Subsequent Skeletal-related Events Research Articles

Hospital use among patients with lung cancer complicated by bone metastases and skeletal- related events: a population-based cohort study in Denmark.

ObjectiveSkeletal-related events (SREs) among patients with bone metastases from lung cancer may be associated with considerable use of health care resources. We analyzed in- and outpatient hospital contacts in relation to SREs among all Danish lung cancer patients with bone metastases.MethodsFor this cohort study, we used the Danish Cancer Registry and the Danish National Registry of Patients to identify all persons diagnosed with first-time lung cancer and bone metastases from 2003 through 2009 in Denmark. We followed these patients until December 31, 2010, for the development of SREs (spinal cord compression; pathological or osteoporotic fracture, surgery to bone; or conventional external radiation therapy). We examined the number of inpatient hospitalizations, inpatient bed-days, hospital outpatient clinic visits, and emergency room visits within three time periods: a pre-SRE period (90-day period prior to the diagnostic period), a SRE diagnostic period (14-day period prior to the SRE), and a post-SRE period (90-day period after the SRE).ResultsWe identified 1,146 patients with lung cancer, bone metastases, and ≥1 subsequent SRE among 28,443 patients with incident lung cancer. Over 75% of patients with SREs (n=852) had more than one SRE. The number of hospital bed-days was high in the post-SRE period compared to the pre-SRE period, as illustrated by patients with multiple SREs who had 10.7 (95% confidence interval, 10.4–10.9) hospital bed-days per 100 person-days in the pre-SRE period and 28.2 (95% confidence interval, 27.8–28.6) bed-days per 100 person-days in the post-SRE period.ConclusionSREs secondary to bone metastases in lung cancer patients are associated with a substantial number of hospital contacts and hospital bed-days.

Cost-effectiveness Analysis of Denosumab in the Prevention of Skeletal-related Events in Patients with Prostate Cancer in Kazakhstan.

IntroductionBone mass loss (BML) is one of the adverse effects of oncological chemotherapy, especially in cases of hormonal types of cancer, such as a prostate cancer (PC). BML is strongly associated with skeletal-related events (SREs), therefore decreasing the quality of patient’s life. Denosumab shows an advantage over zoledronic acid (ZA) in delaying the first onset of SREs and subsequent SREs in adults with PC in several phase III clinical trials. Since generic ZA recently became available, the purpose of the present study was to assess the cost-effectiveness of denosumab vs. brand or generic ZA in the prevention of SREs in Kazakhstani patients with PC.MethodsA Markov model was constructed in Tree-Age Pro 2013 software program with 4-week model cycles to analyze the cost-effectiveness of the treatments from the perspective of Ministry of Health (MoH) over a 10-year PC cohort. Direct costs (in Kazakhstani monetary units “tenge” in 2014) included costs of drug, SRE (pathologic fracture, surgery to bone, radiation to bone, spinal cord compression), and adverse events treatment. All costs were discounted for 3% per year. Effectiveness was appraised based on the number of SREs. Health states were defined according to SRE occurrence, SRE history, and death. The model assumed that a maximum of 1 SRE could occur in each cycle. Transition probabilities were derived from the relevant phase III trials. Results were present in the incremental total cost per SRE avoided. One-way sensitivity analyses were performed to examine the robustness of the model.ResultsOver the 10-year period, denosumab incurred 103,091 tenge higher costs than brand ZA, 677,133 tenge higher costs than generic ZA, and 0.58 fewer SREs per patient with PC. The estimated incremental total direct costs per SRE avoided with the use of denosumab were 177,743 tenge (instead of brand ZA) and 1,167,470 tenge (instead of generic ZA). Results were robust to one-way sensitivity analyses.ConclusionsWith the assumption that brand and generic ZAs are equally effective in the prevention of SREs in PC patients, denosumab seems to be a cost-effective alternative for brand ZA (insignificant difference in costs – less than 5%) and a costly alternative for generic ZA from the perspective of MoH of Kazakhstan.

Bone metastasis, skeletal-related events, and mortality in lung cancer patients: A Danish population-based cohort study

ObjectivesTo estimate the incidence rate of bone metastasis and subsequent skeletal-related events (SREs) (radiation to bone, spinal cord compression, fracture, and surgery to bone) in lung cancer patients and to quantify their impact on mortality. Materials and methodsWe conducted a nationwide cohort study of patients diagnosed with lung cancer between 1999 and 2010 in Denmark. We computed the cumulative incidence (%) of bone metastasis and subsequent SREs (treating death as a competing risk) and corresponding incidence rates (per 1000 person-years). Survival was evaluated using the Kaplan–Meier method for three dynamic lung cancer patient cohorts–no bone metastasis; bone metastasis without SREs; and bone metastasis with SREs. Based on a Cox proportional hazards model, we computed mortality rate ratios (MRRs) comparing mortality rates between these patient cohorts, adjusting for age, comorbidity, stage, and histology. Analyses were conducted for the lung cancer patient cohort overall and by histologic subtype. ResultsWe identified 29,720 patients with incident lung cancer (median follow-up: 7.3 months). The 1-year cumulative incidence of bone metastasis was 5.9%, and the 1-year cumulative incidence of subsequent SREs was 55.0%. The incidence of bone metastasis and SREs was higher in patients with non-small cell lung cancer (NSCLC) versus SCLC. One-year survival was 37.4% in patients with no bone metastasis; 12.1% in patients with bone metastasis without SREs; and 5.1% in patients with both bone metastasis and SREs. When mortality rates between patients with bone metastasis with and without an SRE were compared, 2-month mortality rates were similar, but the >2-month adjusted MRR was 2.0 (95% confidence interval: 1.7–2.2). ConclusionBone metastases predict a poor prognosis in lung cancer patients. The majority of lung cancer patients with bone metastasis will also experience an SRE, which may further increase the rate of mortality.

Prevalence of first and subsequent skeletal-related events (SREs) in U.S. elderly patients with metastatic prostate cancer (mPC).

e16006 Background: SREs are common in men with mPC. While some real-world studies have estimated the prevalence of SREs, the majority don’t address the sequential pattern of first and subsequent SR...

PCN24 - Burden and Timing of First and Subsequent Skeletal Related Events (SRES) in United States Elderly Men with Metastatic Prostate Cancer (MPC)

PCN24 - Burden and Timing of First and Subsequent Skeletal Related Events (SRES) in United States Elderly Men with Metastatic Prostate Cancer (MPC)

MP78-02 CUMULATIVE INCIDENCE OF SKELETAL RELATED EVENTS IN MEN WITH METASTATIC PROSTATE CANCER BASED ON ALTERNATIVE ALGORITHMS

You have accessJournal of UrologyProstate Cancer: Epidemiology & Natural History III1 Apr 2014MP78-02 CUMULATIVE INCIDENCE OF SKELETAL RELATED EVENTS IN MEN WITH METASTATIC PROSTATE CANCER BASED ON ALTERNATIVE ALGORITHMS Abdulla M. Abdulhalim, Eberechukwu Onukwugha, Corinne Woods, Yi Qian, Jorge Arellano, Arun Balakumaran, C. Daniel Mullins, and Arif Hussain Abdulla M. AbdulhalimAbdulla M. Abdulhalim More articles by this author , Eberechukwu OnukwughaEberechukwu Onukwugha More articles by this author , Corinne WoodsCorinne Woods More articles by this author , Yi QianYi Qian More articles by this author , Jorge ArellanoJorge Arellano More articles by this author , Arun BalakumaranArun Balakumaran More articles by this author , C. Daniel MullinsC. Daniel Mullins More articles by this author , and Arif HussainArif Hussain More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2014.02.2485AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Skeletal related events (SREs) are common in men with metastatic prostate cancer (mPC). Several algorithms have been proposed to identify SREs when using claims data. Our aim was to determine how key components of algorithms for identifying SREs from claims impact results on cumulative incidence of SREs in men with mPC. METHODS Algorithms for identifying SREs were developed and applied to data for men aged ≥66 years diagnosed with mPC between 2000-2009 in the SEER-Medicare datasets and followed through 12/31/2010 or until they were lost to follow up. Post-diagnosis SREs were identified using claims that indicated spinal cord compression (SCC), pathologic fracture (PF), surgery to bone (SB), or radiation (suggestive of bone palliative radiation, RAD). Two key components defined alternative algorithms: the window length to consolidate SRE claims into events (14-, 21-, and 28-day windows) and the diagnosis and procedure codes used to identify SREs (′conservative′ and ′extended,′ e.g., PF ′conservative′ definition used codes that specifically indicated pathologic fracture and PF ′extended′ definition used codes that indicated any fracture without accidents/falls within 14 days before fracture). The base case algorithm used a ′conservative′ definition with a 21-day window. RESULTS Among 8,997 mPC men, 3,618 (40.2%) experienced an SRE according to the base case algorithm. Among those with an SRE, 2076 (57%) experienced a subsequent SRE. A total of 8,550 SREs were observed during follow up, with RAD, PF, SCC, and SB constituting 57%, 25%, 10%, and 8%, respectively. (Table) Varying the code definition from ′conservative′ to ′extended′ increased the cumulative incidence of SRE by 65% (Range: 15% [RB] - 200% [PF]). Varying the window length ±7 days from the 21-day base case resulted in a 7% change in SRE cumulative incidence (Range: 0.2% [SB] - 10% [RAD]). CONCLUSIONS The estimated cumulative incidence of SREs using claims data is mostly driven by code definition, and to a lesser extent, by window length. Across the 4 SREs, RAD is most affected by window length and PF is most affected by code definition. Investigators using claims to identify SREs should explicitly define their algorithm for SREs, including the algorithm components based on SRE type. SRE Window Length 14 days 21 days 28 days Ext. Cons. Ext. Cons. Ext. Cons. All SREs 16,313 9,845 14,100 8,550 12,926 7,928 Radiation 6,855 (42) 5,910 (60) 5,638 (40) 4,907 (57) 5,073 (39) 4,439 (56) Pathologic fracture 7,342 (45) 2,318 (23) 6,505 (46) 2,125 (25) 5,990 (46) 2,029 (26) Spinal cord compression 1,473 (9) 974 (10) 1,319 (9) 880 (10) 1,226 (10) 823 (10) Surgery to bone∗ 643 (4) 643 (7) 638 (5) 638 (8) 637 (5) 637 (8) Ext.: Extended code definition; Cons.: Conservative code definition All numbers in parentheses are column %. ∗ Only one set of codes was used for surgery to bone © 2014FiguresReferencesRelatedDetails Volume 191Issue 4SApril 2014Page: e920-e921 Advertisement Copyright & Permissions© 2014MetricsAuthor Information Abdulla M. Abdulhalim More articles by this author Eberechukwu Onukwugha More articles by this author Corinne Woods More articles by this author Yi Qian More articles by this author Jorge Arellano More articles by this author Arun Balakumaran More articles by this author C. Daniel Mullins More articles by this author Arif Hussain More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Denosumab: A bone antiresorptive drug

Bone remodeling is the continuous process by which old bone is removed by bone-resorbing cells, the osteoclasts and replaced by new bone synthesized by bone forming cells, the osteoblasts. Osteoporosis is characterized by a progressive loss of bone mass and microarchitecture, which leads to increased fracture risk. Denosumab, a human monoclonal antibody resembling natural IgG2 immunoglobulin, has antiresorptive activity and is distinguished from other antiresorptive drugs. It mimics osteoprotegerin (OPG) that binds to RANKL and hence does not allow RANKL to bind with RANK receptor, thereby inhibiting osteoclast differentiation, activation and survival exerting primarily antiresorptive action. Denosumab trials have shown its efficacy in postmenopausal women with osteoporosis, unresectable giant cell tumor of bone and significant effect in non-metastatic prostate cancer and delay in the time-to-first skeletal related events (SRE) and subsequent SRE with denosumab than zoledronic acid in patients. It is available as 60 mg/ml in pre-filled syringes and approved for osteoporosis in postmenopausal women (60 mg s.c. twice yearly), unresectable giant cell tumor of bone in adults and skeletally mature adolescents (120 mh s.c. monthly), prevention of skeletal-related events and to increase bone mass in patients at high risk for fracture including androgen deprivation therapy for non-metastatic prostate cancer or adjuvant aromatase inhibitor therapy for breast cancer. Denosumab offers advantages of twice yearly dosing in osteoporosis and monthly dosing in giant cell tumor of bone with its novel mechanism of action and better tolerability.

Abstract P1-16-01: Skeletal-related events (SRE) prevented in breast cancer patients with bone metastases in the United States (US)

Abstract Background: SREs are potentially debilitating consequences of bone metastases in advanced stage cancers. Bone-targeting agents (BTAs), including denosumab and intravenous zoledronic acid (ZA) are approved to prevent SREs. The purpose of this study was to estimate the annual number of SREs that might occur in US women with breast cancer without intervention, and to estimate the SREs that could be prevented with denosumab or with ZA. Methods: A model was developed using US prevalence estimates (Li, et al. 2011), combined with 2012 Census projections to estimate the number of SREs in women with bone metastases from breast cancer in 2012. SREs were defined as fracture, radiation to bone, surgery to bone, or spinal cord compression. The SRE rate in untreated patients was estimated by pooling rates from 8 treatment groups in 4 trials (Lipton 2000; Rosen 2003; Kohno 2005; Stopeck 2010), applying the appropriate relative hazard (RH) of first and subsequent SRE from a network meta-analysis (NMA;Ford 2012), and weighting by the sample size. The denosumab and ZA SRE rates were derived from the pooled rate and the RH estimates from the NMA. Ineligibility was defined as one of the following: all uninsured patients (US Census) and patients discontinuing due to adverse events or non-compliance (ZA 4.6%, denosumab 3.7%; Stopeck 2010). Patients with kidney clearance < 30 ml/min (1.3%; Launay-Vacher 2007) were considered ineligible to receive ZA. Using Monte Carlo sampling, we derived mean estimates and 95% simulation intervals (SI) based on 1,000 samples. Results: Overall, we estimated 96,598 women with breast cancer had bone metastases at any given time in 2012. We estimated 164,673 (95% SI 110,153 to 220,770) SREs would have occurred in 2012 if no women were treated. Assuming all women eligible to receive ZA were treated with ZA (n = 83,870), the number of SREs would have been 108,233 (decline of 56,440, 95% SI 13,744 to 100,098); assuming all women eligible to received denosumab were treated with denosumab (n = 85,780), the number of SREs would have been 86,992 (decline of 77,681, 95% SI 38,327 to 120,521). The incremental difference between denosumab and ZA was 21,242 (95% SI 9,312 to 36,674). Conclusions: The use of BTAs to reduce SRE risk, including denosumab, could result in reductions in the number of adverse skeletal complications in the US. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-16-01.

Denosumab and zoledronic acid treatment in patients with genitourinary cancers and bone metastases.

5079 Background: Phase III trial results showed that denosumab is superior to zoledronic acid (ZA) in preventing skeletal-related events (SREs) in patients with cancer and metastatic bone disease (Lipton et al; 2012, Eur J Cancer). Genitourinary (GU) cancers are some of the most commonly diagnosed cancers worldwide. We now compare the efficacy and safety of denosumab (DMAb) or ZA in a subgroup analysis of patients with GU cancers enrolled in the pivotal phase III trials. Methods: Patients were randomized 1:1 to receive DMAb (120 mg, SC) or ZA (4 mg, IV, adjusted for renal function) every 4 weeks. Daily calcium and vitamin D supplements were strongly recommended. Time to 1st on-study SRE, using a Cox proportional hazards model, time to 1st and subsequent on-study SRE, using the Anderson-Gill model, and safety were evaluated for the GU subgroup in an ad hoc analysis. Results: 2,128 patients (1,052 DMAb; 1,076 ZA) had GU cancers (prostate = 1,901, renal = 155, bladder = 63, and transitional cell = 9). DMAb significantly delayed the time to 1st on-study SRE by 4.0 months compared with ZA (20.7 months vs 16.7 months) in patients with GU cancers (Table). DMAb also significantly delayed the time to 1st and subsequent on-study SRE. Time to disease progression and overall survival were similar between treatment groups. Adverse events (AEs) and serious AEs were reported by similar percentages of patients in both groups (AEs: 96.9% denosumab, 96.8% ZA; serious AEs: 62.8% denosumab, 60.2% ZA). 14.6% of DMAb pts and 15.9% of ZA pts had a renal AE. Hypocalcemia was reported for 12.9% of DMAb patients and 6.2% of ZA patients. There was no significant difference in the incidence of positively adjudicated osteonecrosis of the jaw between the DMAb (2.2%) and ZA (1.6%) groups (p=0.34). Conclusions: Among patients with GU cancers and metastatic bone disease, DMAb was superior to ZA in preventing SREs. Clinical trial information: NCT00330759 and NCT00321620. [Table: see text]

Hospital visits among women with skeletal-related events secondary to breast cancer and bone metastases: a nationwide population-based cohort study in Denmark

ObjectiveSkeletal-related events (SREs) among women with breast cancer may be associated with considerable use of health-care resources. We characterized inpatient and outpatient hospital visits in a national population-based cohort of Danish women with SREs secondary to breast cancer and bone metastases.MethodsWe identified first-time breast cancer patients with bone metastases from 2003 through 2009 who had a subsequent SRE (defined as pathologic fracture, spinal cord compression, radiation therapy, or surgery to bone). Hospital visits included the number of inpatient hospitalizations, length of stay, number of hospital outpatient clinic visits, and emergency room visits. The number of hospital visits was assessed for a pre-SRE period (90 days prior to the diagnostic period), a diagnostic period (14 days prior to the SRE), and a post-SRE period (90 days after the SRE). Patients who experienced more than one SRE during the 90-day post-SRE period were defined as having multiple SREs and were followed until 90 days after the last SRE.ResultsWe identified 569 women with SREs secondary to breast cancer with bone metastases. The majority of women had multiple SREs (73.1%). A total of 20.9% and 33.4% of women with single and multiple SREs died in the post-SRE period, respectively. SREs were associated with a large number of hospital visits in the diagnostic period, irrespective of the number and type of SREs. Women with multiple SREs generally had a higher number of visits compared to those with a single SRE in the post-SRE period, eg, median length of hospitalization was 5 days (interquartile range 0–15) for women with a single SRE and 13 days (interquartile range 4–30) for women with multiple SREs.ConclusionSREs secondary to breast cancer and bone metastases were associated with substantial use of hospital resources.

Bone Metastases and Skeletal-Related Events in Patients With Malignant Pheochromocytoma and Sympathetic Paraganglioma

Bone metastases (BM) can cause severe pain, spinal cord compression, pathological fractures, and/or hypercalcemia. These skeletal-related events (SREs) may cause immobilization, loss of independence, poor quality of life, and reduced survival. There is limited information on the clinical effects of BM and SREs in patients with malignant pheochromocytoma or sympathetic paraganglioma (PHEO/sPGL). We studied the prevalence and clinical characteristics of BM and SREs in patients with PHEO/sPGL and investigated the risk factors for SRE development. Using a large institutional database, we conducted a retrospective study of 128 patients with malignant PHEO/sPGL at The University of Texas MD Anderson Cancer Center from 1967 through 2011. Of the patients, 91 (71%) had BM, and 57 of these (63%) developed metachronous BM at a median time of 3.4 years (range, 5 months to 23 years) after the primary tumor diagnosis. Metastatic disease was confined exclusively to the skeleton in 26 of 128 (20%) patients. Sufficient information to assess SRE occurrence was available for 67 patients, and 48 of 67 (72%) patients had at least 1 SRE. The median overall survival for the 128 patients was 12 years for patients with only BM, 7.5 years for patients with nonosseous metastases, and 5 years for patients with both BM and nonosseous metastases (log rank test P value = .005). We were unable to identify factors predictive of SRE development, but the occurrence of a first SRE was associated with the development of subsequent SREs in 48% of subjects. In responsive patients, the use of systemic therapy was associated with fewer SREs (P < .0001). BM and SREs are frequent in patients with malignant PHEO/sPGL. SREs often develop shortly after the diagnosis of BM; severe pain is the most frequent SRE. These patients should be followed long-term by a multidisciplinary team to promptly identify the need for medical or surgical intervention.

Abstract P3-13-05: Evaluating efficacy of de-escalated bisphosphonate therapy in metastatic breast cancer patients at low-risk of skeletal related events. TRIUMPH: A pragmatic multicentre trial.

Abstract Background: Optimal bisphosphonate (BP) dosing intervals for breast cancer patients (pts) with bone metastases (BM) remain unknown. BP are usually prescribed q3-4 wk regardless of individual pt risk for skeletal related events (SREs). Recent evidence (Amadori J Clin Oncol, 2012 suppl; abstr 9005) shows that q12 wk BP is as effective as q4 wk in pts previously treated with &amp;gt;9 cycles of q4 wk therapy. Hence, further evaluation of modified BP dosing strategies is warranted. The objective of the current study was to show in women with biochemically defined low-risk bone disease that IV BP use every q12 wk for 1 year is sufficient to maintain stability of the bone turnover [measured by serum c-telopeptide (CTx) or bone specific alkaline phosphatase (BSAP)]. Methods: Eligible pts with BM, who had received &amp;gt;3 months of q3-4 wk IV BP and no systemic treatment change within 4 wks of study entry were enrolled. Low risk was defined as serum CTx &amp;lt;600 ng/L. Biochemical failure was defined as CTx levels &amp;gt;600 ng/L at baseline, weeks 6, 12, 24, 36 or 48. Evaluation of palliative benefit of 12-wk IV BP therapy was measured by SREs, analgesic use, and self-reported pain (BPI and FACT-BP). Results: Between Oct. 2010-Sept. 2011, 85 pts consented to screening, with 13 found ineligible. In the 71 accrued pts baseline characteristics were: mean age 60 (SD 13), median time from breast cancer diagnosis to development of bone metastases 4 months (IQR 82), median duration of prior BP therapy 14 months (IQR 19), and mean number of SREs/yr prior to entering study 0.35 (SD 0.76). Baseline median CTx was 120 ng/L (IQR 240) and BSAP 9.2 IU/L (IQR 3). To date: 26/71 pts (36%) remain on study. Reasons for coming off study include; study completion (18), elevation of CTx &amp;gt;600ng/L (10), or on study SRE (3). An elevation of CTx between baseline and wk 6 was significantly associated with coming off study early (p = 0.008). For pts who had had an SRE before study entry the odds ratios for coming off study early due to an on study SRE or elevated CTx was 1.005 (CI 1.002–1.009; p = 0.007) and for coming off early for an SRE was 0.0245 (CI 0.061–0.094; p = 0.046) respectively. Of the 8/13 pts who were ineligible due to baseline CTx &amp;gt;600ng/L, 6 had an SRE within 1 year of screening. Conclusion: De-escalating BP therapy to 12 weekly in low risk pts has advantages for both the pt and the health care system. Individual risk of SREs is highly variable, however baseline serum CTx levels &amp;lt;600 ng/L is associated with a low risk of subsequent SREs. While larger trials are required to assess whether increasing CTx with de-escalated therapy will lead to higher rates of SREs or not (Coleman et al. J Clin Oncol 2012 suppl; abstr 511). However, the results of this study and Amadori et al. would suggest that de-escalated BP treatment will likely become a new standard of care after a limited period of q 4wk treatment. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-13-05.

Management of skeletal-related events in patients with advanced prostate cancer and bone metastases: Incorporating new agents into clinical practice.

Skeletal-related events (SREs) are a common complication of bone metastases, and have serious negative consequences for patients with castrate-resistant prostate cancer (CRPC). SREs can lead to severe pain, increased risk of death, increased health care costs and reduced quality of life. Until recently, zoledronic acid has been the sole standard of care for the prevention of SREs in men with CRPC with bone metastases. Denosumab, a receptor activator of nuclear factor kappa-B ligand (RANK-L) inhibitor, has been recently approved for use in Canada for this indication, thus presenting another option for these patients. Denosumab was shown to be superior to zoledronic acid in delaying the time to first or subsequent SREs in CRPC patients with bone metastases. This review discusses current and previous trials examining agents designed to prevent SREs in men with CRPC and bone metastases. It also discusses the practical aspects of administering a bone-targeted therapy, including choosing a bone-targeted therapy, monitoring at the onset and during therapy, switching from one therapy to another, and assessing potential complications.

Management of skeletal-related events in patients with advanced prostate cancer and bone metastases: Incorporating new agents into clinical practice

Skeletal-related events (SREs) are a common complication of bone metastases, and have serious negative consequences for patients with castrate-resistant prostate cancer (CRPC). SREs can lead to severe pain, increased risk of death, increased health care costs and reduced quality of life. Until recently, zoledronic acid has been the sole standard of care for the prevention of SREs in men with CRPC with bone metastases. Denosumab, a receptor activator of nuclear factor kappa-B ligand (RANK-L) inhibitor, has been recently approved for use in Canada for this indication, thus presenting another option for these patients. Denosumab was shown to be superior to zoledronic acid in delaying the time to first or subsequent SREs in CRPC patients with bone metastases. This review discusses current and previous trials examining agents designed to prevent SREs in men with CRPC and bone metastases. It also discusses the practical aspects of administering a bone-targeted therapy, including choosing a bone-targeted therapy, monitoring at the onset and during therapy, switching from one therapy to another, and assessing potential complications.

JS4-5 - Progress and Future of Bone-Targeted Therapy

ABSTRACT Breast cancer is known to be associated with a high incidence of bone metastases. Recent advances in treatment of breast cancer have improved the prognosis, including in patients with bone metastasis, highlighting the importance of treating bone metastasis to reduce incidence of skeletal complications and improve patients' quality of list (QOL). It has become evident that bone microenvironment such as interaction of cancer cells and osteoclasts or osteoblasts is important for establishment and progression of bone metastases. Bone-targeted therapy that modulates osteoclasts or osteoblasts has been developed recently. Bisphosphonates (BPs), especially zoledronic acid, decrease skeletal-related events (SRE) and are commonly used for the treatment of bone metastasis. BPs have shown evidences of anti-tumor efficacy in several clinical trials, such as ABCSG-12 and AZURE. However, the outcomes of BP therapy leave room for the improvement with regards to their efficacy, safety and convenience, and other bone-targeted therapies are also being developed. Many studies have indicated that receptor-activator of NFkappaB ligand (RANKL) plays an important role in bone resorption by osteoclasts. Denosumab is a fully human monoclonal anti-RANKL antibody, which suppresses differentiation, activation, and survival of osteoclasts by inhibiting the binding of RANKL to its receptor, RANK. In a phase III clinical trial, denosumab significantly decreased the time-to-first and time-to-first and subsequent SRE compared with zoledronic acid in advanced breast cancer patients with bone metastases, and denosumab was recently approved for bone lesions of solid cancer and myeloma. Other targeted agents such as SRC inhibitors and c-MET inhibitors are also being developed. Bone metastasis treatment for cancer patients is expected to evolve further with the development of new bone-targeted agents in the near future.

Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: A combined analysis of 3 pivotal, randomised, phase 3 trials

BackgroundPatients with bone metastases from advanced cancer often experience skeletal-related events (SRE), which cause substantial pain and morbidity. Denosumab, a fully human monoclonal antibody that inhibits RANK Ligand (RANKL), is a novel bone-targeted agent with a distinct mechanism of action relative to the bisphosphonate zoledronic acid, for prevention of SRE. This pre-planned analysis evaluates the efficacy and safety of denosumab versus zoledronic acid across three pivotal studies. MethodsPatient-level data from three identically designed, randomised, double-blind, active-controlled, phase 3 trials of patients with breast cancer, prostate cancer, other solid tumours or multiple myeloma were combined. End-points included time to first SRE, time to first and subsequent (multiple) SRE, adverse events, time to disease progression and overall survival. FindingsDenosumab was superior to zoledronic acid in delaying time to first on-study SRE by a median 8.21months, reducing the risk of a first SRE by 17% (hazard ratio, 0.83 [95% confidence interval (CI): 0.76–0.90]; P<0.001). Efficacy was demonstrated for first and multiple events and across patient subgroups (prior SRE status; age). Disease progression and overall survival were similar between the treatments. In contrast to zoledronic acid, denosumab did not require monitoring or dose modification/withholding based on renal status, and was not associated with acute-phase reactions. Hypocalcaemia was more common for denosumab. Osteonecrosis of the jaw occurred at a similar rate (P=0.13). ConclusionDenosumab was superior to zoledronic acid in preventing SRE with favourable safety and convenience in patients with bone metastases from advanced cancer.

Cost-Effectiveness of Denosumab Compared With Zoledronic Acid in Patients With Breast Cancer and Bone Metastases

BackgroundResults from a phase III clinical trial showed that denosumab significantly reduced the risk of first on-study and subsequent skeletal-related events (SREs) compared with zoledronic acid. This study aims to assess the cost-effectiveness of denosumab vs. zoledronic acid in the prevention of SREs in patients with advanced breast cancer and bone metastases. Materials and MethodsA Markov model was developed with 4-week model cycles and a 1-year time horizon. The health states were defined by SRE status (no SRE, first on-study SRE, subsequent SRE, no SRE but history of SRE) and SRE type (pathologic fracture, radiation to the bone, surgery to the bone, spinal cord compression). Costs (in 2011 US dollars) included drug, SRE treatment, and adverse event (AE) costs and were assessed from a third-party payer perspective. The primary outcome was incremental total cost per SRE avoided; the secondary outcome was incremental total cost per pathologic fracture avoided. One-way and probabilistic sensitivity analyses were used to assess the robustness of the model. ResultsDuring the 1-year treatment period, denosumab incurred $7522 higher costs ($30,033 for denosumab and $23,511 for zoledronic acid), 0.06 fewer SREs, and 0.02 fewer pathologic fractures per patient, which led to an incremental total cost per SRE and pathologic fracture avoided of $114,628 and $290,136, respectively, compared with zoledronic acid. Results were robust to 1-way and probabilistic sensitivity analyses. ConclusionAlthough denosumab demonstrated superiority in preventing SREs in the phase III trial, it may not be cost-effective compared with zoledronic acid because of its high cost.

Cost-Effectiveness of Denosumab Versus Zoledronic Acid in the Management of Skeletal Metastases Secondary to Breast Cancer

BackgroundDenosumab has been approved in the United States for the prevention of skeletal-related events (SREs) in metastatic breast cancer. In a Phase III trial in patients with bone-metastatic breast cancer (N = 2033), denosumab was associated with a significantly delayed time to first SRE (by 18%; P < 0.001 noninferiority; P = 0.01 superiority) and time to first and subsequent SREs (by 23%; P = 0.001). Overall survival (HR = 0.95; 95% CI, 0.81–1.11; P = 0.49) and disease progression (HR = 1.00; 95% CI, 0.89–1.11; P = 0.93) did not differ significantly between groups. Denosumab was associated with a nonsignificant reduction in serious adverse events (44.4% vs 46.5%). ObjectivesGiven the current ambiguity regarding the cost-effectiveness of these agents in light of these trial outcomes, the present analysis assessed, from a US payer perspective, the cost-effectiveness of denosumab versus zoledronic acid in patients with bone metastases secondary to breast cancer. MethodsA literature-based Markov model was developed to estimate the survival, quality-adjusted life-years (QALYs) gained, number and costs of SREs, and drug and administration costs in patients receiving denosumab or zoledronic acid over 27 and 60 months. Clinical inputs reproduced the trial outcomes. SRE-related costs and utilities were literature based. Costs and QALYs were discounted 3% annually. ResultsIn the 27-month base-case analysis, denosumab was associated with fewer SREs (−0.298), more QALYs (+0.0102), and lower SRE-related costs (−$2016), but higher drug-related (+$9123) and total costs (+$7107) versus zoledronic acid. The cost per QALY gained (ie, incremental cost-effectiveness ratio [ICER]) was $697,499. In sensitivity analyses, the ICER ranged from $192,472 to $1,340,901/QALY, depending on assumptions regarding treatment benefits, drug costs, and analytical horizon. In the probabilistic sensitivity analysis, denosumab was cost-effective in 2 of 5000 modeled replicates (0.04%). ConclusionsDespite the limitations of restricted availability of clinical data and uncertainty regarding the price of generic zoledronic acid, the findings from the present analysis suggest that the use of denosumab is associated with a high ICER compared with zoledronic acid. This finding may raise important questions regarding the economic value of denosumab in bone-metastatic breast cancer.

AOS13 Denosumab versus zoledronic acid for the prevention of skeletal-related events in patients with bone metastases secondary to solid tumours: An integrated analysis of three phase 3 studies

Background Skeletal-related events (SREs) cause significant morbidity in patients with solid tumours and bone metastases (BMs). An ad hoc analysis was undertaken to compare the effect of denosumab with zoledronic acid (ZA) in the prevention of SREs in patients with BMs secondary to solid tumours who participated in the denosumab pivotal phase 3 studies. Methods Patients with breast cancer ( N = 2046), prostate cancer ( N = 1901), or other solid tumours ( N = 1597) and BMs were randomly assigned in a 1:1 ratio to receive subcutaneous denosumab 120 mg or IV ZA 4 mg (adjusted for renal function) every 4 weeks. Patient-level data from three identically designed, double-blind, double-dummy studies were combined. Time to first on-study SRE and time to first and subsequent SREs were analysed using the Cox proportional hazards model and Anderson–Gill method, respectively. Findings Patients received denosumab ( N = 2776) or ZA ( N = 2768). Denosumab was superior to ZA in delaying time to first on-study SRE and time to first and subsequent SREs. Denosumab reduced the risk of a first SRE by 18% compared with ZA (HR 0.82 [95% confidence interval (CI): 0.75, 0.89], p p p = 0.18) were similar in both groups. Hypocalcaemia was more frequent with denosumab (9.5% versus 4.8% for ZA) and acute phase reactions (first 3 days) were more common with ZA (20.4% versus 8.7% for denosumab). Interpretation This integrated analysis confirmed results from the individual studies; denosumab was superior to ZA in reducing the risk of both first and multiple SREs among patients with solid tumours and BMs. Funding Amgen Inc. A.T. Stopeck is a consultant for Amgen and Novartis; G. Richardson has received honoraria and research funding from Amgen; S. Siena has no conflicts of interest to declare; A. Lipton is a member of the speakers’ bureau, is a consultant, has received research support from Amgen and Novartis, and has provided expert testimony for Novartis; J. Brown has received consultancy fees from Amgen and Novartis, and payment for lectures from Amgen, Novartis, and Bayer; K. Fizazi has participated in Advisory Boards for Amgen and Novartis; D. Henry is a member of the speakers’ bureau, has participated in research and advisory boards for Amgen and Johnson and Johnson; F. Saad is a consultant and has carried out research for Amgen and Novartis; C. Ke and A. Braun are employed by Amgen and own stock.

Role of denosumab in prostate cancer

Prostate cancer is known to have a tissue tropism for bone. This tissue tropism coupled with the experience with androgen deprivation therapy (ADT) over the past decade has led to heightened awareness of bone complications. Osteopenia and subsequent skeletal-related events (SREs) are one of the more concerning repercussions of ADT along with cardiovascular sequelae. To combat this decrease in bone mineral density, several agents have been developed for bone protection. The largest experience is with bisphosphonates (BPs), but recently (2011) head to head trials have established the role of monoclonal antibodies, particularly in patients with prostate cancer bone metastasis. For patients initiating ADT, monthly denosumab increased bone mineral density, the time for occurrence of any bone metastasis and time for symptomatic bone metastasis. Denosumab is a fully human monoclonal antibody of the IgG(2) subtype that selectively binds and neutralizes receptor activator NF kappa B ligand (RANKL), inhibiting osteoclastogenesis and bone turnover. In vitro binding assays have shown high-affinity binding of denosumab and osteoprotegerin to both soluble and membrane-bound forms of human RANKL. As clinicians may be less familiar with this newer agent, we compiled this review to summarize denosumab's current clinical indications for bone stabilization and mechanism of reduction in tumor burden.