Vol. 19, Bulletin No. 108 August-September 2012 Also in the Bulletin: Denosumab 120mg for Bone Metastases

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1 ה מ ר א פ הביטאון לענייני תרופות ISRAEL DRUG BULLETIN 19 years of unbiased and independent drug information P H A R x M A Vol. 19, Bulletin No. 108 August-September 2012 Also in the Bulletin: Denosumab 120mg for Bone Metastases DENOSUMAB 60mg FOR FRACTURE PREVENTION When injected every 6 months, denosumab, a monoclonal antibody that decreases bone resorption, appeared to reduce fractures in women with postmenopausal osteoporosis in a large placebo-controlled trial. In a placebo-controlled trial with castrated men with prostate cancer, denosumab did not significantly reduce the incidence of symptomatic fractures after 3 years; the incidence of new radiological vertebral fractures did show a significant decline. The effect of denosumab on fracture rates compared with that of other antiresorptive therapies is not known. Patients may prefer the 6-monthly dosing of denosumab but will need to consider its increased risks of infections and malignancies. Denosumab can lower serum calcium concentrations, especially in patients with impaired renal function Due to the lack of long-term safety data, denosumab should be reserved only for patients with osteoporosis or low bone mineral density at risk of osteoporotic fractures for whom use of established treatments to prevent osteoporotic fractures is not possible or contraindicated. Osteoporosis occurs when bone resorption (osteoclast activity) exceeds bone formation (osteoblast activity). Osteoporosis is defined as low bone mass and microarchitectural deterioration of bone tissue, resulting in bone fragility and an increased risk of fracture. The clinically apparent and relevant outcome of osteoporosis is a fragility fracture, which usually occurs in the vertebrae, hip or wrist. The efficacy of bisphosphonates and other drugs in the reduction of fractures remain quite uncertain. In postmenopausal women with severe osteoporosis (low BMD with history of fracture after mild trauma) the standard drug is alendronic acid, despite its modest efficacy. There is inadequate evidence to support the use of drugs to treat osteoporosis in men. There are no drugs with demonstrated efficacy in the reduction in the incidence of fractures in men with bone loss due to hormonal treatment for prostate cancer. Denosumab, a monoclonal antibody that decreases bone resorption, is the first in a new class of drugs to treat osteoporosis. Denosumab 60mg (Prolia; Amgen), given subcutaneously every 6 months, is approved in Israel for the treatment of osteoporosis in fracture prevention in postmenopausal women at increased risk of fractures; for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fracture. Denosumab is the first licensed product to treat osteoporosis in men having androgen-deprivation therapy. Denosumab has also been approved with a different dosage (120mg) and brand name (Xgeva) for prevention of skeletal-related events in adults with bone metastases from solid tumours. An assessment of evidence for this indication is covered in the next article. MODE OF ACTION Denosumab is a human monoclonal antibody that inhibits a cytokine called RANKL (Receptor Activity of Nuclear factor-kappa B Ligand). RANKL binding to the RANK receptor on the surface of osteoclasts stimulates the formation, activity and survival of osteoclasts, 1 thereby increasing resorption of cortical and trabecular bone. Thus denosumab inhibits the development and activity of osteoclasts and leads to decreased bone resorption and increased bone modelling. RANKL also stimulates B and T cell differentiation and maturation. Following a subcutaneous dose of denosumab 60mg, maximum serum concentrations are typically reached 1-4 weeks later and remain high enough to inhibit bone turnover for at least 6 months. By 9 months they fall below the effective range. Denosumab has an elimination halflife of 26 days. It is not eliminated via hepatic metabolism 1

2 and dose adjustment is not needed in patients with renal impairment. CLINICAL STUDIES Clinical evaluation of denosumab with clinical fracture prevention as an endpoint consists only of a single placebo-controlled trial in each of its indications. There are no published trials comparing denosumab with alendronate or other bisphosphonates in terms of fracture. Nor are there such studies on the efficacy in women who do not respond to bisphosphonates. No active comparator could be used in the study in men as there is no therapy currently licensed for the treatment of osteoporosis in men having androgen-deprivation therapy. EFFICACY IN OSTEOPOROSIS IN POSTMENO- PAUSAL WOMEN The approval of denosumab for osteoporosis is mainly based on a large randomised placebo-controlled trial 2 which enrolled 7,868 women aged years (T-scores between -2.5 and -4); in about one quarter of women there was a history of vertebral fracture. Primary endpoint included morphometric fractures which can only be diagnosed radiographically. Denosumab 60mg injected SC every 6 months for 3 years reduced the incidence of vertebral fractures compared to placebo from 7.2% to 2.3%; symptomatic vertebral fractures from 2.6% to 0.8%; hip fracture from 1.2% to 0.7%, and nonvertebral fracture from 8.0% to 6.5%, all statistically significant differences. Bone formation returns to base levels within 1 year after the cessation of denosumab therapy. Although the efficacy data from this trial looks promising, a meta-analysis of three randomised controlled trials found that denosumab was not associated with a significant reduction in fracture risk in postmenopausal women. 3 The lack of trials directly comparing the efficacy of denosumab and alendronate at 3 years justifies an indirect comparison, even though the results provide only weak evidence. On this basis, denosumab does not appear to be superior to alendronate: among 100 women treated for 3 years, respectively 1.8 and 3.0 symptomatic vertebral fractures would be prevented, while 0.5 versus 1.0 hip fractures would be prevented. 4 Effect on BMD and Bone Markers vs Alendronate In a 12-month study in women with low bone mass (Tscore <-2), denosumab 60mg injected SC every 6 months increased bone mineral density (primary endpoint) measured at various skeletal sites, more than 70mg alendronate (3.5% vs 2.6%) taken once weekly. 5 Although this was statistically significant, the clinical significance of this change is unclear. This increase was associated with a more pronounced decrease in markers for bone turnover in the denosumab group. In another study, 504 women with osteoporosis (BMD T-score below -2.0) who had taken alendronate for at least 6 months, switching to denosumab for an additional 12 months was more effective in increasing BMD in total hip, lumbar spine, femoral neck, and 1/3 radius than continuing on alendronate. 6 Patients enrolled were not necessarily intolerant to bisphosphonates or experienced further decline while taking bisphosphonates, limiting the applicability of the results. There was a similar incidence in both treatment groups with regard to adverse events and serious adverse events. In both these studies, 5,6 the incidence of fracture rates were higher in the denosumab treated patients compared to the alendronate-treated patients. However, neither of these studies was powered to compare the fracture rates. EFFICACY IN OSTEOPOROSIS IN CASTRATED MEN WITH PROSTATE CANCER Men (n=1468) with prostate cancer receiving androgen-deprivation therapy with a BMD T-score below - 1 (lumbar spine, total hip or femoral neck) were randomised to treatment with either denosumab 60mg every 6 months or placebo for 3 years. 7 About 20% of the men had a history of vertebral fractures. The primary endpoint was the change in BMD from baseline of the lumbar spine at 24 months: +5.6% in the denosumab group vs -1.0% in the placebo group (p<0.001). Secondary endpoints were the changes in BMD at the total hip, femoral neck, distal third of radius and whole body, p<0.001 for all, in favour of denosumab. Fractures at any site were more prevalent in the placebo group at 36 months (7.2% vs 5.2%) but this was not statistically significant. A higher rate of vertebral fractures occurred in the placebo group compared with the denosumab group at 24 months (3.3% vs 1.0%, p=0.004) and at 36 months (3.9% vs. 1.5%, p=0.006). The incidence of vertebral fractures detected by routine radiography was lower with denosumab (1.5% vs 3.5%, p=0.0125), but the available reports do not indicate whether this translated into a lower incidence of symptomatic fractures. ADVERSE EFFECTS As RANKL is expressed on immune cells denosumab may result in immunosuppression potentially increasing the incidence of cancer and infection. Denosumab is a monoclonal antibody and thus carries a risk of immune reaction although neutralizing antibodies were not found in women taking denosumab. None of the trials saw an increase in the rate of serious infections or neoplasms, though an increased rate of cellulitis and eczema was reported. 1 When a larger safety cohort (over 8000 patients) was analysed, serious infections were more common with denosumab than placebo (3.4% vs 2.8%) and included abdominal, ear and urinary tract infections as well as cellulitis. Endocarditis, 2

3 septic arthritis and skin ulcers were also more frequently reported. Cancers were slightly more common with denosumab than with placebo (7.8% vs 7.1%). These risks should be considered when prescribing denosumab and patients should be informed of them. In the safety cohort, serious pancreatitits occurred more commonly with denosumab than with placebo (9 cases vs 1 case). 4,8 Osteoporosis of the jaw has been reported. Low osteoclast and osteoblast counts have been observed with denosumab. 1 Whether long-term suppression of bone remodeling with denosumab creates a risk of atypical fractures and delayed fracture healing is unknown. Denosumab can lower serum calcium concentrations, especially in patients with impaired renal function; it is contraindicated for use in patients with hypocalcaemia. Calcium and vitamin D supplementation is recommended for all patients. Drug interactions: No studies have been carried out. DOSAGE AND COSTS Anti-Resorptive Therapies: Fracture Prevention Drug Denosumab (Prolia) Annual Cost (NIS)* Dose 60mg SC injection every 6 months 2,658 Alendronic acid (generic) 70mg weekly 1,000 Raloxifene (Evista) 60mg daily 2,993 Risedronate (generic) 35mg weekly 1,304 Strontium ranelate (Protelos) 2gm daily 3,110 Teriperatide (Forteo) 20mcg SC injection daily** 36,396*** Zoledronic acid (Aclasta) 5mg IV infusion yearly 2,347 *based on maximum retail price approved by the MoH. **maximum duration of treatment 18 months; course not to be repeated. **based on 28 doses per 3ml vial. CONCLUSIONS In a placebo-controlled trial denosumab taken for three years was seen to have a modest protective effect on fractures in postmenopausal women with low BMD. The primary endpoint included morphometric fractures which can only be diagnosed radiographically and in practice would not normally be diagnosed and treated. Because there is a lack of head-to-head trials, it is not known how denosumab compares with other treatments for osteoporosis; it appears to be more effective than weekly alendronate in increasing BMD (a surrogate measure). In men receiving androgen-deprivation therapy for prostate cancer, a placebo-controlled trial did not show that denosumab had a significant protective effect in reducing fractures. Clinical trials of denosumab raised significant safety issues; patients will need to consider denosumab's increased risk of infections and malignancies. Long-term data on safety and efficacy are needed. Denosumab may be an option for women with osteoporosis or low BMD at risk of osteoporotic fractures for whom use of established treatments to prevent osteoporotic fractures is not possible or contraindicated. However, studies on the efficacy in women who do not respond to bisphosphonates are lacking. References 1. Lipton A & Goessi C, Bone 48:96, Cummings S et al, N Engl J Med 361:756, Anastasilakis A et al, Horm Metab Res 41:721, Prescrire Int 20:145, Brown J et al, J Bone Miner Res 24:153, Kendler D et al, J Bone Miner Res 25:72, Smith M et al, N Engl J Med 361:745, Australian Prescriber 33:194, DENOSUMAB 120mg for TREATMENT of BONE METASTASES Denosumab, a monoclonal antibody that decreases bone resorption, has been approved at a 120mg dose every 4 weeks for prevention of skeletal-related events in adults with bone metastases from solid tumours. Denosumab 120mg subcutaneous was compared with IV zoledronic acid in patients with breast cancer, with prostate cancer, and with advanced cancers or multiple myeloma. Time to first skeletal-related event was delayed by denosumab by about 17% in all three cancer groups. Data for outcomes such as pain, survival and quality of life did not show consistent benefit over zoledronic acid. The use of denosumab 120mg every 4 weeks in patients with severe renal impairment and its efficacy following IV bisphosphonate therapy were not assessed. Adverse events occurred to a similar extent with denosumab 120mg and zoledronic acid, including osteonecrosis of the jaw. Adverse renal effects occurred to a higher degree in breast cancer studies with zoledronic acid, but to a similar extent in the other two studies. Denosumab carries the risk of hypocalcaemia. About 70% of patients with metastatic breast cancer and prostate cancer develop bone metastases. The risk of developing a pathological fracture in a patient with metastatic bone disease is nearly 4 times more likely over 3

4 a 5-year period than in a patient without metastatic bone disease. 1 Bisphosphonates are currently used to treat such patients: sodium pamidronate and zoledronic acid are given by IV infusion (every 4 weeks) and sodium clodronate is an oral therapy taken daily. The Israel MoH has approved denosumab 120mg (Xgeva; Amgen) for the prevention of skeletal-related events (pathological fracture, radiation to bone, spinal cord compression or surgery to bone) in adults with bone metastases from solid tumours. Denosumab 60mg (Prolia) is also licensed for the treatment of osteoporosis in postmenopausal women at risk of fracture, and for bone loss in men having hormonal ablation for prostate cancer who are at risk of fracture. Denosumab is a monoclonal antibody that decreases bone resorption; details of its mode of action can be found in the previous article. CLINICAL STUDIES Denosumab has been compared in three double-blind studies with zoledronic acid for treating bone metastases in patients with advanced breast cancer, 2 castrationresistant prostate cancer 3 and advanced cancer (excluding breast and prostate) or multiple myeloma. 4 All three studies had the same design: patients were randomised to either denosumab 120mg by SC injection or zoledronic acid 4mg by IV infusion (dose adjusted to renal function), every 4 weeks, plus matching placebo. The primary endpoint was time to first on-study skeletal related event (SRE) (non-inferiority). SRE were defined as pathologic fracture (assessed by X-rays every 12 weeks or radiographic assessments during the course of standard care), radiation therapy or surgery to bone or spinal cord compression. The secondary endpoints were time to first SRE (superiority test, only carried out if noninferiority proven) and time to first and subsequent SRE. In clinical practice, assessment of fractures by skeletal surveys (X-rays) every 12 weeks may not take place. Breast cancer: 2 The time to first SRE was significantly delayed with denosumab vs zoledronic acid (32.4 months vs 27.4 months; p=0.01 for superiority). The proportion of patients with multiple SREs at the time of the extended analysis was 38.9% in the zoledronic acid group vs 32.9% in the denosumab group. The mean skeletal morbidity rate was significantly reduced with denosumab vs zoledronic acid, with significant difference in event rates (0.45 vs 0.58 events per patients per year, respectively, p=0.004). Prostate cancer: 3 The time to first SRE was significantly reduced by 3.6 months with denosumab (20.7 vs 17.1 months, p=0.008 for superiority). First study events occurred in 341 (36%) treated with denosumab and 386 (40.8%) treated with zoledronic acid. Advanced cancer: 4 The time to first SRE was significantly reduced by 6 months with denosumab treatment (21.4 vs 15.4 months, p=0.034 for superiority). The time to first and subsequent SREs was significantly reduced with denosumab (HR 0.85, p=0.048), with a cumulative mean number of SREs of 374 in patients treated with zoledronic acid and 328 in those treated with denosumab. Denosumab delayed the development of moderate to severe pain in patients with no or mild pain and delayed pain worsening compared with zoledronic acid. Overall survival and disease progression were similar between the treatment arms in all three studies. However, in multiple myeloma the rates of overall survival and disease progression were worse in patients treated with denosumab. Denosumab is not approved for nonsolid tumours. Integrated Analysis Integrated analysis of the primary and secondary endpoints from the above studies was carried out stratified by study and by factors within each study. 5 A total of 2988 SREs occurred, 1360 in the denosumab arm (n=2862) and 1628 in the zoledronic acid arm (n=2861). Time to first SRE was delayed by 17% with denosumab treatment, with median time to first SRE of 27.7 months with denosumab and 19.5 months with zoledronic acid (p<0.0001, for both non-inferiority and superiority endpoints). Time to clinically significant pain worsening (>-2-point increase from baseline) was delayed 6 with denosumab compared with zoledronic acid: 181 days vs. 169 days (p=0.026). In patients with no or with mild pain at baseline, the time to moderate/severe pain was 198 days with denosumab vs 143 days with zoledronic acid (p=0.002). Fewer patients with no or mild pain at baseline who were treated with denosumab reported moderate or severe pain, compared with those treated with zoledronic acid. This was statistically significant from week 13 onwards (p<0.05). ADVERSE EFFECTS Fatigue, dyspnoea, diarrhoea and nausea are commonly reported adverse effects. Denosumab can lower serum calcium concentrations, especially in patients with impaired renal function. It should not be used in patients with severe, untreated hypocalcaemia. Denosumab had a lower incidence of acute phase reactions (occurring in the first 3 days post-administration) than zoledronic acid (8.7% vs 20.2%). 5 Adverse renal effects occurred to a higher degree with zoledronic acid than with denosumab the breast cancer study (8.5% vs 4.9%), p=0.001), 2 but to a similar extent between the treatment arms in the other two studies. 3,4 Osteonecrosis of the jaw occurred in both treatment arms and most were associated with known risks such as tooth extractions or poor dental health. In the integrated analysis, the incidence was 1.8% in the denosumab arm and 1.3% in the zoledronic arm (p=0.13). 5 4

5 DOSAGE AND COSTS Anti-Resorptive Therapies: Bone Metastases Monthly Cost Drug Dose (NIS)* Denosumab (Xgeva) 120mg SC injection every 4 weeks 2,465 Disodium pamidronate (Aredia) 90mg IV infusion every 4 weeks 826 Zoledronic acid (Zomera) 4mg IV infusion every 4 weeks 1,795 *based on maximum retail price approved by the MoH. CONCLUSIONS The evidence directly comparing denosumab with zoledronic acid suggests that denosumab is more clinically effective in preventing skeletal-related events than zoledronic acid in the three cancer groups for which there were trial evidence. However, data for other outcomes such as pain, quality of life and survival did not show a consistent benefit over zoledronic acid. The optimal duration of denosumab treatment is unknown. Although denosumab may be given without the need for renal monitoring unlike zoledronic acid, it carries the risk of hypocalcaemia. Hypocalcaemia should be corrected prior to treatment with denosumab. The use of denosumab 120mg every 4 weeks in patients with severe renal impairment was not assessed. There may be some patients who could benefit from the administration of denosumab 120mg, such as those who do not respond adequately to bisphosphonates; those who are intolerant or contraindicated to bisphosphonates; those at risk of or have renal dysfunction and those with poor intravenous access. The efficacy of denosumab following IV bisphosphonate therapy was not assessed. There would be little point in administering denosumab and bisphosphonates together: denosumab suppresses bone turnover to a greater extent than IV bisphosphonates, so concurrent bisphosphonate treatment would not be expected to result in significant further suppression of bone resorption nor added clinical efficacy. The adverse effects of bisphosphonate treatment would still be expected. (Denosumab was also assessed in a double-blind placebo-controlled trial for prevention of bone metastases or death in non-metastatic castration-resistant prostate cancer patients at high risk of bone metastasis. 7 The findings do not support the non-approved use of denosumab 120mg as a preventive agent for bone metastases in prostate cancer.) References 1. Bottiglieri S and Adams V, Orthopedics 33:557, Stopeck A et al, J Clin Oncol 28:5132, Fizazi K et al, Lancet 377:813, Henry D et al, J Clin Oncol 29, 1125, Lipton A et al, Ann Oncol 21:viii:380 (abstract 1249P), Cleeland C et al, Ann Oncol 21:viii:380 (abstract 1248P), Smith M et al, Lancet 379:39, Although great care has been taken in compiling the contents of this publication, the publisher and the editor are not responsible or in any way liable for the accuracy of the information, for any errors, omissions or inaccuracies, or from any consequences therefrom. Inclusion or exclusion of any product does not imply its use is either advocated or rejected. Opinions expressed do not necessarily reflect the views of the publisher or editor. In addition to the information supplied herein, reference should always be made to the manufacturer s literature in respect of each drug before it is prescribed. PHARMA Drug Bulletin is a Member of the International Society of Drug Bulletins 5