid in delaying time to first on-study SRE in patients with no prior SRE (HR 0.80; 95% CI: 0.67 to 0.95; P
= 0.011) and no or mild pain at baseline (HR 0.77; 95% CI: 0.63 to 0.95; P
Decreases in bone turnover markers were significantly greater for men in the denosumab group (42% in uNTX/Cr and 65% in bone-specific alkaline phosphate) demonstrating greater suppression of bone turnover with denosumab.12
Further illuminating denosumab’s role in the suppression of bone turnover, a meta-analysis of two Phase II studies of denosumab in men and women with bone metastases showed marked suppression of bone resorption markers even in patients who had little biological response to prior bisphosphonate treatment.60
Nearly all patients in the Phase III prostate cancer trial of denosumab (97% in both arms) experienced adverse effects, with serious adverse affects recorded for 63% of men in the denosumab group and 60% of men in the zoledronic acid group. Hypocalcemia was recorded in twice as many men in the denosumab group as in the zoledronic acid group (13% versus 6%; P
< 0.001). Osteonecrosis of the jaw occurred in 2% of men in the denosumab group and in 1% of men in the zoledronic acid group.12
Two other pivotal Phase III studies comparing denosumab and zoledronic acid enrolled 2046 breast cancer patients with bone metastases, and 1776 patients with other solid tumors or myeloma and bone metastases. Inclusion and exclusion criteria were similar to those used in the prostate cancer trial, and patients were randomized 1:1 to receive 120 mg denosumab subcutaneously or zoledronic acid.42
These trials also found denosumab to be superior to zoledronic acid, except in patients with myeloma. When the FDA approved denosumab as a treatment for the prevention of SREs in bone metastases, it included patients with solid tumors, but not those with myeloma.
Phase III trials evaluating treatments for extending bone metastasis-free survival
Denosumab’s effectiveness in extending bone metastasis-free survival was evaluated in a Phase III trial that enrolled 1432 men with castration-resistant prostate cancer who were at high risk of developing bone metastases based on a PSA ≥ 8 μg/L and/or a PSA doubling time < 10 months. Men in the denosumab arm saw a risk reduction of 15% and extension of metastasis-free-survival of 4.2 months (29.5 versus 25.2 months, HR = 0.85, P
= 0.028). Risk of symptomatic bone-metastases was 33% lower in the denosumab arm (HR = 0.67, P
On February 8, 2012, the FDA Oncologic Drugs Advisory Committee voted 12 to 1 against the approval of denosumab for the treatment of men with castration-resistant prostate cancer who are at high risk of developing bone metastases. The reasoning was based on the modest improvement in metastasis-free survival relative to how frequently patients undergo bone scan imaging in routine clinical practice, and the 5% incidence of osteonecrosis of the jaw, which correlated with time on the drug, and the absence of a survival benefit.61
On April 26, 2012 the FDA issued a letter saying that denosumab did not have a sufficiently favorable risk– benefit profile to be approved for the treatment of men with nonmetastatic castration-resistant prostate cancer.62
The study of denosumab in extending metastasis-free survival is the latest in a series of studies of drugs that have shown important benefits in late stage disease that did not confer substantial benefit in earlier stage disease, including clodronate, atrasentan, and zoledronic acid.63
The consistent inability to meet primary endpoints and/or to gain FDA approval reflects a challenge in treating relatively healthy patients suffering from a slow-growing disease with drugs that have limited effects and cause significant time-dependent cumulative toxicities.
Pharmacoeconomics of denosumab
Having shown significant clinical advantages over zoledronic acid, denosumab has gained rapid adoption by physicians treating prostate cancer patients with bone metastases. However, at twice the cost per injection of zoledronic acid, the cost effectiveness of denosumab is controversial. One study conducted by a commercial health economics firm found that the higher cost of denosumab led to an incremental cost per quality-adjusted-life-year of US$1,250,000, well over the US$50,000 to US$100,000 per quality-adjusted-life- year, which was considered a “good value for a medical intervention.”66
A second, more favorable economic evaluation found that the total cost per prostate cancer patient, including drug and nondrug costs for one year of treatment with denosumab was US$35,431 versus US$27,528 for zoledronic acid. The study also calculated the total incremental cost per SRE avoided with denosumab instead of zoledronic acid was US$71,027 for 1 year and US$51,319 for 3 years.67
Despite the price difference, most insurers provide reimbursement for either zoledronic acid or denosumab. A few insurers, on the other hand, are questioning not only the cost effectiveness of denosumab, but also the methodology used in determining that denosumab was superior to zoledronic acid. An insurer in the Northwest that covers two million people has decided to pay for denosumab only for patients who are unable to use zoledronic acid or a similar drug, pamidronate. That insurer questioned the evidence of denosumab’s superiority, and claimed one clinical study of denosumab in breast cancer patients was “flawed” both because of the metrics used, and because more than half of the patients didn’t complete the study.68
The difference in cost between the two drugs may be overstated because the cost of administration and the time required of caregivers is lower for the subcutaneously injected denosumab as compared with zoledronic acid, which requires a 15–30 minute infusion, as well as a delay for the laboratory studies of creatinine levels required prior to each infusion.