Denosumab for the treatment of bone metastases in advanced breast cancer

The Breast 22 (2013) 585e592

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The Breast journal homepage: www.elsevier.com/brst

Review

Denosumab for the treatment of bone metastases in advanced breast cancer Ana Casas a, *, Antonio Llombart b, d, Miguel Martín c, e a

Medical Oncology Department, Universitary Hospital Virgen del Rocio, Sevilla, Spain Medical Oncology Department, FISABIO, Hospital Arnau de Vilanova, Valencia, Spain c Medical Oncology Department, Health Research Institute, Universitary Hospital Gregorio Marañon, Complutense University of Madrid, Spain b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 1 February 2013 Received in revised form 25 April 2013 Accepted 9 May 2013

In women with advanced breast cancer, approximately three-quarters develop metastases to the bone, with a median survival after diagnosis of 2e3 years. Receptor activator of nuclear factor-kB (RANK) and RANK ligand (RANKL) belong to a signal pathway highly implicated in the development of bone metastases. Denosumab, a human monoclonal antibody with high affinity and specificity for RANKL, prevents the RANKL/RANK interaction and inhibits osteoclast formation and function, thereby decreasing bone resorption and increasing bone mass. Denosumab compared with zoledronic acid showed superior efficacy in delaying time to first-on study SRE and time to first- and subsequent-on study SREs as well as reduction in bone turnover markers. These results led to the approval of denosumab by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), for the prevention of SREs in adults with bone metastases from solid tumors, including breast cancer. Ó 2013 Elsevier Ltd. All rights reserved.

Keywords: RANK RANKL Bisphosphonates Denosumab Skeletal-related events

Introduction Bone is one of the most common sites of cancer metastases, and in particular breast cancers spread to the bone with high frequency.1 Approximately three-quarters of patients who have advanced breast cancer will develop bone metastases.2e4 In breast cancer, bone metastases are predominately osteolytic.5 The median overall survival after the diagnosis of bone metastases in patients with breast cancer is between 2 and 3 years.6 While bone metastases contribute significantly to the morbidity associated with breast cancer, they are rarely the cause of diseaserelated deaths. However, serious complications are associated with them, including chronic bone pain, hypercalcemia, skeletal-related events (SREs), incontinence and paralysis, which can lead to a dramatic decrease in the quality of life for breast cancer patients.1,2,7 The current standard of care for the treatment of bone metastases includes systemic therapy, such as chemotherapy and

* Corresponding author. Hospital Universitario Virgen del Rocío, Avda. Manuel Siurot, s/n, 41013 Sevilla, Spain. Tel.: þ34 955 013 068; fax: þ34 955 013 473. E-mail addresses: [email protected] (A. Casas), [email protected] (A. Llombart), [email protected] (M. Martín). d Hospital Universitario Arnau de Vilanova, Calle de la Marina Alta, s/n, 46015 Valencia, Spain. Tel.: þ34 963 987 320; fax: þ34 963 868 794. e Hospital Universitario Gregorio Marañón, Calle Doctor Esquerdo, 46, 28007 Madrid, Spain. Tel.: þ34 915 868 000; fax: þ34 915 868 018. 0960-9776/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.breast.2013.05.007

bisphosphonates, as well as local treatments, such as surgery or radiation to bone. Treatment with intravenous bisphosphonates (IV-BPs) has been the current standard of care for maintaining skeletal integrity and preventing skeletal complications.2,7e11 In particular, in patients with breast cancer, IV-BPs have been demonstrated to reduce the risk of SREs.12e15 Based on these data, the American Society of Clinical Oncology (ASCO) recommends initiating treatment with IV-BPs in breast cancer patients who have evidence of bone destruction on plain radiographs.9 However, despite the availability of bisphosphonates such as zoledronic acid, pamidronate, clodronate and ibandronate for the treatment of skeletal complications, not all patients respond to them. Moreover, the usage of bisphosphonates is limited by renal toxicity and osteonecrosis of the jaw (although infrequently) and most of them need to be administered through intravenous injections.16,17 Additionally, acute-phase reactions or flu-like symptoms following IVBP infusions, characterized by symptoms such as pyrexia, chills, flushing, bone pain, arthralgias and myalgias, occur frequently and may further complicate the management of these patients.18 Lastly, a study showed that approximately 20% of patients receiving IV-BPs continued to have moderate to high bone resorption marker levels at some point during treatment, which increased the risk of SREs or the progression of bone lesions as compared with patients who had low bone resorption marker levels while on IV-BPs treatment,19 although, at this point, bone resorption marker levels do not have a relevant clinical indication. In fact, in several phase III trials, it has

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been observed that 38e43% of patients with solid tumors experienced an SRE while receiving zoledronate,14,20,21 suggesting an unmet medical need and demonstrating the necessity for more effective therapies. Thus, alternative therapeutic options that further reduce the occurrence of SREs and minimize toxicities are needed to treat bone metastases in cancer patients. Denosumab is a 100% human monoclonal antibody that inhibits osteoclast function and bone resorption, providing a potential treatment of bone loss caused by bone metastases or osteoporosis. In this review, we will look at the factors implicated in the development of bone metastases, as well as the characteristics and mechanism of action of denosumab. Also, we will specifically review the efficacy and safety profile of denosumab in the treatment of bone metastases from patients with advanced breast cancer. Development and control of normal bone remodeling The adult skeleton is continually being remodeled by the activity of osteoclasts and osteoblasts. There is a well-balanced remodeling sequence in normal bone. Bone is first resorbed by osteoclasts and then regenerated by osteoblasts to mature bone. When osteoclasts resorb bone, they eventually undergo apoptosis. This physiological process is regulated by locally produced cytokines and systemic hormones. A triad of molecules has been shown to regulate osteoclast maturation, differentiation, and survival such as receptor activator of nuclear factor-kB (RANK), RANK ligand (RANKL) and osteoprotegerin. These molecules are also important for the control of lymph node organogenesis, the development of thymic medullary epithelial cells,22 central thermoregulation,23 and the formation of the lactating mammary gland during pregnancy.24 RANK is a receptor expressed by both osteoclasts and their precursors. RANKL is a member of the tumor necrosis factor (TNF) family that is produced by numerous cell types including cells of the osteoblast lineage and activated T cells.25 When RANKL binds to RANK, it stimulates

osteoclast formation, activation, adherence, and survival, leading to increased bone resorption.26e29 There are at least three forms of RANKL, two of which have a transmembrane domain that positions the biologically active domain in the extracellular milieu. These two forms can remain on the cell surface or can be proteolytically cleaved into soluble forms that possess osteoclast-stimulating activity within their TNF-homologous domains.30 T cells express both soluble and membrane-bound forms of RANKL.25 Factors such as 1,25dihydroxyvitamin D3, parathyroid hormone, parathyroid hormonerelated protein, prostaglandin E2, interleukin (IL)-1 and 6, TNF, prolactin, and corticosteroids, increase the expression of RANKL making it a key stimulator of bone resorption.31 On the other hand, estrogens, calcitonin, transforming growth factor (TGF)-b, platelet-derived growth factor and calcium-induced osteoprotegerin (another member of the TNF receptor superfamily that binds to RANKL) expression prevent the activation of RANKL’s single cognate receptor RANK, which is able to prevent excessive bone resorption in the normal state. Osteoprotegerin is expressed in osteoblasts and other stromal cells.31,32 Fig. 1 represents the interaction between these molecules. Expression of RANK and RANKL has been found in a wide variety of tissues outside the bone, including lymphoid tissues, skeletal muscle, thymus, liver, colon, small intestine, heart, brain, adrenal gland and mammary gland.33 The binding of RANKL to RANK involves a direct interaction between the extracellular receptor binding domain of RANKL and the cysteine-rich domains of RANK. This interaction causes the activation of several signal transduction pathways, especially the activation of nuclear factor-kB (NF-kB), which upregulates the expression of c-fos to induce the transcription of osteoclastogenic genes.34 Other roles of RANK and RANKL Apart from their role in the development and control of normal bone remodeling, RANK and RANKL also have an important

Fig. 1. Mechanism of action of denosumab. Dashed lines: Activation or induction routes; Dotted lines: Inhibition routes; Black arrows: Production routes. BMP: bone morphogenetic protein; IGF: insulin growth factor; IL: interleukin; OPG: osteoprotegerin; RANK: Receptor activator of nuclear factor-kB; RANKL: Receptor activator of nuclear factor-kB ligand; TGFb: transforming growth factor beta; TNF: tumor necrosis factor.

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function in the development of the mammary gland. Preclinical studies in mice have shown that the absence or overexpression of RANK results in lactation defects and a non-functional mammary gland. RANKL signaling mediates progesterone-induced proliferation and expansion of the stem-cell compartment in the mouse mammary gland.35 RANKL expression is induced by progesterone, specifically in cells that express estrogen and progesterone receptors.36 Also, results from some studies have demonstrated that the RANK and the NF-kB pathways are implicated in mammary tumor development in mice.37,38 The increase in the expression of RANK and RANKL signaling in mammary epithelial cells could be a risk factor for breast cancer development and enhance the resistance to chemotherapy in the clinical setting.38 RANKL, through RANK on mammary epithelial cells, drives these cells into the cell cycle and protects mouse and human mammary-gland epithelial cells from apoptosis in response to DNA damage.38 The reduction of tumorigenesis upon RANKL inhibition is preceded by a reduction of preneoplasias as well as rapid and sustained reductions in hormone- and carcinogen-induced mammary epithelial proliferation.37 RANK and RANKL may also promote lung tumorigenesis, as it has been reported that RANKL triggers migration in several human RANK-expressing cancer cell lines, including breast, prostate and melanoma, and increases bone metastases in these models.39 These results indicate that mechanisms other than progesterone may exist to deregulate and activate the RANK pathway in breast cancer, extending its relevance not only to estrogen- and progesterone-positive tumors but also to other breast cancer subtypes, as RANKL can be delivered by infiltrating lymphocytes.40 These findings may constitute the first direct evidence for a role of RANK/RANKL in metastasis to organs other than the bone. Thus, because mammograms detect microcalcifications and glandular density, and RANK and RANKL are crucial in bone metabolism, the RANK/RANKL system could contribute to the formation of such microcalcifications and glandular density.

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has been reported in most primary human breast tumor samples as well as in cancer cells present in local lymph node metastases and in bone metastases.48 Also, RANK expression has been found to be a predictive marker of bone metastases and skeletal disease-free survival in a large population of breast cancer patients.49 Thus, lower levels of RANK correlate with longer overall survival (p ¼ 0.0078) and disease survival (p ¼ 0.059).49 Patients with bone metastases often have increased bone turnover, and this can be measured using biochemical markers of bone resorption and formation such as urinary N-telopeptide (NTX), serum C-telopeptide (sCTX), aminoterminal propeptide type-1 procollagen (P1NP), osteocalcin, bone-specific alkaline phosphatase (BSAP) and tartrate-resistant acid phosphatase 5b (TRAP-5b). Elevated levels of bone turnover markers represent excessive bone resorption and are predictive of SREs, disease progression, and death.19,50e52 A key objective in the management of bone metastases is to minimize skeletal morbidity by re-establishing the homeostasis of bone metabolism. Thus, if excessive osteolysis is inhibited, skeletal complications caused by bone metastases may be prevented or delayed. Targeting the RANKL with denosumab Denosumab (AMG 162; Amgen, Inc., Thousand Oaks, CA) is a fully human monoclonal antibody of IgG2 subtype that has high affinity and specificity for RANKL.53 It was firstly developed to treat osteoporosis in postmenopausal women at increased risk of fractures and to treat bone loss induced by hormone ablation in prostate cancer patients, but is also used to treat cancer patients with bone metastases from solid tumors, such as prostate and breast cancer.54,55 Denosumab is administered by subcutaneous bolus injection, eliminating the requirement of most bisphosphonates for intravenous infusion. Pharmacokinetics of denosumab

Cancer-induced bone loss Cancer itself adversely affects bone and mineral metabolism through a broad spectrum of mechanisms. The affinity of breast, prostate and several other solid tumors to grow in bone results from the special microenvironment provided by bone.41 Within the bone microenvironment, tumor cells secrete growth factors and cytokines, such as parathyroid hormone-related protein, IL-1, IL-6, IL-8, IL-11, and TNF-a, that stimulate stromal cells and osteoblasts to express and secrete RANKL, which binds to its receptor RANK on the surface of precursor and mature osteoclasts, causing excessive bone resorption.42 RANKL may also be expressed by tumor cells.43,44 It has been observed that RANKL expression is elevated in patients with multiple myeloma,45,46 and in some breast cancer cell lines.42 Osteoclast-mediated bone resorption releases growth factors such as TGF-b, insulin-like growth factor (IGF), basic fibroblast growth factor, and bone morphogenetic protein (BMP) from the bone matrix, that further stimulate tumor growth, metastases, and survival, thus resulting in a propagation of bone destruction and tumor cell proliferation.47 Also, RANKL has recently been shown to promote migration of RANK-expressing tumor cells to bone.39 This is why RANKL is a key mediator in the pathogenesis of a broad range of skeletal diseases. During breast cancer progression, RANKL has been found to be expressed in 11% of human breast tumors, and not only confined to the tumor but also often detected in sporadic infiltrating mononuclear cells present in most tumor stroma (67%) and in fibroblastlike cells in the stroma of rare tumors (5%).37,48 RANK expression

Data from a range of subcutaneous doses (0.01e3.0 mg/kg body weight) and data from fixed subcutaneous doses (30e180 mg) consistently show that denosumab displays nonlinear pharmacokinetics across a wide dose range. However, at doses at or above 60 mg (approximately 1.0 mg/kg), a trend of less nonlinear pharmacokinetics was observed.53e55 For the prevention of SREs in adults with advanced malignancies involving bone, denosumab needs to be administered subcutaneously once every 4 weeks at a dose of 120 mg.54,55 The mechanism of absorption, bioavailability and distribution is not well defined, and it is speculated that it is the same as other monoclonal antibodies administered subcutaneously. On the other hand, two mechanisms of elimination for denosumab are suggested. Thus, one saturable mechanism predominates at low doses and another nonsaturable mechanism governs the rate of denosumab elimination at higher doses. The saturable mechanism of elimination is likely related to denosumab binding to RANKL and elimination of the antibody-RANKL complex. The nonsaturable mechanism of denosumab elimination is likely a nonspecific catabolism in cells of the reticuloendothelial system. The high molecular weight (approximately 150 kD) of denosumab precludes renal excretion as a route of elimination.54,55 As a human IgG2 molecule, denosumab was shown to have a long circulatory residence time and result in a rapid and sustained decrease of bone resorption in healthy postmenopausal women following a single subcutaneous dose.53 The corresponding mean half-life value that described the disposition of denosumab over a large proportion of exposure (t1/2,b) was approximately 32 days.53

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Pharmacodynamics of denosumab The mechanism of action of denosumab differs from that of bisphosphonates. Bisphosphonates are intercalated into bone and inhibit the osteoclast’s ability to resorb bone. Denosumab binds to RANKL, preventing the activation of its receptor, RANK, on the surface of osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone. Because denosumab effectively inhibits osteoclast formation, maturation, and survival, it may be effective for patients in whom osteoclasts persist or are still formed despite treatment with bisphosphonates. In vitro studies have shown that denosumab binds with high affinity to human RANKL (Kd 3  1012 M). As denosumab is highly specific for human RANKL, it does not bind to other TNF family member proteins such as TNF-a, TNF-b, CD40 ligand and TNF-related apoptosis-inducing ligand (TRAIL).55 Fig. 1 shows the point where denosumab interferes with the bone resorption induced by tumor cells. Efficacy of denosumab was evaluated through the percentage change from baseline in urinary NTX and the incidence of SREs.56e 59 In one study, breast cancer patients with bone metastases who did not receive prior IV-BPs were randomized to receive IV-BPs or one of the 5 different schedules of denosumab, either every 4 weeks (30, 120 or 180 mg) or every 12 weeks (60 or 180 mg), through a 24-week regimen.57,58 The authors concluded that denosumab and IV-BPs showed similar efficacy and safety profile in IV-BPs-naive patients with advanced breast cancer. Another study evaluated the efficacy of denosumab in cancer patients with bone metastases and elevated urinary NTX levels despite ongoing IV-BPs therapy.56 Patients were randomized to continue with IV-BPs or to receive subcutaneous denosumab 180 mg every 4 or 12 weeks. In this study, urinary NTX levels were more frequently normalized and less patients experienced on-study SREs with denosumab than with IV-BPs. These studies showed that treatment with denosumab was associated with a rapid and sustained suppression of bone turnover markers. Delay of SREs in denosumab arm was observed only in previously IV-BPs treated patients.59 Moreover, the doses of 120 mg and 180 mg did not differ with respect to the maximum

serum concentration of urinary NTX. Because of that, the dosing of 120 mg of denosumab every 4 weeks was chosen for further clinical development.57,58 Efficacy of denosumab in breast cancer patients with bone metastases Safety and efficacy of denosumab has been studied in a wide range of cancer types such as prostate cancer, multiple myeloma, renal cell carcinoma, and small- and nonsmall-cell lung cancer.60,61 Several phase I, II and III trials have demonstrated that a subcutaneous injection of denosumab every 4 weeks is effective for the treatment of bone metastases from breast cancer. A summary of those trials is shown in Table 1. Phase I trials To determine the maximum tolerated dose of denosumab, a dose-escalation clinical trial was performed in patients with advanced breast cancer and bone metastases (n ¼ 29) or with multiple myeloma (n ¼ 25).62 Patients were randomized to receive a single dose of denosumab (0.1, 0.3, 1.0, and 3.0 mg/kg sc) or pamidronate (90 mg iv). Pharmacokinetics analyses of denosumab were based on blood samples drawn at baseline and thereafter that showed a rapid and prolonged absorption, starting 1 h postdose and reaching average maximum serum levels between 7 and 21 days later. To assess the effect of denosumab administration on bone metabolism, urinary and serum NTX, serum BSAP, and serum albumin-adjusted calcium were assessed prestudy and periodically following dosing. In the breast cancer stratum, a significant reduction in median urinary NTX was observed as early as one day after single dose of denosumab. The duration of suppression of urinary NTX was dose dependent in the denosumab cohorts. Median urinary NTX levels started to return to baseline levels at 21 days after a dose of 0.1 mg/kg denosumab, but remained suppressed at 84 days with a denosumab dosage of 3.0 mg/kg. Changes from baseline in serum NTX were not as pronounced as those observed with urinary NTX, but the profiles were generally similar and confirmed the potency of the intermediate dose of denosumab 1.0 mg/kg.

Table 1 Efficacy of denosumab in the treatment of bone metastases from breast cancer. Trial

Phase

Body, et al. 200662

I

Yonemory, et al. 200864

Patients

Treatment

Dose

Median % decrease from baseline of uNTX

On-study SREs

54

A: Denosumab B: Pamidronate

A: 0.1, 0.3, 1.0, 3.0 mg/kg B: 90 mg

NR

I

18

Denosumab

A: 1  60 mg B: 1  180 mg C: 3  180 mg Q4W

Lipton, et al. 200857,58

II

255

A: Denosumab B: IV-BPa

Fizazi, et al. 200956,b

II

111

A: Denosumab B: IV-BPc

A Q4W: 30, 120 or 180 mg; A Q12W: 60 or 180 mg B: Q4WK A: 180 mg Q4W or Q12W B: Q4WK

Stopeck, et al. 201016

III

2046

A: Denosumab B: Zoledronic acid

A: 120 mg Q4W B: 4 mg Q4W

uNTX at day 85: A: 0.1, 17%; 0.3, 72%; 1.0, 72%; 3.0, 71% B: 30% uNTX at day 85: A: 91% B: 62% C: 85% uNTX at week 13: A: 73% B: 79% uNTX at week 13: A: 78% B: 33% uNTX at week 13: A: 80% B: 68%, p < 0.001

NR

Percentage of SREs: A: 12% B: 16%, p ¼ ns Percentage of SREs: A: 8% B: 17%, p ¼ ns Mean skeletal morbidity rate: A: 0.45 B: 0.58, p ¼ 0.004

IV-BP: intravenous bisphosphonates; NR: no reported; ns: no significant; Q4W: every 4 weeks; Q12W: every 12 weeks; SREs: skeletal related events; uNTX: urinary Ntelopeptide. a IV-BP could be zoledronic acid, pamidronate or ibandronate at the physician’s discretion. b Results are from all patients included, not only breast cancer patients. c IV-BP could be zoledronic acid or pamidronate.

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The inhibitory effect of denosumab lasted for at least three months, with similar pharmacodynamics and pharmacokinetics between the two highest doses of denosumab. Bone turnover suppression seemed to be much longer with higher doses of denosumab than with pamidronate, which is one of the standard therapies for patients with multiple myeloma or bone metastases from breast cancer.10,12 This greater efficacy could be partly due to the prolonged circulatory residence time of denosumab, whereas bisphosphonates disappear rapidly from the blood after administration.63 The treatment was well tolerated and the most common reported adverse events were fatigue and asthenia, and no cases of symptomatic or persistent hypocalcemia and nephrotoxicity were observed. Renal toxicity and osteonecrosis of the jaw are a potential complications of bisphosphonates administration.16,17 Denosumab was effective in decreasing bone resorption rapidly and for a sustained period of time in patients with breast cancer metastatic to bone. Changes in bone resorption markers occurred within one day following a single dose of denosumab and the duration of bone resorption suppression was dose-dependent and persisted for up to 84 days after single subcutaneous dose of 1.0 or 3.0 mg/kg of denosumab. Another phase I trial was developed to evaluate the safety, pharmacokinetics, and pharmacodynamics of denosumab in Japanese women with bone metastases associated with breast cancer.64 Eighteen patients received a single subcutaneous injection of 60 mg or 180 mg of denosumab or three doses of 180 mg denosumab (once every 4 weeks). Treatment was well tolerated and no major safety concerns related to denosumab were noted in any cohort. Most adverse events were grade 2 and only one patient reported grade 4 myositis and grade 3 anemia, malaise, and dysphagia that the investigator deemed treatment-related. The possible etiology of the myositis could be a paraneoplastic syndrome. The patient who developed myalgia exhibited higher levels of creatine phosphokinase and was taking three concomitant medications, which made it difficult to establish the role of denosumab in the development of myositis. Pharmacokinetics of denosumab was approximately dose-linear, causing rapid, substantial and sustained suppression of bone resorption markers with all doses. As well as in the previous study, no dose-limiting toxicity was observed at any dosage. Phase II trials Two phase II trials were carried out to assess the efficacy and safety profile of denosumab for the treatment of patients with breast cancer-related bone metastases.56e58 In one of them, patients with bone metastases not previously treated with IV-BP therapy (n ¼ 255) were randomized to receive IV-BP every 4 weeks (zoledronic acid, pamidronate, or ibandronate) or subcutaneous denosumab (30, 120 or 180 mg every 4 weeks or 60 or 180 mg every 12 weeks).57,58 The median percentage decrease of urinary NTX from baseline until week 13 was 73% in patients treated with denosumab and 78% in patients treated with IV-BP. Similar results were observed at week 25 (75% and 71%, respectively). At week 25, 52% of denosumab-treated patients and 46% of IV-BP-treated patients had urinary NTX reductions of >65%. The incidence of serious adverse events was similar between both cohorts of patients. In another study, patients with bone metastases from breast cancer or other tumors and with elevated levels of bone resorption urinary markers despite ongoing IV-BP treatment (n ¼ 111) were randomized to continue receiving IV-BP every 4 weeks (zoledronic acid or pamidronate) or subcutaneous denosumab (180 mg every 4 weeks or every 12 weeks). The percentage of patients reaching urinary NTX levels lower than 50 nmol/L at week 13 was defined as the primary study endpoint. Secondary endpoints included

589

evaluating this marker at week 25.56 Patients treated with denosumab experienced a rapid and sustained reduction in bone turnover regardless of screening urinary NTx or tumor types. After 13 weeks, the reduction of urinary NTX was achieved by 71% of denosumab patients and 29% of IV-BP patients (p < 0.001). The level of suppression was generally maintained over 25 weeks. Moreover, the median time to reduction of urinary NTX levels was 9 days for denosumab arms and 65 days for the IV-BP arm. The effect of denosumab was rapid and sustained, and appeared to be consistent regardless of tumor type. Also, among breast cancer patients, the difference in other bone turnover markers such as TRAP-5b at week 25 was substantial, with a median reduction of 74% in denosumab arm and of 0.2% in IV-BP arm. The lesser effect of IV-BP with respect to denosumab lowering this bone turnover marker suggests that denosumab in contrast with IV-BP actively inhibits osteoclast formation. SRE incidence was low across both study arms, but the rate of first on-study SRE in those patients previously treated with IV-BP was lower in the denosumab group (8%) than in the IV-BP group (17%; odds ratio [OR]: 0.31, 95% confidence interval [CI]: 0.08e1.18). Patients treated with IV-BP experienced SRE earlier than those treated with denosumab. No serious or adverse events related to denosumab occurred, and the rates of adverse events were similar between treatment groups in both studies. Results from both studies support the use of the higher dosing regimen of denosumab 120 mg every 4 weeks for the greatest suppression of bone resorption. Phase III trials Denosumab was compared with zoledronic acid in delaying or preventing SREs in patients with breast cancer metastatic to bone.15 A total of 2046 bisphosphonate-naïve patients (except previous treatment with oral bisphosphonates for osteoporosis) were randomly assigned to receive either subcutaneous denosumab (120 mg) and intravenous placebo or intravenous zoledronic acid (4 mg adjusted for creatinine clearance) and subcutaneous placebo every 4 weeks. Also, patients were strongly recommended to take daily supplementation with calcium (500 mg/day) and vitamin D (400 IU/day). Denosumab was superior to zoledronic acid in delaying the time to first on-study SRE by 18% (HR: 0.82, 95% CI: 0.71e0.95; p < 0.001), the time to first and subsequent on-study SREs by 23% (HR: 0.77; 95% CI: 0.66e0.89, p ¼ 0.001) and the time to first radiation to bone by 26% (HR: 0.74; 95% CI: 0.59e0.94, p ¼ 0.0121). Median time to first on-study SRE was 26.4 months in patients receiving zoledronic acid, and was not reached at the time of statistical analysis in the denosumab group. Also, denosumab reduced the mean skeletal morbidity rate by 22% compared with zoledronic acid (0.45 vs. 0.58 events per patient per year, respectively; p ¼ 0.004; Fig. 2). The treatment effect of denosumab was consistent over time compared with zoledronic acid. Also, reduction in bone turnover markers was greater with denosumab. At study week 13, levels of urinary NTX decreased by a median of 80% with denosumab and 68% with zoledronic acid (p < 0.001) and levels of BSAP decreased by a median of 44% with denosumab and 37% with zoledronic acid (p < 0.001). Overall survival, disease progression, and rates of severe and serious adverse events were similar between both study arms. In separate analyses evaluating the respective effects of zoledronic acid and denosumab on pain and health-related quality of life (HRQoL) in all patients included in the study, a similar time to pain improvement was observed in both treatment arms (85 vs. 82 days, respectively; HR: 1.02; 95% CI: 0.91e1.15; p ¼ 0.72). However, patients with a baseline score of no/mild pain significantly had longer median time to develop moderate/severe pain when treated

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Safety profile of denosumab

Fig. 2. Mean skeletal morbidity rate of denosumab compared with zoledronic acid in patients with advanced breast cancer (n ¼ 2046).16 SREs: Skeletal-related events.

with denosumab (295 days) compared with zoledronic acid (176 days; HR: 0.78; 95% CI: 0.67e0.92; p ¼ 0.0024).65 Moreover, a greater percentage of patients treated with denosumab than with zoledronic acid had a clinically meaningful improvement in HRQoL, regardless of their pain level at baseline (p < 0.05).66,67 These results are in agreement with those obtained in other phase III trials performed in patients with advanced cancer such as prostate, other solid tumors or multiple myeloma.68,69 Moreover, a recent integrated analysis performed with the results of three pivotal trials that included a broad cancer population confirmed the superiority of denosumab over zoledronic acid in delaying the time to first on-study SRE (HR: 0.83; 95% CI: 0.76e0.90; p < 0.0001) and time to first and subsequent on-study SRE (HR: 0.82; 95% CI: 0.75e 0.89; p < 0.0001).70 Also, the integrated analysis of the three pivotal phase III trials showed that denosumab delayed worsening of pain in comparison with zoledronic acid (181 days vs. 169 days, respectively; HR: 0.92; 95% CI: 0.86e0.99; p ¼ 0.026). As a consequence, a lower percentage of patients treated with denosumab needed to increase analgesic use over time.71 This superiority suggests that a greater inhibition of osteoclast-induced bone resorption of denosumab compared with zoledronic acid, as evident by increased suppression of bone turnover markers, translates into improved clinical outcomes, such as the prevention of SRE.

Denosumab has been generally well tolerated in several clinical trials conducted in advanced cancer patients. RANKL has been identified as a costimulatory cytokine for T-cell activation, and this is the reason for expecting a higher risk for infectious diseases.72 However, preclinical studies revealed no increased risk of bacterial infections.73 Also, in a phase III study comparing denosumab with zoledronic acid in metastatic breast cancer, there was no increase in the number of infectious adverse events (48.8% with zoledronic acid vs. 46.4% with denosumab) or infectious serious adverse events (8.2% zoledronic acid vs. 7.0% denosumab).15 In fact, in that trial only toothache and hypocalcemia were more frequently observed with denosumab. In contrast, acute-phase reactions (including pyrexia, fatigue, bone pain, chills, arthralgia and headache) were 2.7 times more common with zoledronic acid than with denosumab (27.3% vs. 10.4%, respectively) as well as adverse events potentially associated with renal toxicity (8.5% vs. 4.9%, respectively). This fact was observed in spite that in the zoledronic acid arm 12.9% of patients required initial dose adjustments and another 6.6% of patients had to withheld treatment due to serum creatinine levels, whereas no dose adjustments or dose withholding were planned or required in the denosumab arm.74 Renal toxicity might include increased blood creatinine and blood urea, oliguria, renal impairment, proteinuria, decreased creatinine clearance, acute renal failure and chronic renal failure. Thus, denosumab represents a valid therapeutic option for patients with bone metastases suffering from chronic renal failure.15 Lastly, a low incidence of osteonecrosis of the jaw was anticipated in metastatic cancer patients. Results from three phase III clinical trials including 5677 patients with bone metastases indicated that denosumab and bisphosphonates have a similar risk of osteonecrosis of the jaw (1.8% vs. 1.3%, respectively; p ¼ 0.13).75 Cumulative incidences of osteonecrosis of the jaw for denosumab and zoledronic acid were 0.8% vs. 0.5% between months 0e12, 1.8% vs. 1.0% between months 0e24, and 1.8% vs. 1.3% between months 0e36, respectively. Future perspectives As previously stated, there are evidences of the role of RANK/ RANKL in the development of metastasis to organs other than the bone. Based on these findings, several randomized clinical trials with denosumab in cancer patients at earlier disease stages are currently ongoing (http://www.clinicaltrials.gov). One of the most

Fig. 3. Incremental benefits in risk reduction of skeletal-related events in breast cancer patients using bisphosphonates.76

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important trials is the D-CARE trial. Its objective is to evaluate whether denosumab prevents disease recurrence in the bone or in any other part of the body in patients with early breast cancer. The rationale behind this study is that the bone acts as a reservoir of circulating tumor cells that are capable of spreading to other parts of the body and metastasizing. To evaluate this hypothesis, a randomized, double-blind, placebo-controlled phase III study of denosumab as adjuvant treatment for women with early breast cancer at high-risk of disease recurrence was set up. The trial has completed the enrollment of 4500 patients in a time period of 3 years. Patients were assigned to denosumab or to placebo. Primary endpoint is to compare bone metastases-free survival in both study arms. Preliminary results are anticipated by 2016. Conclusions Although bisphosphonates are until now the standard of care for the treatment of bone metastases from breast cancer because they reduce the number of SREs, there is a need for better treatment alternatives as these events might continue occurring despite their administration. The discovery of RANKL and the essential role of RANK signaling in osteoclast differentiation, activity and survival have led to the development of denosumab. Denosumab represents a new therapeutic approach by targeting the RANKL pathway essential for osteoclast differentiation, activation, and function, and whose expression seems to be induced by cancer cells. The key pharmacological difference between denosumab and bisphosphonates is the distribution of the drugs within bone and their effects on precursors and mature osteoclasts. This fact may explain the differences observed in the degree and the speed of reduction of bone resorption with both types of drugs, their different activity on trabecular and cortical bone and, lastly, the reversibility of their actions. Currently, denosumab is approved by the EMA and the FDA for the prevention of SREs in adults with bone metastases from solid tumors. These approvals are based on data reported from randomized clinical trials of denosumab in patients with bone metastases from different types of solid tumors, which demonstrates that denosumab is superior to zoledronic acid in preventing and/or delaying SREs (Fig. 3). Additionally, the incidence of serious adverse events was similar with zoledronic acid and denosumab, although there was a higher incidence of renal toxicity with zoledronic acid and of hypocalcemia and toothache with denosumab. Osteonecrosis of the jaw occurred infrequently with both bisphosphonates and denosumab. However, denosumab with its convenient monthly subcutaneous injection and the lack of need for renal monitoring and dose adjustments represents a potential alternative to treat bone metastases from breast cancer. Lastly, the results of several clinical trials have shown that the RANK/RANKL system is an important molecular link between progestins and epithelial carcinogenesis. The expression of RANK in primary tumors has been demonstrated to be a predictive marker of bone metastases occurrence and skeletal disease-free survival in early breast cancer patients. For this reason, RANK inhibition is being considered as a novel approach for the prevention of disease spread to the bones. Conflict of interest statement The authors declare that they do not have any conflict of interest that may inappropriately influence this work. Acknowledgments The authors acknowledge the financial support of Amgen to maintain the necessary meetings to elaborate the contents of this

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