The RANK Ligand Inhibitor Denosumab As Novel Therapeutic Agent in the Spectrum of Cancer Bone Disease

Pharmacotherapy

The RANK ligand inhibitor denosumab as novel therapeutic agent in the spectrum of cancer bone disease

T. Van den Wyngaert, M.T. Huizing

Recently, the monoclonal antibody denosumab has been registered as a new first-in-class treatment option for the prevention of skeletal-related events (SREs) in patients with bone metastases from a solid tumour, for the treatment of treatment-induced bone loss (TIBL) in prostate cancer, and the treatment of post-menopausal osteoporosis. The present article reviews the mechanism of action of denosumab and the research leading to the registered indications in cancer patients. (Belg J Med Oncol 2012;6:118-123)

Introduction receiving hormonal treatment.2 Preserving skeletal integrity is an increasingly rec- Recently, the monoclonal antibody denosumab has ognised issue in patients with all stages of cancer. been registered as a new first-in-class treatment op- While the use of bone modifying agents in the tion for the prevention of SREs in patients with bone presence of bone metastases is standard of care, the metastases from a solid tumour, for the treatment awareness of the fracture risk with the use of hor- of TIBL in prostate cancer, and the treatment of monal therapies has only recently been incorporated post-menopausal osteoporosis. in the treatment guidelines of major professional societies.1 In contrast, the potential benefits of these agents on disease recurrence and overall survival (OS) A new therapeutic target in the patho- remain the subject of further study and fierce debate. physiology of cancer-induced bone The potent nitrogen containing bisphosphonates disease (including zoledronic acid, pamidronate, and iban- In normal physiological conditions, bone turnover is dronate) are used most frequently to prevent skeletal a highly regulated process involving two specialised related events (SREs) in bone metastatic disease, cell types. Osteoblasts and osteoclasts are in turn while less potent and lower dosed bisphosphonates responsible for bone formation and resorption, and (including alendronate and risedronate) are the numerous regulators are involved in maintaining a standard of care to treat treatment-induced bone tight balance in the activity of both cells.3 loss (TIBL) in breast- and prostate cancer patients The hormonal changes induced by gonadotropin-

Authors: T. Van den Wyngaert MD PhD, Antwerp University Hospital, Department of Nuclear Medicine, Antwerp, Belgium; Prof. M.T. Huizing MD PhD, Department of Medical Oncology, Antwerp University Hospital, Antwerp, Belgium. Please send all correspondence to: T. Van den Wyngaert MD PhD, Antwerp University Hospital, Department of Nuclear Medicine, Wilrijkstraat 10, 2650 Edegem, Belgium; tel. nr. +32 3 821 34 97, email: [email protected]. Conflict of interest: T. Van den Wyngaert has received lecture fees from Novartis and has participated in advisory boards for Novartis and Amgen, in particular with respect to ONJ prevention. Keywords: denosumab, bone metastases, skeletal-related events, treatment-induced bone loss, RANK ligand.

Belgian Journal of Medical Oncology volume 6, issue 4, 2012 118 releasing hormone (GnRH) agonists or aromatase protect denosumab against lysosomal degradation, inhibitors in patients with prostate- or breast cancer extending its half-life and influencing tissue distri- is associated with increased bone resorption and bution, as shown in rodent studies. In humans, the fracture risk.1-4 Similarly, the invasion of bone marrow mean half-life of denosumab over a large range of by tumour cells in metastatic disease, disrupts exposure was approximately 30 days and was inde- the delicate balance between bone formation and pendent of renal function. Thus, no dose adjust- resorption, driving the bone micro-environment to ments are required with different degrees of renal tumour-induced osteolysis.5 By increasing osteoclast impairment. In patients with osteoporosis, this activity and subsequent bone resorption, higher pharmacokinetic profile was not altered by prior levels of bone-derived growth factors become alendronate therapy. locally available, favouring local tumour growth The change in the bone resorption marker uNTx and progression.6 Therefore, inhibiting osteoclast (amino[N]-terminal cross-linked telopeptide of type I function is an attractive therapeutic target to control collagen) was used to determine the pharmacody- excessive bone turnover. namic effect of denosumab on bone turnover and Recently, a cytokine from the tumour necrosis factor to select the optimal dose and regimen. Data from (TNF) superfamily has been identified with an im- trials in patients with bone metastases showed that portant role in differentiation and activation of os- the dose of 120 mg every four weeks was well-tolerated, teoclasts. This new therapeutic target for inhibiting resulted in high serum denosumab levels throughout bone turnover was initially known by different the dosing interval, and achieved maximal suppres- names, but eventually, the name Receptor Activator sion of uNTx in a high proportion of subjects.9,10 of the Nuclear factor κB Ligand (RANKL) prevailed. Normally, the action of RANKL is balanced by the production of osteoprotegerin (OPG), which acts as Prevention of treatment-induced bone a decoy receptor. However, RANKL is overproduced loss and fractures in the presence of bone metastases. Early attempts Denosumab has been studied in women with breast to target this novel pathway by creating different cancer receiving adjuvant therapy with an aroma- forms of recombinant OPG were abandoned for rea- tase inhibitor and documented osteopaenia (T-score sons of unfavourable pharmacokinetics. In addition, between -1.0 and -2.5). Denosumab (60mg SC q6m) this strategy was associated with the potential dan- (n=127) or a placebo (n=125) was administered for ger of inducing an immune response against endog- two years. After twelve months of therapy, a mean enous OPG, leading to potentially catastrophic bone increase in lumbar spine bone mineral density (BMD) resorption. Subsequently, denosumab was developed of 5.5% was observed with denosumab compared as a fully human monoclonal antibody of the IgG2 to placebo (p<0.001).11 Because this trial was not subtype that directly blocks the binding of RANKL powered to detect a difference in fracture rate, the to its natural receptor on osteoclast precursors, pre- results of the larger ABCSG-18 study (n=3,400) are venting further cell differentiation and activation.8 awaited to assess this endpoint. In men with prostate cancer receiving gonadotropin- releasing hormone agonists or bilateral orchiectomy, Pharmacokinetic and pharmacodynamic denosumab (60mg SC q6m) (n=734) was compared profile of denosumab to placebo (n=734) during three years. Patients were After subcutaneous administration, the biodistribution 70 years or older, or had documented osteopaenia of denosumab in preclinical studies was not specific or a history of prior osteoporotic fracture. After two to bone and the agent could be found in nearly all years of therapy, there was a significant mean tissues. As with other antibodies, the clearance of increase in lumbar BMD of 6.7% (p<0.001) and denosumab is likely mediated through internalisation a lower rate of vertebral fractures after three years of followed by intracellular degradation, in part through therapy (1.5% versus 3.9%; p=0.006).12 the reticuloendothelial system and an independent These trials demonstrate the efficacy of denosumab in target-mediated pathway. Interestingly, binding to breast and prostate cancer patients with a moderate the Fc region of the neonatal receptor FcRn may to high risk of fracture, but the use of placebo com-

Belgian Journal of Medical Oncology volume 6, issue 4, 2012 119 4 Pharmacotherapy

plicates any meaningful comparisons to other (ge- SRE benefit was limited to patients with no or only nerically) available treatments. mild pain at baseline.16 The efficacy and safety of denosumab in patients with multiple myeloma has not been unequivocally Prevention of skeletal-related events demonstrated. In the small group of multiple my- in patients with bone metastases eloma patients (n=180) enrolled in the trial with Three large randomised controlled double-blind tri- various other histologies (n=1,776), the time to first als have compared denosumab 120mg SC q4w to on-study SRE was not different between denosum- zoledronic acid 4mg IV q4w in patients with bone ab and zoledronic acid (HR 1.03; 95% CI 0.68 - metastases from breast cancer, or prostate cancer 0.57; p=0.89).17,18 Suprisingly, OS in the multiple and rising PSA, and finally, another solid tumour or myeloma cohort was worse in denosumab treated multiple myeloma. In an integrated analysis of these patients (HR 2.26; 95% CI 1.13 – 4.50; p<0.05).17 trials including 5,723 patients, denosumab was However, these subgroup analyses may be biased convincingly non-inferior (primary end-point) to by differences in baseline prognostic factors and zoledronic acid in the time to the occurrence of a should therefore be considered carefully. A large first skeletal related event (SRE)(p<0.0001). In a dedicated trial in multiple myeloma patients subsequent pre-planned superiority analysis with (n=1,520) is currently recruiting. Reassuringly, correction for multiplicity, the confidence interval the OS and progression free survival (PFS) was not was found to exclude parity in favour of denosumab different between denosumab and zoledronic (HR 0.83; 95% CI 0.76 – 0.90; p<0.0001).13 More acid in any of the individual trials, nor in the inte- specifically, denosumab demonstrated a 17% rela- grated analysis.13 tive risk reduction in time to first SRE compared to zoledronic acid. Furthermore, denosumab was shown to be associated with an 18% relative risk reduction Safety in time to first and subsequent SREs, (HR[95%CI]: The safety profile of denosumab as used in the pre- 0.82[0.75-0.89]; p<0.0001).13 At 24 months, about vention of TIBL (60mg SC q6m) is favourable and 46% of patients in the zoledronic acid group was comparable to placebo.11,12 A similar dosing schedule SRE-free, compared to 53% with denosumab. From was used in the larger trials with women with post- these numbers, it can be estimated that approximately menopausal osteoporosis (n=6,000). Data from fifteen patients (95% CI 12 – 29) would need to be these studies show that denosumab is associated treated with denosumab for two years to keep one with skin conditions, including cellulitis, but the additional patient free of SREs (number needed to absolute risk difference with placebo was very small treat; NNT).14 The mean absolute differences at the (1.4%; 95% CI 0.7 – 2.1%).19 Transient hypocalcaemia level of individual SRE components between both with a nadir occurring approximately ten days after agents ranged from 0.2 to 3.1% (Figure 1), with the administration was more frequent with denosumab, largest difference in radiation to bone. but never clinically symptomatic. A number of subgroup analyses from these trials When used for the prevention of SREs (120mg have in the meantime been reported, indicating a SC q4w), hypocalcaemia and osteonecrosis of the potential role for pain as clinical predictor of benefit. jaw (ONJ) are the most important adverse effects of In breast cancer patients, the time to increase in denosumab therapy. In contrast, denosumab was reported pain was similar for both treatments (HR associated with 22% relative risk reduction in adverse 0.90; 95% CI 0.80 – 1.01; p=0.08), as was the onset renal events (p=0.001), and caused less acute phase of analgesic effect in patients with pain at onset of reactions in comparison with zoledronic acid.13 therapy (HR 1.02; 95% CI 0.91 – 1.15; p=0.72). Hypocalcaemia occurred in 9.6% of patients treated However, in a subgroup with no or mild pain at with denosumab, compared to 5.0% in the zole- baseline, a modest increase in the time to severe dronic acid group (RR 1.93; 95% CI 1.59 - 2.35; pain was observed with denosumab (HR 0.78; 95% p<0.0001).13 Similarly, grade 3 or 4 hypocalcaemia CI 0.67 – 0.92; p=0.002).15 Likewise, a subgroup was also more frequent with denosumab (3.0% vs analysis from the prostate cancer trial suggests that 1.2%; p<0.0001).17,20,21 Recently, rare cases of fatal

Belgian Journal of Medical Oncology volume 6, issue 4, 2012 120 Figure 1. Absolute frequency of skeletal complications in patients with bone metastases (data taken from the placebo arms of the registrational trials of pamidronate and zoledronic acid), and the impact of pamidronate, zoledronic acid, and denosumab therapy. [17, 20, 21] Abbreviations: BC=breast cancer; OST=other solid tumour; PC=prostate cancer; SRE=skeletal-related event. hypocalcaemia have also been reported as part of entity could be identified: dental extraction, poor post-marketing surveillance, with a possible asso- oral hygiene, or dental prosthesis.25 This finding ciation with impaired renal function and pre-existing emphasises the importance of adequate prevention borderline serum calcium levels.22 Due to the double- strategies for ONJ, including avoiding invasive blind design of the phase 3 trials, patients with a dental procedures during denosumab therapy. calculated clearance <30 ml/min were excluded, as the use of zoledronic acid would be off-label. There- fore, the experience with denosumab in patients Effect of modifying the bone micro- with impaired renal function is limited, but environment on disease recurrence this group may have a higher risk of symptomatic and progression hypocalcaemia. In these patients, active monitoring The anti-tumour effects of bisphosphonates and in of serum calcium is advised.23 particular of zoledronic acid have been convincingly The combined incidence of ONJ in the three regis- demonstrated in preclinical models.26 Nevertheless, trational trials was 1.8% in patients treated with despite some successes in the subgroup of post- denosumab, compared to 1.3% with zoledronic menopausal breast cancer patients and multiple acid (RR 1.40; 95% BI 0.92 – 2.13; p=0.11). How- myeloma, the current body of evidence has not been ever, with increasing exposure and in the trials deemed sufficiently compelling to be practice chang- demonstrating denosumab superiority, a numerical ing or warrant official registration by regulatory increase in ONJ risk was observed (RR 1.61; 95% authorities.27,28 Likewise, the use of denosumab to BI 0.99 – 2.62; p=0.052).24 In approximately 80% prevent the occurrence of bone metastases in high- of patients with ONJ, a known risk factor for this risk castrate-resistant prostate cancer patients (n=1,432)

Belgian Journal of Medical Oncology volume 6, issue 4, 2012 121 4 Pharmacotherapy

Key messages for clinical practice

• Denosumab is a fully human monoclonal antibody directed against the receptor activator of the nuclear factor κB ligand (RANKL), a powerful mediator of osteoclast differentiation and activation.

• Denosumab is administered subcutaneously, 60mg every six months for the treatment of treatment-induced bone loss in prostate cancer, and 120mg every four weeks for the prevention of skeletal-related events in patients with bone metastases from a solid tumour.

• Compared to zoledronic acid, denosumab offers a 17% relative risk reduction in the time to first SRE and a small improvement in quality of life scores, but no difference in (progression free) survival. There is no direct renal toxicity associated with denosumab and dose adjustments in patients with renal impairment are not required. Acute phase reactions occur less frequently with denosumab.

• Hypocalcaemia occurs more often with denosumab compared to zoledronic acid. In particular, patients with impaired renal function appear more susceptible to symptomatic hypocalcaemia, that in rare cases can be fatal. Supplemental calcium and vitamin D, as well as active monitoring of serum calcium is recommended.

• The incidence of ONJ is numerically higher with denosumab, underscoring the importance of adequate prevention strategies, with emphasis on avoiding invasive dental procedures during denosumab therapy.

has recently yielded very promising results with a plicate comparisons to existing (generic) treatments. median increase of bone-metastasis free survival In the setting of skeletal metastases, denosumab of 4.2 months compared to placebo (p=0.028).29 showed a modest clinical benefit over zoledronic acid However, due to the lack of an OS benefit (HR 1.01, with regard to both SREs and quality of life (includ- 95% CI 0. 85 - 1.20; p=0.91), combined with a 5% ing pain scores). As such, denosumab can be a valu- risk of ONJ, the use of denosumab in this setting able addition to the clinician’s toolbox because of the remains as yet off-label. Recently, RANK has also largely non-overlapping toxicity with bisphospho- been implicated in the pathogenesis of breast cancer, nates, with the exception of ONJ. This will enable a sparking interest in the potential inhibitory effect of tailored choice of bone modifying therapy based on denosumab on tumourigenesis.30 In patients with individual patient profile, incorporating factors such curatively treated breast cancer, the adjuvant use of as expected toxicity of concomitant anti-cancer therapy, denosumab to prevent recurrence is currently under availability of intravenous access, comorbidities such active investigation (D-CARE study) with final data as renal impairment, and finally patient preference. collection for the primary outcome measure expected Hypocalcaemia is more frequent with denosumab, in October 2016. including grade 3 and 4, and some fatal cases have recently emerged. In particular, patients with impaired renal function appear more susceptible to sympto- Conclusions matic hypocalcaemia and require close monitoring Denosumab is an attractive new treatment option for and correction of serum calcium levels. Prevention of the prevention of TIBL and skeletal complications in ONJ remains equally important with denosumab patients with bone metastases from a solid tumour. use, preferably in close cooperation with experienced However, the use of placebo in the TIBL studies com- dental professionals. Further health-economics research

Belgian Journal of Medical Oncology volume 6, issue 4, 2012 122 will be necessary to determine the cost-effectiveness 17. Henry DH, Costa L, Goldwasser F et al. Randomized, double-blind study of denosumab therapy, especially considering the of denosumab versus zoledronic acid in the treatment of bone metastases availability of generic zoledronic acid as early as the in patients with advanced cancer (excluding breast and prostate cancer) or end of next year. multiple myeloma. J Clin Oncol 2011;29:1125-32. 18. Henry D, von Moos R, Hungria V et al. Delaying skeletal-related events in a randomized phase III study of denosumab versus zoledronic acid in patients References with advanced cancer. J Clin Oncol 2010;28:9133. 1. Hadji P, Aapro MS, Body JJ et al. Management of aromatase inhibitor- 19. Center for Drug Evaluation and Research Food and Drug Administration. associated bone loss in postmenopausal women with breast cancer: prac- Background Document for Meeting of Advisory Committee for Reproductive tical guidance for prevention and treatment. Ann Oncol 2011;22:2546-55. Health Drugs. http://www.fda.gov/downloads/AdvisoryCommittees/Commit- 2. Coleman RE, McCloskey EV. Bisphosphonates in oncology. Bone teesMeetingMaterials/Drugs/ReproductiveHealthDrugsAdvisoryCommittee/ 2011;49:71-6. UCM176605.pdf (16/06/2012, date last accessed). 3. Katagiri T, Takahashi N. Regulatory mechanisms of osteoblast and 20. Stopeck AT, Lipton A, Body JJ et al. Denosumab compared with zole- osteoclast differentiation. Oral Dis 2002;8:147-59. dronic acid for the treatment of bone metastases in patients with advanced 4. Shahinian VB, Kuo YF, Freeman JL, et al. Risk of fracture after androgen breast cancer: a randomized, double-blind study. J Clin Oncol 2010;28:5132-9. deprivation for prostate cancer. N Engl J Med 2005;352:154-64. 21. Fizazi K, Carducci M, Smith M et al. Denosumab versus zoledronic acid 5. Roodman GD. Mechanisms of bone metastasis. N Engl J Med for treatment of bone metastases in men with castration-resistant prostate 2004;350:1655-64. cancer: a randomised, double-blind study. Lancet 2011;377:813-22. 6. Mundy GR. Metastasis to bone: causes, consequences and therapeutic 22. Amgen Canada Inc. XGEVA® (denosumab) – Risk of severe symptomatic opportunities. Nat Rev Cancer 2002; 2:584-93. hypocalcemia, including fatal cases. http://hc-sc.gc.ca/dhp-mps/alt_formats/ 7. Dougall WC. Molecular pathways: osteoclast-dependent and osteoclast- pdf/medeff/advisories-avis/prof/2012/xgeva_hpc-cps-eng.pdf (16/06/2012, independent roles of the RANKL/RANK/OPG pathway in tumourigenesis and date last accessed). metastasis. Clin Cancer Res 2012;18:326-35. 23. European Medicines Agency. CHMP assessment report for XGeva. 8. Lacey DL, Boyle WJ, Simonet WS et al. Bench to bedside: elucidation http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_ of the OPG-RANK-RANKL pathway and the development of denosumab. assessment_report/human/002173/WC500110384.pdf (16/06/2012, date Nat Rev Drug Discov 2012;11:401-19. last accessed). 9. Lipton A, Steger GG, Figueroa J et al. Randomized active-controlled 24. Van den Wyngaert T, Wouters K, Huizing MT, et al. RANK ligand inhibition phase II study of denosumab efficacy and safety in patients with breast cancer- in bone metastatic cancer and risk of osteonecrosis of the jaw (ONJ): non bis related bone metastases. J Clin Oncol 2007;25:4431-7. in idem? Support Care Cancer 2011;19:2035-40. 10. Fizazi K, Lipton A, Mariette X et al. Randomized phase II trial of denosumab 25. Saad F, Brown JE, Van Poznak C et al. Incidence, risk factors, and out- in patients with bone metastases from prostate cancer, breast cancer, or other comes of osteonecrosis of the jaw: integrated analysis from three blinded neoplasms after intravenous bisphosphonates. J Clin Oncol 2009;27:1564-71. active-controlled phase III trials in cancer patients with bone metastases. Ann 11. Ellis GK, Bone HG, Chlebowski R et al. Randomized trial of denosumab Oncol 2012;23:1341-7. in patients receiving adjuvant aromatase inhibitors for nonmetastatic breast 26. Clezardin P. Bisphosphonates’ antitumour activity: an unravelled side of a cancer. J Clin Oncol 2008;26:4875-82. multifaceted drug class. Bone 2011;48:71-9. 12. Smith MR, Egerdie B, Hernandez Toriz N et al. Denosumab in men re- 27. Gnant M, Mlineritsch B, Stoeger H et al. Adjuvant endocrine therapy plus ceiving androgen-deprivation therapy for prostate cancer. N Engl J Med zoledronic acid in premenopausal women with early-stage breast cancer: 2009;361:745-55. 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol 13. Lipton A, Siena S, Rader M et al. Comparison of denosumab versus 2011;12:631-41. zoledronic acid (ZA) for treatment of bone metastases in advanced cancer 28. Morgan GJ, Davies FE, Gregory WM et al. First-line treatment with zole- patients: an integrated analysis of 3 pivotal trials. Ann Oncol 2010;21:1249. dronic acid as compared with clodronic acid in multiple myeloma (MRC 14. Barratt A, Wyer P, Guyatt G, et al. NNT for studies with long-term follow- Myeloma IX): a randomised controlled trial. Lancet 2010;376:1989-99. up. Canadian Medical Association Journal 2005;172:613-5. 29. Smith MR, Saad F, Coleman R et al. Denosumab and bone-metastasis- 15. Stopeck A, Fallowfield L, Patrick D et al. Effects of denosumab versus free survival in men with castration-resistant prostate cancer: results of a zoledronic acid (ZA) on pain in patients (pts) with metastatic breast cancer: phase 3, randomised, placebo-controlled trial. Lancet 2012;379:39-46. Results from a phase III clinical trial. J Clin Oncol 2010;28:1024. 30. Palafox M, Ferrer I, Pellegrini P et al. RANK Induces Epithelial-Mesenchymal 16. Shore N, Smith M, Jievaltas M, et al. Effect of denosumab versus zoledronic Transition and Stemness in Human Mammary Epithelial Cells and Promotes acid in patients with castrate-resistant prostate cancer and bone metastases: Tumourigenesis and Metastasis. Cancer Res 2012;72:2879-88. Subgroup analyses by prior SRE and baseline pain. J Clin Oncol 2011;29:4533.

Belgian Journal of Medical Oncology volume 6, issue 4, 2012 123 4