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Skeletal Complications of Malignancy
Introduction: Denosumab, a fully human monoclonal antibody, targets the receptor activator of nuclear factor-kappaB (RANK) ligand, a protein essential for osteoclast differentiation, activity and survival. Loss of osteoclasts from the bone surface reduces bone turnover and bone loss in malignant and benign diseases. In breast cancer, bone metastases are frequently observed; cancer treatment-induced bone loss (CTIBL) may result as a consequence of endocrine treatment or chemotherapy. Furthermore, preclinical studies suggest a direct role of the RANK/RANK-ligand pathway in breast tumorigenesis. This paper reviews preclinical and clinical data on denosumab in breast cancer. Materials and methods: Studies were identified through the Medline database. Key search terms included: AMG-162, bisphosphonates, denosumab, RANK-ligand and zoledronic acid. Information available in abstract form only was retrieved from major oncology meetings, such as the American Society of Clinical Oncology (ASCO) annual meeting, ASCO breast meeting, European Cancer Organization, European Society of Medical Oncology and the San Antonio Breast Cancer Symposium. Results: Denosumab was consistently well tolerated throughout clinical trials, although the observed incidence of osteonecrosis of the jaw was comparable to that with bisphosphonates. Efficacy as determined by a reduction of skeletal-related events was at least equal to zole- dronic acid, and superior in one phase III study conducted in patients with metastatic breast cancer. Clinical trials investigating the role of denosumab for the prevention of CTIBL and breast cancer recurrences are currently ongoing. Conclusion: In conclusion, denosumab appears to be an effective and safe treatment option in patients with bone metastases from breast cancer with the potential of also preventing CTIBL. Correspondence to: Keywords: bisphosphonates, bone metastases, cancer treatment-induced bone loss, denosu- Guenther G. Steger, MD Department of Medicine, mab, osteoporosis, receptor activator of nuclear factor-kappaB Clinical Division of Oncology, Comprehensive Cancer Centre, Medical University of Vienna, Waehringer Guertel Introduction the receptor activator of nuclear factor-kappaB 1820, A-1090 Vienna, (RANK)/RANK-ligand pathway, rendering Austria guenther.steger@ Breast cancer RANK-ligand an attractive target for the preven- meduniwien.ac.at Breast cancer is the most common malignant dis- tion of bone loss. Recent preclinical data suggest Rupert Bartsch, MD ease in women worldwide [American Cancer that this pathway may also play a role in breast Department of Medicine, Clinical Division of Society, 2009]. Bone loss and bone degradation tumorigenesis, opening the stage for new options Oncology, Comprehensive are frequently observed in breast cancer patients of breast cancer prophylaxis and therapy [Beleut Cancer Centre, Medical University of Vienna, and occur as a treatment side effect, that is, et al. 2010; Schramek et al. 2010]. Vienna, Austria cancer treatment induced bone loss (CTIBL) [Amir et al. 2010] or directly due to bone metas- Bone metastases in breast cancer tases [Coleman, 2001]. Bone resorption requires Bone metastases are common in breast cancer; osteoclasts, cells specialized in the degradation of indeed, up to 60% of patients with advanced bone tissue. Osteoclast activation is triggered by breast cancer will eventually develop bone http://tam.sagepub.com 233 Therapeutic Advances in Medical Oncology 3 (5) metastases during their course of disease [Kanis et al. 1997]. Tamoxifen was regarded as [Coleman, 2001]. According to radiographic the standard of care for the treatment of endo- appearance, lesions are classified as being osteo- crine-responsive breast cancer for nearly two dec- lytic, osteoblastic or mixed [Roodman, 2004], ades. This selective oestrogen receptor modulator with the majority of breast cancer bone metasta- exhibits antiresorptive properties in bone tissue, ses belonging to the mixed or lytic types [Yin thereby preventing the development of osteopo- et al. 2005]. Therefore, complications such as rosis. Aromatase inhibitors, however, are superior hypercalcaemia, fractures or spinal cord com- to tamoxifen as adjuvant therapy for early breast pressions may occur [Mundy, 2001]. Fractures cancer [Thu ¨ rlimann et al. 2005]. This class of as well as spinal cord compression and the con- drugs acts by blocking aromatase, the main secutive local interventions (e.g. surgery to bone, source of oestrogen production in postmeno- radiotherapy to bone) are summarized by the pausal women. Reduction of oestrogen blood term ‘skeletal-related events’ (SREs) [Ross et al. levels, on the other hand, increases annual bone 2003]. In most phase III clinical trials, reduction loss to 2.6% [Eastell et al. 2006; Perez et al. of SREs is chosen as the primary endpoint in 2006]. This is clinically relevant, as such bone order to measure the activity of drugs blocking loss eventually translates into higher fracture bone resorption. In phase I and II studies, bio- rates (11% in patients treated with aromatase markers of bone turnover, for example, urinary- inhibitors compared with 8% on tamoxifen) N-telopeptide/creatinine ratio (uNTX/Cr), are [Howell et al. 2005]. often substituted as a surrogate endpoint [Brown et al. 2003]. CTIBL may also occur in premenopausal women due to chemotherapy-induced ovarian failure Current treatment options for bone metastases [Hines et al. 2009] or suppression of ovarian Apart from systemic antitumour therapy and function by gonadotropin-releasing hormone local interventions, bisphosphonates and denosu- analogues [Gnant et al. 2007]. Furthermore, mab were developed as direct inhibitors of bone fracture rates are increased by androgen depriva- resorption. Through different mechanisms of tion in male patients with prostate cancer [Smith action, these bone-specific agents block osteo- et al. 2009]. clast function. Bisphosphonates have a unique property of selective uptake by their target Bisphosphonates, when given in conjunction with organ. After binding strongly to hydroxyapatite endocrine therapy, prevent CTIBL as evidenced bone mineral, they are internalized by osteoclasts by a decreased reduction of bone mineral density located on the bone surface [Baron et al. 2011]. [Van Poznak et al. 2010; Gnant et al. 2007]. Once taken up, bisphosphonates that contain a Other trials even observed an increase of bone nitrogen residue on a side chain (amino- mineral density in patients receiving bisphospho- bisphosphonates) inhibit the enzyme farnesyl- nates [Eidtmann et al. 2010; Brufsky et al. 2009]. pyrophosphate synthase within osteoclasts, However, this effect might not translate into a thereby preventing prenylation of certain signal- reduction in fracture rates [Valachis et al. transduction GTPases, such as Ras, Rho and 2010]. In this context, however, it is important Rac, which, in turn, induces apoptosis to realize that the reason such a decrease in frac- [Luckmann et al. 1998]. Non-nitrogen-contain- ture rates was not observed may be related to the ing bisphosphonates, on the other hand, are fact that bisphosphonates in most trials were only metabolized into ATP analogues, which again initiated when patients developed a T-score of less eventually leads to cell degradation [Frith et al. than -2.0. Furthermore, many of those studies 2001]. were not adequately powered to detect such an effect. Denosumab on the other hand was found In contrast, denosumab acts by blocking osteo- to reduce the incidence of new vertebral fractures clast differentiation from osteoclast precursor in prostate cancer patients on androgen depriva- cells [Bekker et al. 2004]. This mechanism and tion in a large, adequately powered phase III its clinical relevance will be discussed in this study [Smith et al. 2009]. Phase III clinical article. trials of denosumab for the prevention of CTIBL CTIBL in breast cancer are currently ongoing Under physiological conditions, a postmeno- [ClinicalTrials.gov identifier: NCT0056374; pausal woman loses 1% of bone mass per year Bartsch and Steger 2009]. 234 http://tam.sagepub.com GG Steger and R Bartsch Bone metabolism [Kitazawa and Kitazawa, 2002; Chikatsu et al. 2000; Thomas et al. 1999]. As outlined, this Osteoclast activation leads to increased osteoclast differentiation; As outlined, osteoclasts are key mediators of resulting bone resorption mobilizes growth fac- bone resorption. Osteoclasts derive from osteo- tors, such as transforming growth factor beta clast precursors (OCPs). Those cells derive (TGF-b), insulin-like growth factor, basic fibro- from bone marrow cells of mononuclear linage, blast growth factor and bone morphogenetic pro- linking bone metabolism with the immune tein (BMP) from the bone matrix. Those system. Under physiological conditions, a bal- cytokines in turn stimulate tumour proliferation ance of bone synthesis and degradation exists; and support tumour cell survival [Yin et al. 2005; therefore, osteoblasts were suggested to mediate Roodman, 2004; Kostenuik et al. 1992; osteoclast activation via a hypothetical ‘osteoclast Hauschka et al. 1986] (Figure 1). activating factor’ [Rodan and Martin, 1981]. This assumption was eventually proven correct The resulting vicious cycle is potentially inhibited when the RANK-ligand was identified (reviewed by OPG, which leads to the development of com- by Geusens [2009]). This protein is part of a pounds that inhibit the RANK/RANK-ligand system of interacting cytokines of the tumour pathway as therapeutic agents [Body et al. 2003]. necrosis factor (TNF) family that regulates bone turnover. In the RANK/RANK-ligand As outlined in Figure 1, certain malignancies, pathway, RANK-ligand, which is secreted by such as prostate cancer and multiple myeloma, osteoblasts and bone marrow stromal cells, acti- may produce RANK-ligand directly [Farrugia et vates RANK on the surface of OCPs, inducing al. 2003; Brown et al. 2001]. Furthermore, a differentiation of precursors into mature cells. RANK-ligand independent mechanism of osteo- This step is antagonized by osteoprotegerin clast differentiation mediated by IL-1, IL-6, IL-8 (OPG) (reviewed by Vega et al. [2007]). and TNF-a exists [Bendre et al. 2005; Kudo et al. 2003], suggesting a potential mechanism of resis- RANK/RANKL/OPG pathway in breast cancer tance to RANK-ligand inhibition. bone metastases In breast cancer bone metastases, the interaction RANK pathway in breast tumorigenesis of tumour cells, bone matrix and bone cells Recently, it was suggested that RANK-ligand results in a vicious cycle of bone destruction may also have a direct role in breast cancer [Giuliano et al. 2004]. Tumour cells secrete cyto- tumorigenesis. In a mouse model developed by kines and growth factors, such as parathyroid Beleut and colleagues, adult ovarectomized mice hormone-related peptide, interleukin (IL)-1, IL- were exposed to progesterone [Beleut et al. 6, IL-8, IL11 and TNF-a, thereby causing stroma 2010]. In this model, progesterone drove the pro- cells and osteoblasts to secrete RANK-ligand liferation of mammary gland epithelial cells Osteoclast precursor RANK-ligand RANK li d Cytokines Tumour- (() IL-1, IL-6, IL-8, TNF-a) Inhibition Inhibition b by y cell Differentiation OPG Cytokines RANK-ligand Bone marrow Stimulation Osteoclast stroma cells of tumour growth C Cyto t ki kine release l Bone destruction (BMP, IGF, TGF-b) Figure 1. Vicious cycle of bone destruction. BMP, bone morphogenetic protein; IGF, insulin-like growth factor; IL, interleukin; OPG, osteoprotegerin; RANK-ligand, receptor activator of nuclear factor-kappaB ligand; TGF-b, transforming growth factor beta; TNF-a, tumour necrosis factor alpha. http://tam.sagepub.com 235 Therapeutic Advances in Medical Oncology 3 (5) (MECs) in two waves. A first, smaller wave of Phase II clinical trials of denosumab proliferation occurred in progesterone receptor in malignancies and CTIBL (PR)-positive cells and was found to require Two randomized phase II studies of denosumab cyclin D1. A second, larger wave, however, in advanced cancer patients were initiated based relied on RANK-ligand signalling. upon those results. One trial included 255 bisphosphonate-naı ¨ve patients with metastatic Ablation of RANK in the mammary epithelium breast cancer. Patients were randomly assigned blocked progesterone-induced morphogenesis. to different doses and schedules of denosumab On the other hand, systemic administration of or a control group receiving zoledronic acid. RANK-ligand also triggered proliferation in the Reduction of uNTX/Cr was defined as a primary absence of PR signalling, and injection of recom- study endpoint. Overall, denosumab and zole- binant OPG as a RANK signalling inhibitor dronic acid yielded similar results and denosu- blocked progesterone-induced proliferation mab at 120 mg administered every 4 weeks was [Beleut et al. 2010]. identified as the optimal schedule for further investigations. Serious adverse events were In line with these data, Schramek and colleagues observed less frequently in patients treated with showed that the administration of medroxypro- denosumab compared with the bisphosphonate gesterone acetate (MPA) triggered an induction group (9% vs. 16%) [Lipton et al. 2007]. of RANK-ligand in MECs. Results showed that inactivation of the RANK pathway in MECs pre- A second randomized phase II study included vented the expansion of a stem cell-enriched pop- patients already receiving various bishosphonates ulation in response to MPA and, furthermore, (i.e. ibandronate, pamidronate and zoledronic sensitized those cells to DNA damage-induced acid) for bone metastases of solid cancers and cell death. Consequently, deletion of RANK multiple myeloma. It consisted of 111 patients decreased incidence and delayed onset of MPA- with intermediate-to-high levels of uNTX at driven mammary cancers [Schramek et al. 2010]. baseline randomized to denosumab or continua- tion of bisphosphonates. The percentage of This data may offer a possible hypothesis for the patients reaching uNTX levels of more than induction of breast cancers by hormone replace- 50 nmol/L at week 13 was defined as the primary ment therapy with a combination of oestrogen study endpoint. This endpoint was met by 71% and progestins and opens an opportunity for of patients in the denosumab group compared new approaches in breast cancer prevention. with 29% of patients who continued on bispho- sphonates (p< 0.001). Adverse events were com- parable between both groups [Fizazi et al. 2009]. Development of denosumab When considering this trial, however, it is impor- Early development of drugs targeting RANK/ tant to understand that the patients included RANK-ligand started with recombinant OPG were resistant to biphosphonates as evidenced (AMGN-0007). While OPG was active and by intermediate-to-high baseline uNTX; it is well tolerated [Body et al. 2003; Bekker et al. not entirely clear whether results can be trans- 2001], AMG162, later named denosumab, a ferred to a general population. fully human antibody targeting RANK-ligand, reduced levels of bone turnover markers to a The role of denosumab for the prevention of greater extent [Bekker et al. 2004]. CTIBL was evaluated in another phase II trial: 252 patients with early breast cancer and reduced In patients with osteoporosis, the effects of deno- bone mass who received aromatase inhibitors in sumab on levels of bone turnover markers were the adjuvant setting were included and random- sustained for up to 6 months, enabling an admin- ized to denosumab 60 mg or placebo every 6 istration schedule similar to that for intravenous months. In the denosumab group, bone mineral bisphosphonates [Bekker et al. 2004]. Further density increased significantly over time (5.5% studies were conducted in patients with bone and 7.6%, at 12 and 24 months, respectively; metastases from solid cancers and multiple mye- p< 0.0001 [both time points]). Again, treatment loma. Importantly, neither antibodies against was generally well tolerated and adverse events denosumab nor any drug-related serious adverse were similar between the respective denosumab events were observed [Body et al. 2006]. and placebo groups [Ellis et al. 2008]. 236 http://tam.sagepub.com GG Steger and R Bartsch Denosumab for the treatment of bone metas- associated with bone metastases [Kretzschmar tases: results from phase III clinical trials et al. 2007]. In a separate analysis evaluating Recently, results of the first phase III trial to com- the respective effects of zoledronic acid and pare directly denosumab to zoledronic acid in denosumab on pain in all patients included in patients with metastatic breast cancer patients Amgen 20050136, a similar time to pain were published (Amgen 20050136 [Clinical improvement was observed in both treatment Trials.gov identifier: NCT00321464]). A total arms. Patients with a baseline score of no/mild of 2046 biphosphonate-naı ¨ve patients (except pain had a significantly longer median time to treatment with oral bisphosphonates for osteopo- development of moderate/severe pain when trea- rosis) were included and randomized to denosu- ted with denosumab compared with zoledronic mab 120 mg or zoledronic acid 4 mg every 4 acid [Stopeck et al. 2010a]. weeks in a randomized, double-blind, active-con- trolled trial. Primary study endpoint was time to Rates of severe (defined as Common first on-study SRE (noninferiority); secondary Terminology Criteria of Adverse Events grade endpoints consisted of time to first on-study 3) and serious adverse events (e.g. life threat- SRE (superiority) and time to first and subse- ening or requiring hospitalization) once again quent on-study SREs. In the denosumab group, were similar between both treatment groups. In a significant delay in time to first on-study SRE general, those adverse events were mainly attrib- was observed (hazard ratio [HR] 0.82; 95% con- utable to concomitant anticancer therapies. As fidence interval [CI] 0.710.95; p< 0.001 non- expected, significantly more cases of pyrexia, inferiority; p = 0.01 superiority). Indeed, median bone pain, arthralgia and renal failure were time to first on-study SRE was 26.4 months in observed in the zoledronic acid group, while patients receiving zoledronic acid, and was not hypocalcaemia and toothache, not associated reached in the denosumab group [Stopeck et al. with the development of osteonecrosis of the 2010b]. This was recently updated at the 2010 jaw (ONJ), were seen more often in patients San Antonio Breast Cancer Symposium where a receiving denosumab. Importantly, the overall median time to first on-study SRE of 32.4 rate of ONJs, defined as exposed necrotic bone months was reported in the denosumab group that persists for at least 8 weeks [Cartsos et al. [Stopeck et al. 2010c]. Furthermore, denosumab 2008], was similar in the respective treatment reduced the risk of experiencing multiple SREs groups. Furthermore, known risk factors for (analysis of time to first and subsequent on-study ONJ, such as prior dental extractions and poor SRE) significantly (HR 0.77; 9% CI 0.660.89; oral hygiene, were present in the vast majority of p = 0.001) [Stopeck et al. 2010b]. The results are all ONJ cases [Stopeck et al. 2010b]. summarized in Table 1. Another phase III trial was conducted in a mixed Bisphosphonates are known to have considerable population of patients with different advanced activity on control and palliation of pain solid cancers (excluding prostate and breast Table 1. Comparison of denosumab vs. zoledronic acid in metastatic breast cancer (n = 2046). Endpoint HR 95% CI p value Primary endpoint Time to first on-study SRE (noninferiority) 0.82 0.71-0.95 >0.0001 Secondary endpoints Time to first on-study SRE (superiority) 0.82 0.71-0.95 0.01 Time to first and subsequent on-study SRE 0.77 0.66-0.89 0.001 Exploratory endpoints Overall disease progression 1.00 0.89-1.11 NS Overall survival 0.95 0.81-1.11 NS Skeletal morbidity rate (mean) D: 0.45; 0.004 (number of SREs per year) ZA: 0.58 CI, confidence interval; D, denosumab; HR, hazard ratio; NS, not significant; SRE, skeletal-related event (i.e. pathologic fracture, irradiation to bone, surgery to bone, spinal cord compression); ZA, zoledronic acid. http://tam.sagepub.com 237 Therapeutic Advances in Medical Oncology 3 (5) cancer) and multiple myloma. Similar to mechanisms, synergistic activity of bisphospho- NCT00321464, the primary study endpoint, nates in combination with chemotherapy, immu- noninferiority to zoledronic acid, was met (HR nomodulatory properties as well as an anti- 0.84; 95% CI 0.710.98; p = 0.0007), although angiogenic effect were proposed [Neville-Webbe and Coleman, 2010]. While there is some clinical a superiority of denosumab was not established data in support of these assumptions, there is no [Henry et al. 2011]. clear-cut evidence yet. The ABCSG-12 study Finally, another phase III trial of denosumab randomized premenopausal patients receiving versus zoledronic acid was conducted in men adjuvant endocrine therapy to additive treatment with castration-resistant prostate cancer with zoledronic acid or control. A significant [ClinicalTrials.gov identifier: NCT00321620]. reduction of breast cancer recurrence events Overall, 1904 patients with bone metastases, all was observed in the bisphosphonate group naı ¨ve for intravenous bisphosphonates were [Gnant et al. 2009]. included. Again, time to first on-study SRE was chosen as the primary study endpoint. In patients In the postmenopausal bone protection trial receiving denosumab, median time to first on- (ZO-FAST [ClinicalTrials.gov identifier: NC study SRE was 20.7 months compared with T00171314]), early breast cancer patients on 17.1 months in the zoledronic acid group (HR letrozole were randomly assigned to a group that 0.82; 95% CI 0.710.95; p< 0.001 noninferior- received upfront zoledronic acid or a group that ity; p = 0.008 superiority). In line with the afore- received bisphosphonates only when a drop in mentioned studies, the overall rate of serious bone mineral density was observed [Eidtmann adverse events was similar (63% vs. 60%), et al. 2010]. In support of ABCSG-12 results, while once again a numerical increase in the significantly fewer recurrences occurred in the rate of ONJ was observed in patients receiving upfront group (HR 0.59; 95% CI 0.380.92; denosumab (22 [2%] vs. 12 [1%]; p = 0.09) p = 0.0176). In the smaller ZO-FAST study, [Fizazi et al. 2011]. however, no significant difference between both groups was observed [Brufsky et al. 2009]. EZO- FAST even found a nonsignificantly increased recurrence risk with immediate bisphosphonate Trials of denosumab in CTIBL administration [Coleman et al. 2009]. A com- As outlined, bisphosphonates are active in the bined analysis of those study results could prevention of CTIBL [Van Poznak et al. 2010; not be performed as the Gail-Simon test was sta- Gnant et al. 2007]. It is still not proven, however, tistically significant for a quantitative interaction whether this effect eventually translates into a between the studies (p = 0.047) [Coleman et al. reduction in fracture rates [Valachis et al. 2009]. 2010]. Denosumab, on the other hand, was found to lower the rate of vertebral fractures sig- The AZURE trial (BIG 01/04; chemotherapy nificantly in patients on androgen-deprivation and/or hormone therapy with or without zoledro- therapy for prostate cancer [Smith et al. 2009]. nate in women with stage II or stage III breast Further studies are currently ongoing: the cancer [ClinicalTrials.gov identifier: Austrian Breast and Colorectal Cancer Study NCT00072020]) was the most recent of adjuvant Group Study 18 (ABCSG-18) randomized post- bisphosphonates studies to report results menopausal patients treated with aromatase [Coleman et al. 2010]. In contrast to ABCSG- inhibitors as adjuvant therapy for hormone recep- 12, addition of zoledronic acid caused no reduc- tor-positive early breast cancer to denosumab or tion in recurrence-free survival events in 3360 placebo. This study is among the first phase III patients randomized to receive (neo) adjuvant trials evaluating denosumab in the prevention of chemotherapy and/or endocrine therapy with or CTIBL in breast cancer and also includes rele- without zoledronic acid (377 disease-free survival vant oncological treatment goals as secondary events with zoledronic acid, 375 in the control endpoints [ClinicalTrials.gov identifier: group; HR 0.98; 95% CI 0.851.13; p = 0.79). NCT00556374]. Therefore, the exact role of bisphosphonates in Clinical antitumour efficacy of bisphosphonates the prevention of breast cancer recurrences and denosumab awaits further clarification. Table 2 outlines the Preclinical data suggested a direct antitumour different results in terms of recurrence risk in the effect of zoledronic acid. Among other respective trials. 238 http://tam.sagepub.com GG Steger and R Bartsch As for denosumab, there are currently no clinical adverse events (48.8% zoledronic acid vs. data concerning a direct antitumour effect, 46.4% denosumab) or infectious serious adverse although preclinical studies implicate a consider- events (8.2% zoledronic acid vs. 7.0% denosu- able role for the RANK/RANK-ligand pathway mab). In contrast, a meta-analysis of nine ran- in breast cancer tumorigenesis [Beleut et al. domized controlled trials involving 10,329 2010; Schramek et al. 2010]. As mentioned, participants with postmenopausal osteoporosis, ABCSG-18 evaluates the role of denosumab in early breast cancer and rheumatoid arthritis, the prevention of CTIBL [ClinicalTrials.gov identified a significant increase in the risk of seri- identifier: NCT00556374]. Here, recurrence- ous infection in patients receiving denosumab free survival is assessed as a secondary endpoint. (odds ratio 4.45; 95% CI 1.1517.14; p = 0.03) Another ongoing phase III trial, D-CARE (study [Anastasilakis et al. 2009]. of denosumab as adjuvant treatment for women with high-risk early breast cancer receiving neo- The FREEDOM study [ClinicalTrials.gov iden- adjuvant or adjuvant therapy [ClinicalTrials.gov tifier: NCT00089791; Cummings et al. 2009], a identifier: NCT01077154]) even defined bone large randomized study including more than metastasis-free survival as the primary study end- 7000 patients with osteoporosis, however, yielded point. Results are eagerly awaited, as these trials different results: no increase in the risk of infec- will yield important information concerning a tions was observed in the denosumab group. potential role of denosumab in the prevention Furthermore, the risk for developing cancer was of breast cancer recurrences. not increased. This is of considerable impor- tance, as denosumab might bind to a TNF- related apoptosis-inducing ligand, thereby Side effects increasing tumour cell survival. Therefore, at Denosumab was generally well tolerated in sev- the moment, there is no clear signal that the eral clinical trials conducted in advanced cancer risk for serious infections is increased with deno- patients. As RANK-ligand was identified as a costimulatory cytokine for T-cell activation, a sumab treatment. higher risk for infectious diseases was anticipated In studies of denosumab in osteoporosis, no cases [Wong et al. 1997]. Preclinical studies, however, revealed no increased risk of bacterial infections of ONJ were observed. Therefore, a lower inci- [Stolina et al. 2003], or altered virus clearance in dence of ONJ was anticipated also in metastatic response to influenza infections in vivo [Miller cancer patients. Results from three phase III clin- et al. 2007]. Importantly, in the aforementioned ical trials including 5677 patients with bone phase III study comparing denosumab to zole- metastases, however, clearly indicated a risk of dronic acid in metastatic breast cancer, there ONJ associated with denosumab treatment simi- was no increase in the number of infectious lar to that with bisphosphonates: 37 (1.3%) cases Table 2. Randomized trials of zoledronic acid in early breast cancer. Study Number Design HR Comment ABCSG-12 1803 Premenopausal HR 0.64; 95% Significantly fewer recurrences CI 0.460.91; p = 0.01 in ET +/- ZA patients receiving ZA Z-FAST 602 Postmenopausal HR 0.80; Trend towards fewer recurrences 95% CI 0.451.41; NS in ET + early vs. delayed ZA patients treated with ZA ZO-FAST 1065 Postmenopausal HR 0.59; Significantly fewer recurrences 95% CI 0.380.92; in ET + early vs. delayed ZA patients p = 0.0176 receiving ZA E-ZO-FAST 527 Postmenopausal HR 1.76; Trend towards more recurrences 95% CI 0.833.69; NS in ET + early vs. delayed ZA patients treated with ZA AZURE 3360 Pre/postmenopausal HR 0.98; 95% No effect of ZA in addition to standard CI 0.851.13; NS CT and/or ET +/- ZA therapy CI, confidence interval; CT, chemotherapy; ET, endocrine therapy; HR, hazard ratio; NS, not significant; ZA, zoledronic acid. See text for explanation of study name acronyms. http://tam.sagepub.com 239 Therapeutic Advances in Medical Oncology 3 (5) Table 3. Major differences between denosumab and zoledronic acid. Denosumab Zoledronic acid Type of substance Monoclonal antibody Chemical agent Mode of action Inhibition of osteoclast differentiation Induction of osteoclast apoptosis Application Subcutaneous Intravenous Direct antitumour effect Possible, not yet observed Suggested from preclinical and inconsistent clinical data Inhibition of T-cell function Suggested from in vitro data; Not observed increased infection rate not fully excluded Osteonecrosis of the jaw Relevant side effect in patients Relevant side effect in patients receiving receiving denosumab for bone metastases. zoledronic acide for bone metastases Not observed in patients treated for osteoporosis and osteoporosis Renal toxicity Not observed Relevant side effects were recorded in patients treated with zoledronic patients with advanced breast cancer, as these acid compared with 52 (1.8%) cases in patients drugs were shown to reduce effectively the receiving denosumab [Brown et al. 2010]. number of SREs. However, SREs might occur Recently, Van den Wyngaert and colleagues despite therapy, highlighting the need for alterna- reported pooled ONJ safety data from all three tive treatment approaches. randomized phase III trials. A total of 89 ONJ cases were reported with 52 (1.83%; 95% CI Derangement of the balance in the RANK/ 1.372.39) occurring in the denosumab group RANK-ligand/OPG pathway is a major driving and 37 (1.30%; 95% CI 0.921.79) in the zole- force in the development of malignant bone dronic acid group, respectively. Overall, there was lesions. Denosumab is a fully human antibody no significant difference in the pooled risk ratio blocking RANK-ligand, thereby interfering with (RR) for ONJ (RR 1.40; 95% CI 0.922.13; p = the vicious cycle of bone destruction. Clinical 0.11). It is necessary to remember, however, that studies suggest at least similar efficacy as zoledro- neither separately nor pooled, those trials had nic acid, with one large prospectively randomized adequate statistical power (>80%) to detect an phase III trial also showing superiority of deno- excess relative risk of ONJ [Van den Wyngaert sumab versus zoledronic acid in terms of delaying et al. 2011]. Therefore, postmarketing risk- SREs in advanced breast cancer. Overall, deno- benefit studies focusing on incidence of ONJ sumab was well tolerated, with generally mild appear warranted. side effects observed. However, an increased risk for infectious disease cannot fully be Renal toxicity is another side effect associated excluded, the risk for developing ONJs was sim- with bisphosphonates. In AMG20050136, renal ilar to bisphosphonates; therefore, the same toxicity (defined as increased blood creatinine safety recommendations apply for this condition. and blood urea, oliguria, renal impairment, pro- Moreover, preclinical studies also suggest an teinuria, decreased creatinine clearance, acute important role for the RANK/RANK-ligand renal failure and chronic renal failure) was more pathway in breast tumorigenesis. Thus, ongoing frequently observed with zoledronic acid, espe- clinical studies are evaluating the effect of deno- cially in patients with baseline clearance of sumab on CTIBL and also breast cancer recur- 60 ml/min. Therefore, denosumab represents a rences in the adjuvant setting. valid therapeutic option for patients with bone metastases suffering from chronic renal failure In conclusion, data from clinical trials of denosu- [Stopeck et al. 2010b]. mab in bone metastases from solid tumours in general and from breast cancer in particular seri- Major differences between zoledronic acid and ously challenge the current standard of care for denosumab are summarized in Table 3. these conditions, which is the use of bisphospho- nates. Based on the published results of phase III Conclusion clinical trials aiming at the delay of SREs in Bisphosphonates are currently the standard of patients with bone metastases from solid care for the treatment of bone metastases in tumours, denosumab has already been licensed 240 http://tam.sagepub.com GG Steger and R Bartsch Bendre, M.S., Margulies, A.G., Walser, B., Akel, N.S., by the US Food and Drug Administration for the Bhattacharrya, S., Skinner, R.A. et al. (2005) Tumour prevention of SREs in patients with bone metas- derived interleukin-8 stimulates osteolysis independent tases from solid tumours including breast cancer of the receptor activator of nuclear factor-kappa B (XGEVA ) in the USA. In Europe, the data have ligand pathway. Cancer Res 65: 1100111009. been filed with the European Medicines Agency Body, J.J., Facon, T., Coleman, R.E., Lipton, A., and the decision is expected in the third quarter Geurs, F., Fan, M. et al. (2006) A study of the bio- of 2011. logical receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer. Clin Cancer Res 12: 12211228. Funding This research received no specific grant from any Body, J.J., Greipp, P., Coleman, R.E., Facon, T., funding agency in the public, commercial, or not- Geurs, F., Fermand, J.P. et al. 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Therapeutic Advances in Medical Oncology – SAGE
Published: Jun 20, 2011
Keywords: bisphosphonates; bone metastases; cancer treatment-induced bone loss; denosumab; osteoporosis; receptor activator of nuclear factor-kappaB
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