Michelle Fan

Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastases in Patients With Advanced Breast Cancer: A Randomized, Double-Blind Study

PURPOSE This randomized study compared denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor κ B (RANK) ligand, with zoledronic acid in delaying or preventing skeletal-related events (SREs) in patients with breast cancer with bone metastases. PATIENTS AND METHODS Patients were randomly assigned to receive either subcutaneous denosumab 120 mg and intravenous placebo (n = 1,026) or intravenous zoledronic acid 4 mg adjusted for creatinine clearance and subcutaneous placebo (n = 1,020) every 4 weeks. All patients were strongly recommended to take daily calcium and vitamin D supplements. The primary end point was time to first on-study SRE (defined as pathologic fracture, radiation or surgery to bone, or spinal cord compression). RESULTS Denosumab was superior to zoledronic acid in delaying time to first on-study SRE (hazard ratio, 0.82; 95% CI, 0.71 to 0.95; P = .01 superiority) and time to first and subsequent (multiple) on-study SREs (rate ratio, 0.77; 95% CI, 0.66 to 0.89; P = .001). Reduction in bone turnover markers was greater with denosumab. Overall survival, disease progression, and rates of adverse events (AEs) and serious AEs were similar between groups. An excess of renal AEs and acute-phase reactions occurred with zoledronic acid; hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred infrequently (2.0%, denosumab; 1.4%, zoledronic acid; P = .39). CONCLUSION Denosumab was superior to zoledronic acid in delaying or preventing SREs in patients with breast cancer metastatic to bone and was generally well tolerated. With the convenience of a subcutaneous injection and no requirement for renal monitoring, denosumab represents a potential treatment option for patients with bone metastases.

A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer.

PURPOSE: Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for the differentiation, function, and survival of osteoclasts, which play a key role in establishment and propagation of skeletal disease in patients with multiple myeloma or bone metastases as well as many other skeletal diseases. Denosumab (AMG 162), a fully human monoclonal antibody to RANKL, was developed to treat patients with skeletal diseases. EXPERIMENTAL DESIGN: This was a randomized, double-blind, double-dummy, active-controlled, multicenter study to determine the safety and efficacy of denosumab in patients with breast cancer (n = 29) or multiple myeloma (n = 25) with radiologically confirmed bone lesions. Patients received a single dose of either denosumab (0.1, 0.3, 1.0, or 3.0 mg/kg s.c.) or pamidronate (90 mg i.v.). Bone antiresorptive effect was assessed by changes in urinary and serum N-telopeptide levels. Pharmacokinetics of denosumab also were assessed. RESULTS: Following a single s.c. dose of denosumab, levels of urinary and serum N-telopeptide decreased within 1 day, and this decrease lasted through 84 days at the higher denosumab doses. Pamidronate also decreased bone turnover, but the effect diminished progressively through follow-up. Denosumab injections were well tolerated. Mean half-lives of denosumab were 33.3 and 46.3 days for the two highest dosages. CONCLUSIONS: A single s.c. dose of denosumab given to patients with multiple myeloma or bone metastases from breast cancer was well tolerated and reduced bone resorption for at least 84 days. The decrease in bone turnover markers was similar in magnitude but more sustained than with i.v. pamidronate.

Randomized trial of denosumab in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast cancer

PURPOSE Adjuvant aromatase inhibitor therapy is well established in postmenopausal women with hormone receptor-positive breast cancer, but such therapy is complicated by accelerated bone loss and increased fracture risk. We investigated the ability of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, to protect against aromatase inhibitor-induced bone loss. PATIENTS AND METHODS Eligible women with hormone receptor-positive nonmetastatic breast cancer treated with adjuvant aromatase inhibitor therapy were stratified by duration of aromatase inhibitor therapy (< or = 6 v > 6 months), received supplemental calcium and vitamin D, and were randomly assigned to receive placebo (n = 125) or subcutaneous denosumab 60 mg (n = 127) every 6 months. At enrollment, all patients were required to have evidence of low bone mass, excluding osteoporosis. The primary end point was percentage change from baseline at month 12 in lumbar spine bone mineral density (BMD). RESULTS At 12 and 24 months, lumbar spine BMD increased by 5.5% and 7.6%, respectively, in the denosumab group versus placebo (P < .0001 at both time points). Increases were observed as early as 1 month and were not influenced by duration of aromatase inhibitor therapy. Increases in BMD were also observed at the total hip, total body, femoral neck, and the predominantly cortical one-third radius. Bone turnover markers decreased with denosumab treatment. Overall incidence of treatment-emergent adverse events (AEs) was similar between treatment groups. CONCLUSION In women with nonmetastatic breast cancer and low bone mass who were receiving adjuvant aromatase inhibitor therapy, twice-yearly administration of denosumab led to significant increases in BMD over 24 months at trabecular and cortical bone, with overall AE rates similar to those of placebo.

Randomized Active-Controlled Phase II Study of Denosumab Efficacy and Safety in Patients With Breast Cancer-Related Bone Metastases

PURPOSE Denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor-kappaB ligand, suppresses bone resorption. In this study, we evaluated the efficacy and safety of five dosing regimens of denosumab in patients with breast cancer-related bone metastases not previously treated with intravenous bisphosphonates (IV BPs). PATIENTS AND METHODS Eligible women (n = 255) with breast cancer-related bone metastases were stratified by type of antineoplastic therapy received and randomly assigned to one of six cohorts (five denosumab cohorts [blinded to dose and frequency]; one open-label IV BP cohort). Denosumab was administered subcutaneously every 4 weeks (30, 120, or 180 mg) or every 12 weeks (60 or 180 mg). The primary end point was percentage of change in the bone turnover marker urine N-telopeptide corrected for urine creatinine (uNTx/Cr) from baseline to study week 13. The percentage of patients achieving more than 65% uNTx/Cr reduction, time to more than 65% uNTx/Cr reduction, patients experiencing one or more on-study skeletal-related events (SRE), and safety were also evaluated. RESULTS At study week 13, the median percent reduction in uNTx/Cr was 71% for the pooled denosumab groups and 79% for the IV BP group. Overall, 74% of denosumab-treated patients (157 of 211) achieved a more than 65% reduction in uNTx/Cr compared with 63% of bisphosphonate-treated patients (27 of 43). On-study SREs were experienced by 9% of denosumab-treated patients (20 of 211) versus 16% of bisphosphonate-treated patients (seven of 43). No serious or fatal adverse events related to denosumab occurred. CONCLUSION Subcutaneous denosumab may be similar to IV BPs in suppressing bone turnover and reducing SRE risk. The safety profile was consistent with an advanced breast cancer population receiving systemic therapy.

Microarchitectural deterioration of cortical and trabecular bone: Differing effects of denosumab and alendronate

The intensity of bone remodeling is a critical determinant of the decay of cortical and trabecular microstructure after menopause. Denosumab suppresses remodeling more than alendronate, leading to greater gains in areal bone mineral density (aBMD). These greater gains may reflect differing effects of each drug on bone microarchitecture and strength. In a phase 2 double‐blind pilot study, 247 postmenopausal women were randomized to denosumab (60 mg subcutaneous 6 monthly), alendronate (70 mg oral weekly), or placebo for 12 months. All received daily calcium and vitamin D. Morphologic changes were assessed using high‐resolution peripheral quantitative computed tomography (HR‐pQCT) at the distal radius and distal tibia and QCT at the distal radius. Denosumab decreased serum C‐telopeptide more rapidly and markedly than alendronate. In the placebo arm, total, cortical, and trabecular BMD and cortical thickness decreased (−2.1% to −0.8%) at the distal radius after 12 months. Alendronate prevented the decline (−0.6% to 2.4%, p = .051 to <.001 versus placebo), whereas denosumab prevented the decline or improved these variables (0.3% to 3.4%, p < .001 versus placebo). Changes in total and cortical BMD were greater with denosumab than with alendronate (p ≤ .024). Similar changes in these parameters were observed at the tibia. The polar moment of inertia also increased more in the denosumab than alendronate or placebo groups (p < .001). Adverse events did not differ by group. These data suggest that structural decay owing to bone remodeling and progression of bone fragility may be prevented more effectively with denosumab.

Romosozumab or Alendronate for Fracture Prevention in Women with Osteoporosis

BACKGROUND Romosozumab is a monoclonal antibody that binds to and inhibits sclerostin, increases bone formation, and decreases bone resorption. METHODS We enrolled 4093 postmenopausal women with osteoporosis and a fragility fracture and randomly assigned them in a 1:1 ratio to receive monthly subcutaneous romosozumab (210 mg) or weekly oral alendronate (70 mg) in a blinded fashion for 12 months, followed by open‐label alendronate in both groups. The primary end points were the cumulative incidence of new vertebral fracture at 24 months and the cumulative incidence of clinical fracture (nonvertebral and symptomatic vertebral fracture) at the time of the primary analysis (after clinical fractures had been confirmed in ≥330 patients). Secondary end points included the incidences of nonvertebral and hip fracture at the time of the primary analysis. Serious cardiovascular adverse events, osteonecrosis of the jaw, and atypical femoral fractures were adjudicated. RESULTS Over a period of 24 months, a 48% lower risk of new vertebral fractures was observed in the romosozumab‐to‐alendronate group (6.2% [127 of 2046 patients]) than in the alendronate‐to‐alendronate group (11.9% [243 of 2047 patients]) (P<0.001). Clinical fractures occurred in 198 of 2046 patients (9.7%) in the romosozumab‐to‐alendronate group versus 266 of 2047 patients (13.0%) in the alendronate‐to‐alendronate group, representing a 27% lower risk with romosozumab (P<0.001). The risk of nonvertebral fractures was lower by 19% in the romosozumab‐to‐alendronate group than in the alendronate‐to‐alendronate group (178 of 2046 patients [8.7%] vs. 217 of 2047 patients [10.6%]; P=0.04), and the risk of hip fracture was lower by 38% (41 of 2046 patients [2.0%] vs. 66 of 2047 patients [3.2%]; P=0.02). Overall adverse events and serious adverse events were balanced between the two groups. During year 1, positively adjudicated serious cardiovascular adverse events were observed more often with romosozumab than with alendronate (50 of 2040 patients [2.5%] vs. 38 of 2014 patients [1.9%]). During the open‐label alendronate period, adjudicated events of osteonecrosis of the jaw (1 event each in the romosozumab‐to‐alendronate and alendronate‐to‐alendronate groups) and atypical femoral fracture (2 events and 4 events, respectively) were observed. CONCLUSIONS In postmenopausal women with osteoporosis who were at high risk for fracture, romosozumab treatment for 12 months followed by alendronate resulted in a significantly lower risk of fracture than alendronate alone. (Funded by Amgen and others; ARCH ClinicalTrials.gov number, NCT01631214.)

Bone-Related Complications and Quality of Life in Advanced Breast Cancer: Results from a Randomized Phase III Trial of Denosumab versus Zoledronic Acid

Purpose: Denosumab was shown to be superior to zoledronic acid in preventing skeletal related events (SRE) in patients with breast cancer and bone metastases in a randomized, double-blind phase III study. We evaluated further results from this study related to skeletal complications and health-related quality of life (HRQoL). Experimental Design: Patients were randomized 1:1 to receive subcutaneous denosumab 120 mg (n = 1,026) and intravenous placebo, or intravenous zoledronic acid 4 mg (n = 1,020) and subcutaneous placebo every 4 weeks. Analyses reported here include the proportion of patients with one or multiple on-study SREs, time to first radiation to bone, time to first SRE or hypercalcemia of malignancy, and change in HRQoL (functional assessment of cancer therapy–general). Results: Fewer patients receiving denosumab than zoledronic acid had an on-study SRE (31% vs. 36%, P = 0.006). The incidence of first radiation to bone was 12% (n = 123) with denosumab versus 16% (n = 162) with zoledronic acid. Denosumab prolonged the time to first radiation to bone by 26% versus zoledronic acid (HR, 0.74; 95% confidence interval [CI], 0.59–0.94, P = 0.012) and prolonged the time to first SRE or hypercalcemia of malignancy by 18% (HR, 0.82; 95% CI, 0.70–0.95; P = 0.007). Ten percent more patients had a clinically meaningful improvement in HRQoL with denosumab relative to zoledronic acid, regardless of baseline pain levels. Conclusions: Denosumab was superior to zoledronic acid in reducing bone-related complications of metastatic breast cancer and maintained HRQoL, providing an efficacious, well-tolerated treatment option for patients with bone metastases from breast cancer. Clin Cancer Res; 18(17); 4841–9. ©2012 AACR.

A Comparison of Denosumab Versus Zoledronic Acid for the Prevention of Skeletal-Related Events in Breast Cancer Patients with Bone Metastases.

Background: Up to 75% of advanced breast cancer patients develop bone metastases (BM) that induce increased osteoclast activity resulting in local bone destruction. The ensuing skeletal complications, including fractures, may have serious consequences. Denosumab, a fully human monoclonal antibody, inhibits RANKL, a key mediator of osteoclast activity. Denosumab has been shown to increase bone mineral density and reduce fractures in postmenopausal women with low bone mass. Primary results from a recently completed randomized pivotal study demonstrated that denosumab was superior to zoledronic acid (ZA) in delaying and preventing skeletal-related events (SREs) in breast cancer patients with bone metastases. Here, we describe results of other endpoints from the study.Methods: Patients with breast cancer and BM (N=2046) who had not been treated with intravenous (IV) bisphosphonates were randomized 1:1 to receive either subcutaneous (SC) denosumab 120 mg and IV placebo, or SC placebo and IV ZA 4 mg every 4 weeks. All patients were encouraged to take daily supplemental calcium (≥500 mg) and vitamin D (≥400 IU). The primary endpoint was time to first on-study SRE (predefined as pathologic fracture, radiation to bone, surgery to bone, or spinal cord compression). Other endpoints included time to first radiation of bone; time to first on-study SRE or hypercalcemia of malignancy (HCM); skeletal morbidity rate (SMR; the number of SREs per year); and the proportion of patients with at least 1 on-study SRE. SMR was defined as the ratio of the number of SREs, allowing for one event every 21 days, divided by the patient9s time at risk.Results: As previously reported, denosumab was superior to ZA in significantly delaying the time to first on-study SRE (hazard ratio [HR] 0.82; 95% CI: 0.71, 0.95; P Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 22.

P3-16-07: Denosumab in Patients with Breast Cancer and Bone Metastases Previously Treated with Zoledronic Acid or Denosumab: Results from the 2-Year Open-Label Extension Treatment Phase of a Pivotal Phase 3 Study.

Background Primary results from a phase 3, randomized, double-blind double-dummy trial showed that compared with zoledronic acid (ZA), denosumab reduced the risk of developing a first on-study SRE by 18% (hazard ratio, 0.82; 95% CI 0.71 to 0.95; P = 0.01), and the risk of multiple SREs by 23% (rate ratio, 0.77; 95% CI 0.66 to 0.89; P = 0.001) in patients with breast cancer and bone metastases. Based on superior efficacy and favorable safety data from the study9s primary analysis (Stopeck et al, 2010), all patients who remained on treatment were offered open-label denosumab in a prespecified 2-year extension treatment phase. Materials and Methods : A total of 2046 patients with breast cancer and bone metastasis were randomized to receive either subcutaneous (SC) denosumab 120 mg and intravenous (IV) placebo or IV ZA 4 mg (adjusted for renal function) and SC placebo Q4W in the double-blinded treatment phase. Patients who completed the double-blinded treatment phase were offered open-label denosumab Q4W for up to 2 years from the start of the open-label treatment phase. Patients who did not participate in the open-label treatment were followed for survival every 12 weeks for up to 2 years after their last dose of investigational product in the double-blinded treatment phase. Results : Of the 752 patients who completed the double-blinded treatment phase, 667 (89%) patients entered the open-label treatment phase: 325 (48.7%) initially randomized to the denosumab group (DD) and 342 (51.3%) to the ZA group in the double-blinded treatment phase (ZD). Demographics were comparable between groups. The total median (Q1, Q3) cumulative denosumab exposure (including double-blinded and open-label treatment phases) for DD patients was 19.3 months (9.2, 32.2) (range 0.9−59.8 months). Adverse events (AEs) were comparable between groups (n = 283/318 [89%] for DD patients; n = 303/334 [91%] ZD patients). An additional 20 patients in the DD group and 18 patients in the ZD group reported osteonecrosis of the jaw, resulting in a cumulative incidence of 4.7% for DD patients and 3.5% for ZD patients for the entire study duration of 5 years. Hypocalcemia AEs during the open-label treatment phase were comparable between groups (n = 12 DD; n = 9 ZD). The most common AEs were nausea, fatigue, and back pain. Serious AEs were reported in 126 (39.6%) DD patients and 133 (39.8%) ZD patients. Overall survival was similar between groups over the entire study: median 34.4 months (95% CI 31.5 to 39.3) for DD patients, 34.2 months (95% CI 31.0 to 37.6) for ZD patients. Conclusion: A two-year open-label extension treatment phase confirmed the long-term safety profile of denosumab in these breast cancer patients with bone metastases who continued receiving denosumab for up to 5 years or who switched from ZA to denosumab. No new safety signals were observed with up to 5 years of monthly denosumab therapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-16-07.

Abstract P6-14-01: Effect of Denosumab Versus Zoledronic Acid Treatment in Patients with Breast Cancer and Bone Metastases: Results from the Extended Blinded Treatment Phase

Background: Denosumab is a fully human monoclonal antibody which inhibits RANKL, a key mediator of osteoclast activity. Results from the primary analysis of this pivotal phase 3 trial showed that denosumab was superior to zoledronic acid (ZA) in delaying the time to first on-study skeletal-related events (SRE) in patients with breast cancer and bone metastases. We now report results including an additional 4 months of blinded treatment. Methods: Randomized patients received either subcutaneous (SC) denosumab (120 mg) and intravenous (IV) placebo or IV ZA (4 mg, adjusted for renal function) and SC placebo every 4 weeks. No dose adjustments were made for SC denosumab. All patients were advised to take daily calcium (≥500 mg) and vitamin D (≥400 IU) supplements. The primary endpoint was time to first on-study SRE (predefined as pathologic fracture, radiation or surgery to bone, or spinal cord compression). Time to first and subsequent SRE (multiple event analysis) and safety endpoints were also evaluated. Analyses for the extended treatment phase are considered exploratory. Results: Overall, 2046 patients enrolled: 1026 were randomized to denosumab and 1020 were randomized to ZA. Denosumab was superior to ZA in delaying the time to first on-study SRE by 18%, and the time to first and subsequent on-study SRE by 22% (Table). The median time to first on-study SRE was 5 months longer for the denosumab group (32.4 months) than the ZA group (27.4 months). Overall survival and disease progression were similar for both treatment groups. Similar percentages of subjects reported adverse events (AEs; 96.2% denosumab, 97.4% ZA) and serious AEs (47.9% denosumab, 50.2% ZA). Positively adjudicated cases of osteonecrosis of the jaw were reported in 2.5% (n=26) of denosumab-treated patients and 1.8% (n=18) of ZA-treated patients (P=0.29). Hypocalcemia was reported by 62 (6.1 %) patients in the denosumab group and 37 (3.7%) patients in the ZA group. Conclusion: Among patients with breast cancer and bone metastases, denosumab was superior to ZA in delaying or preventing SREs, and continued treatment with denosumab resulted in a median time to first SRE that was 5 months longer than treatment with ZA. Denosumab, with its novel mode of action, may represent a potential treatment option for patients with breast cancer and bone metastases without the need for dose adjustment or renal monitoring. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P6-14-01.