Risk Of Skeletal-related Events Research Articles

Abstract P1-20-02: A machine learning approach to identify risk factors associated with skeletal-related events following denosumab cessation among patients with bone metastases from breast cancer

Abstract Background: The anti-RANKL monoclonal antibody denosumab has been demonstrated to be superior to the bisphosphonate zoledronate in preventing skeletal-related events (SREs) among patients with incident bone metastases (BMs) from solid tumors (STs), including breast cancer. Clinical guidelines recommend the use of a bone-targeting agent for SRE prevention for ≥2 years. However, the denosumab treatment duration is often <1 year in the US. We applied a supervised machine learning approach using real-world data to estimate patient-level SRE risk following cessation of denosumab and determine risk factors associated with increased SRE risk. The method selected prior SREs, shorter denosumab treatment duration, and higher number of clinic visits as the top-ranked risk factors among a diverse group of patients with BMs from STs (Stopeck et al., ASCO 2021). Here, we report the top-ranked risk factors for the subgroup of patients with BMs from breast cancer. Methods: Using the Optum PanTher Electronic Health Record repository, patients diagnosed with incident BMs from a primary ST between January 1, 2007, and September 1, 2019, were evaluated for inclusion in the study. Eligible patients must have received ≥2 consecutive 120 mg denosumab doses on every 4-week (±14 days) schedule and had a minimum follow-up ≥1 year after the last denosumab dose or an SRE occurrence between days 84 and 365 following denosumab cessation. An SRE risk prediction model was developed using extreme gradient boosting and evaluated on an independent test dataset. Multiple variables associated with patient demographics, comorbidities, laboratory values, treatments, and denosumab exposures were examined as potential risk factors for SREs. After denosumab cessation, the impact and relative importance of these factors were extracted from the model using Shapley Additive Explanations (SHAP). In addition, findings from univariate analyses on risk factors with high importance from the breast cancer model were reported. Results: Of 1414 patients who met the inclusion criteria, 563 (40%) had BMs from breast cancer. Following denosumab cessation, 167 (30%) patients in the breast cancer subgroup experienced ≥1 SRE. The breast cancer model performance was meaningful, as evidenced by the area under the receiver operating characteristic (AUROC) score of 73%. SHAP resulted in several significant factors that predicted an increased SRE risk for the subgroup following denosumab cessation, including denosumab treatment duration of ≤8 months, prior SREs, and an average of >2 clinic visits per month (Table). Univariate analyses showed a positive correlation between increased SRE risk and prior SREs, while they revealed an inverse relationship between increased SRE risk and longer durations of denosumab. Conclusion: Shorter denosumab treatment duration, prior SREs, and higher number of clinic visits are top-ranked risk factors associated with SREs after discontinuation of denosumab treatment in patients with BMs from STs, including breast cancer. A machine learning approach to SRE risk factor identification may help clinicians assess the risks of discontinuing denosumab treatment and improve clinical outcomes for patients with BMs from breast cancer. SHAP Risk Factors That Increase SRE Risk 3-12 Months After Denosumab Cessation in Patients With BMsDenosumab therapy decisions: denosumab duration ≤8 months, time to denosumab initiation ≤2 months after BM diagnosisPrior SREs: ≥2 cumulative number of SREs since baseline up to cessationa, SRE occurrence (from denosumab initiation to cessation)Comorbidities: patients with anxietyVisits: >2 average number of visits per month (hospitalization, emergency room, and other visits [excluding nonphysician interaction]), ≥1 hospitalization, ≥1 emergency room visitaBaseline was defined as 180 days before the date of initial BM diagnosis. BM, bone metastasis; SHAP, Shapley Additive Explanations; SRE, skeletal-related event Citation Format: Alison Stopeck, Celestia Higano, David Henry, Basia Bachmann, Marko Rehn, Dionna Jacobson, Benoit Cadieux, Hossam Saad. A machine learning approach to identify risk factors associated with skeletal-related events following denosumab cessation among patients with bone metastases from breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-20-02.

Bone Metastases, Skeletal-Related Events, and Survival in Patients With Metastatic Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors.

Bone metastases and skeletal-related events (SREs) are a frequent cause of morbidity in patients with metastatic non-small cell lung cancer (mNSCLC). Data are limited on bone metastases and SREs in patients with mNSCLC treated using immune checkpoint inhibitors (ICIs), and on the efficacy of bone-modifying agents (BMAs) in this setting. Here we report the incidence, impact on survival, risk factors for bone metastases and SREs, and impact of BMAs in patients with mNSCLC treated with ICIs in a multi-institutional cohort. We conducted a retrospective study of patients with mNSCLC treated with ICIs at 2 tertiary care centers from 2014 through 2017. Overall survival (OS) was compared between patients with and without baseline bone metastases using a log-rank test. A Cox regression model was used to evaluate the association between OS and the presence of bone metastases at ICI initiation, controlling for other confounding factors. We identified a cohort of 330 patients who had received ICIs for metastatic disease. Median patient age was 63 years, most patients were treated in the second line or beyond (n=259; 78%), and nivolumab was the most common ICI (n=211; 64%). Median OS was 10 months (95% CI, 8.4-12.0). In our cohort, 124 patients (38%) had baseline bone metastases, and 43 (13%) developed SREs during or after ICI treatment. Patients with bone metastases had a higher hazard of death after controlling for performance status, histology, line of therapy, and disease burden (hazard ratio, 1.57; 95% CI, 1.19-2.08; P=.001). Use of BMAs was not associated with OS or a decreased risk of SREs. Presence of bone metastases at baseline was associated with a worse prognosis for patients with mNSCLC treated with ICI after controlling for multiple clinical characteristics. Use of BMAs was not associated with reduced SREs or a difference in survival.

Association of Concomitant Bone Resorption Inhibitors With Overall Survival Among Patients With Metastatic Castration-Resistant Prostate Cancer and Bone Metastases Receiving Abiraterone Acetate With Prednisone as First-Line Therapy

Bone resorption inhibitors (BRIs) are recommended by international guidelines to prevent skeletal-related events (SREs) among patients with metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. Abiraterone acetate with prednisone is currently the most common first-line therapy for the treatment of patients with mCRPC; however, the clinical impact of the addition of BRIs to abiraterone acetate with prednisone in this disease setting is unknown. To evaluate the association of the use of concomitant BRIs with overall survival (OS) and time to first SRE among patients with mCRPC and bone metastases receiving abiraterone acetate with prednisone as first-line therapy. This retrospective cohort study collected data from 745 consecutive patients who began receiving abiraterone acetate with prednisone as first-line therapy for mCRPC with bone metastases between January 1, 2013, and December 31, 2016. Data were collected from 8 hospitals in Canada, Europe, and the US from June 15 to September 15, 2019. Patients were classified by receipt vs nonreceipt of concomitant BRIs and subclassified by volume of disease (high volume or low volume, using definitions from the Chemohormonal Therapy Vs Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer [CHAARTED] E3805 study) at the initiation of abiraterone acetate with prednisone therapy. The primary end point was OS. The secondary end point was time to first SRE. The Kaplan-Meier method and Cox proportional hazards models were used. Of the 745 men (median age, 77.6 years [interquartile range, 68.1-83.6 years]; 699 White individuals [93.8%]) included in the analysis, 529 men (71.0%) received abiraterone acetate with prednisone alone (abiraterone acetate cohort), and 216 men (29.0%) received abiraterone acetate with prednisone plus BRIs (BRI cohort). A total of 420 men (56.4%) had high-volume disease, and 276 men (37.0%) had low-volume disease. The median follow-up was 23.5 months (95% CI, 19.8-24.9 months). Patients in the BRI cohort experienced significantly longer OS compared with those in the abiraterone acetate cohort (31.8 vs 23.0 months; hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; P < .001). The OS benefit in the BRI cohort was greater for patients with high-volume vs low-volume disease (33.6 vs 19.7 months; HR, 0.51; 95% CI, 0.38-0.68; P < .001). The BRI cohort also had a significantly shorter time to first SRE compared with the abiraterone acetate cohort (32.4 vs 42.7 months; HR, 1.27; 95% CI, 1.00-1.60; P = .04), and the risk of a first SRE was more than double in the subgroup with low-volume disease (HR, 2.29; 95% CI, 1.57-3.35; P < .001). In the multivariable analysis, concomitant BRIs use was independently associated with longer OS (HR, 0.64; 95% CI, 0.52-0.79; P < .001). In this study, the addition of BRIs to abiraterone acetate with prednisone as first-line therapy for the treatment of patients with mCRPC and bone metastases was associated with longer OS, particularly in patients with high-volume disease. These results suggest that the use of BRIs in combination with abiraterone acetate with prednisone as first-line therapy for the treatment of mCRPC with bone metastases could be beneficial.

Novel CT-Based Bone Strength Assessment By Finite Element Analysis for Monitoring Bone Involvement in Myeloma: a Proof of Concept Study

IntroductionMyeloma (MM) is characterized by osteolytic bone disease, detected in up to 80% of patients, increasing the risk for skeletal related events (SREs), causing morbidity, undermining quality of life and impairing survival. Current imaging modalities provide qualitative measures of bone involvement, often after irreversible damage has occurred.Bone strains are a biomechanical measure of bone strength which quantifies bone relative deformation in response to applied force. As a result of load on bone strains develop which may lead to fracture, once strain magnitude reaches the yield strain. Lytic bone lesions cause local weakening expressed by an increase in local strains.We developed CT-based finite element analysis (CTFEA), a novel measure designed to accurately estimate bone strains based on conventional CT scans. We hypothesize this tool may enable quantifying changes in bone strength over time, by monitoring strain. In this concept study we explore the sensitivity and responsiveness of CTFEA in myeloma patients to detect bone-disease progression and treatment response, and explore clinical correlates.MethodsPatients: A pilot retrospective study. After approval by the institutional ethics committee, 16 MM patients, with at least 2 consecutive CT scans including the spine and at least the proximal 1/3 of the femur since 2010 were identified. Demographic, clinical and radiographic data were abstracted from medical records.CTFEA: Femurs of interest were segmented from the CT scan, and a computational model was created with “stiffness” changing from point to point according to CT's gray values. The computational model was loaded virtually with a physiological stance position contact hip force (2.5 X body weight) applied on the femur's head. An elastic finite element analysis was performed that predicts the displacements and strains at any point within the bone (Figure 1). The locations of interest where the larger change in material properties may occur between consecutive CT scans were determined by computing the relative difference in Hounsfield unit (HU) radio-density along bone's axis. At these locations the principal strains were extracted and monitored. A monotonic increase in strains implies deterioration of bone strength, and vice versa. For patients with lytic lesions, bone strength is quantified by monitoring the principal strains in lesions vicinity. Healing is quantified by a decrease in strains. The CTFEA results were compared to conventional radiographic and laboratory measures.ResultsTable 1 summarizes individual patient clinical data at the time points of each of the CT-scans as well as the calculated CTFEA strain values at the location of maximum HU change of the initial 7 patients. Complete analysis of femur and vertebral strain for 16 patients will be presented at the meeting. Indeed no visible change in strain is demonstrated for smoldering MM (SMM) patients (Pts 15 and 16), whereas a monotonic increase is seen for patient 3, RRMM, with successive relapses without visible tumor identified in the femur in CT scans.Patient 17 (RRMM) with a lytic tumor at the distal femur, shows an initial deterioration of bone strength followed by a monotonic improvement until almost full regain of strength after 19 months.Patient 10 (NDMM) with a lytic tumor in the vicinity of the lesser trochanter, achieved a partial response of MM following anti-myeloma induction within 6 weeks, and as well as a significant increase in bone strength. Patient 13 had a rapid MM response but parallel worsening strain in the right femur, patient 18 had a MM partial response over 5 months with slight worsening of strain.ConclusionsPromising trends were found between CTFEA strain prediction and MM clinical course. SMM patients had minimal changes whereas a patient with progressive disease had a monotonic increase in strains. A decrease in strain was seen in some but not all who responded to therapy. The preliminary study is to be enhanced by considering vertebrae, analyzing further patients as well as prospective validation against SREs, to refine calibrate and tailor this measurement. By providing a quantitative metric of bone strain, this tool may allow monitoring bone strength throughout myeloma evolvement, prior to development of SREs. This may support physicians making personalized medical and surgical treatment decisions and provide a useful surrogate endpoint for clinical drug development. [Display omitted] DisclosuresYosibash:PerSimiO: Equity Ownership, Membership on an entity's Board of Directors or advisory committees. Trabelsi:PerSimiO: Equity Ownership, Membership on an entity's Board of Directors or advisory committees.

Patterns and Predictors of Initiation of Intravenous Bisphosphonates Among Patients with Multiple Myeloma in the United States

▪Introduction:Osteolytic lesions are detected in approximately 90% of patients with multiple myeloma (MM) and increase the risk of skeletal related events (SREs), including fractures and other bone complications. Intravenous bisphosphonates (IV BPs) are recommended for patients diagnosed with MM with or without detectable osteolytic lesions to prevent SREs and possibly slow the progression of myeloma. There are limited data available describing the use of IV BPs in this population. We examined the cumulative incidence of IV BP initiation, accounting for the competing risk of death, and assessed predictors of initiation, overall and by IV BP type.Methods: An overall cohort of patients was identified using a sample of electronic health records from oncology clinics across the United States (Flatiron Health, Inc.) that linked to the MarketScan® employer-based and Medicare Supplemental administrative health insurance claims databases (Truven Health Analytics, Inc.) at any point before the MM diagnosis. Patients were aged 18 years or older and had a new MM diagnosis (ICD9, 203.00; ICD10, C90.00) between January 1, 2011 and April 30, 2016. Patients were excluded if they had an IV BP administration in the six months prior to the MM diagnosis, concurrent cancer in the 12 months prior to diagnosis, or did not have a healthcare encounter in the 30 days following the diagnosis. The cumulative incidence of IV BP initiation was estimated using competing risk models to account for death. To estimate predictors of initiation, we created a subcohort of patients who were additionally required to have continuous enrollment in MarketScan in the six months before the MM diagnosis. A multivariable generalized linear model was fit to estimate risk differences for predictors of initiation, and 95% confidence intervals (CIs) were obtained by a parametric bootstrap. Laboratory results, comorbidities, other therapies and SREs were included as time-varying variables in the model.Results: Among the 1875 patients in the overall cohort with a MM diagnosis, 60% were 65 years and older, 65% were white, and 13% had stage III MM at diagnosis. These characteristics were similar for the subcohort (N = 758). The cumulative incidence of IV BP initiation was 24% (95% CI: 22, 26%) at 30 days, 38% (35, 40%) at 90 days, and 44% (42, 46%) at 1 year. The cumulative incidence of treatment initiation was similar for patients diagnosed with MM in all calendar years of the study, but was higher for patients receiving anti-myeloma therapies. Zoledronic acid was the most commonly initiated IV BP; among those treated with an IV BP, 93% were administered zoledronic acid while only 7% were administered pamidronate. In the multivariate model, whites (compared with Blacks), patients with Stage III MM at diagnosis (compared to Stage I), patients with hypercalcemia, and patients undergoing other treatments (some anti-myeloma therapies, opioids, and glucocorticoids) were more likely to initiate an IV BP. Experiencing an SRE was the strongest predictor of IV BP initiation. Patients who had an SRE were more likely to initiate zoledronic acid, but less likely to initiate pamidronate. Patients with severely impaired renal function, defined as eGFR <30 mL/min, or patients with indicators of frailty were less likely to initiate an IV BP.Conclusions: In this study of patients diagnosed with MM who had employer-based commercial insurance or Medicare Supplemental coverage, the incidence of IV BP administration was lower than expected. Less than half of patients initiated an IV BP in the two years after diagnosis, indicating that a considerable number of patients with MM may be at increased risk for experiencing a bone complication. There are clinical reasons why patients may go untreated such as frailty or severely impaired renal function. Taking these patient characteristics into account, these real-world data revealed that an SRE was the strongest predictor of IV BP initiation, underscoring the need to manage the bone health of patients with MM more proactively. [Display omitted] DisclosuresHernandez:Amgen Inc.: Employment, Equity Ownership. Liede:Amgen Inc.: Employment, Equity Ownership. Brookhart:Amgen Inc.: Other: Scientific advisor, Research Funding; AstraZeneca: Research Funding; Merck: Other: Scientific advisor; GSK: Other: Scientific advisor; UCB: Other: Scientific advisor; Genentech: Other: Scientific advisor; TargetPharma: Other: Scientific advisor; RxAnte: Other: Scientific advisor.

Multiple Myeloma Patients and Risk of Skeletal Related Events - Real-World Evidence in US Oncology Clinics

Introduction: SEER estimates that 30,280 new cases of multiple myeloma (MM) will be diagnosed in the US in 2017. Osteolytic disease is a hallmark feature of myeloma at diagnosis. Skeletal related events (SRE) including pathological fractures, spinal cord compressions, radiation and surgery to bone are frequent complications for myeloma patients. However, there have been few reports of the incidence of and risk of developing an SRE in the myeloma population, particularly relative to concomitant anti-myeloma therapy.Methods: A database of oncology electronic health records (EHR) contained in Amgen's Oncology Services Comprehensive Electronic Records (OSCER) database, generated by Flatiron Health (New York, NY, April 30, 2016) were linked to administrative claims data from the Truven Marketscan database. Patients identified were individuals 18 years or older diagnosed with MM (ICD-9: 203.00; ICD-10: C90.00), had at least 1 clinic visit within 1 month of diagnosis, and at least 1 year of follow-up after MM diagnosis. The study period was from January 1, 2011 to December 31, 2016. The baseline period for co-morbidities was 12 months prior to multiple myeloma diagnosis date. Patient diagnosis, treatment dates and administrations were ascertained from the EHR. SREs were ascertained from diagnosis codes in insurance claims. Primary outcomes of interest were occurrence of and time to SRE. Multiple SRE that occurred within a 21-day span were considered as a single SRE and ordered based on the following hierarchy: 1.) spinal cord compression, 2.) pathological fracture, 3.) surgery to bone, then 4.) radiation to bone. SRE occurring within 60 days of MM diagnosis were considered as baseline SRE. Results are also stratified by line of anti-myeloma therapy.Results: A total of 343 patients were included in this study. Approximately 55% of patients were age >65, 54% male, and 70% white race. About one-third of patients had an eGFR below 60 at MM diagnosis, 69% presented with anemia, and 35% had a baseline history of SRE (includes SREs recorded within two months after diagnosis). During a median follow-up of 25.7 months after diagnosis, 34% of patients (n=117) experienced an SRE and the median time to SRE was 228 days. Among patients that experienced a SRE, 68% occurred within the first year (n=79). Among patients with a baseline history of SRE (n=119), 61% experienced a SRE during follow-up at a median of 149 days compared to 20% of patients without SRE history (n=45) at a median of 365 days. The incidence rate of SRE for these patients with a baseline history was 103/100 person-years (PY) (n=58) versus 16/100PY compared to no baseline history (n=21) one year following MM diagnosis. The incidence rate of SRE in each of line therapy within three months of the initiation of each line increased with each subsequent line (line 1: 81/100PY, line 2: 118/100PY, line 3: 150/100PY).Conclusions: Most patients experience their first SRE soon after MM diagnosis or at the beginning of each relapse. Patients with a baseline SRE had a higher risk of future SRE. Recently relapsed patients had a higher rate of SRE compared to patients who have been on therapy for an extended period, and the incidence rate was progressively higher among patients receiving later lines of therapy. Additionally, among patients experiencing SRE, multiple SRE can occur, highlighting the importance of continued surveillance and proper management of myeloma associated bone disease. The overall SRE rate was lower than expected likely due to selection bias or recording bias in the administrative claims database. [Display omitted] DisclosuresBhatta:Amgen: Employment. Fonseca:Jansen: Consultancy; Merck: Consultancy; Mayo Clinic & Dr Fonseca: Patents & Royalties: Prognostication of myeloma via FISH, ~$2000/year; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Celgene Corporation: Consultancy, Research Funding; Sanofi: Consultancy; Takeda: Consultancy; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy; Pharmacyclics: Consultancy; AMGEN: Consultancy. Hernandez:Amgen Inc.: Employment, Equity Ownership. Kim:Amgen, Inc.: Employment, Equity Ownership.

Risk factors associated with skeletal-related events following denosumab cessation among patients with bone metastases from solid tumors: A real-world machine learning approach.

1567 Background: The anti-RANKL monoclonal antibody denosumab has been shown to be superior to the bisphosphonate zoledronate for the prevention of skeletal-related events (SREs) in patients with incident bone metastases (BM) from solid tumors (ST). Clinical guidelines recommend the use of a bone-targeting agent for SRE prevention for ≥ 2 years. However, real-world treatment patterns in the U.S. suggest that the denosumab treatment duration is often &lt; 1 year. Applying a machine learning approach, we sought to identify risk factors associated with SRE incidence following cessation of denosumab to help inform optimal clinical SRE prevention strategies. Methods: Using the Optum PanTher Electronic Health Record repository, patients diagnosed with incident BM from a primary ST between 1 Jan 2007 and 1 Sep 2019 were evaluated for inclusion in the study. Eligible patients had to receive ≥ 2 consecutive 120 mg denosumab doses on an every 4-week (± 14 days) schedule and have a minimum follow-up ≥ 1 year after the last denosumab dose or an SRE occurring between days 84 and 365 after denosumab cessation. Extreme gradient boosting was used to develop an SRE risk prediction model evaluated on a test dataset. Impact and relative importance of available medical, clinical, and treatment factors on SRE risk following denosumab cessation were extracted from the model using Shapley additive explanations (SHAP). Univariate analyses on risk factors with the highest importance from pooled and tumor-specific models were also conducted. Results: A total of 1,414 patients (breast, n = 563 [40%]; prostate, 421 [30%]; lung, 180 [13%]; other cancers, 250 [17%]) met inclusion criteria, with a median of 253 (min, 88; max, 2726) days of denosumab treatment; 490 (35%) experienced ≥ 1 SRE following denosumab cessation. With a meaningful model performance based on an area under the receiver operating characteristic (AUROC) score of 77%, SHAP identified several significant factors that predicted an increased SRE risk following denosumab cessation, including prior SREs, shorter denosumab treatment duration, and a higher number of clinic visits as the top-ranked factors (Table). Conclusions: A machine learning approach to SRE risk factor identification may help clinicians better assess the individualized patient’s need for denosumab treatment persistence and improve patient outcomes. Results from tumor-specific groups will be presented at the meeting.[Table: see text]

Bone modifying agents and skeletal related events in patients with metastatic non-small cell lung cancer treated with immune checkpoint inhibitors.

e18593 Background: Bone metastases and skeletal related events (SREs) are a common cause of morbidity among patients with metastatic non-small cell lung cancer (mNSCLC). SREs include pathologic bone fractures, spinal cord compression, orthopedic surgery/stabilization, and palliative radiation to bone. Bone modifying agents (BMA) such as bisphosphonates and RANK ligand inhibitors are often used for mNSCLC patients with bone metastases to reduce the incidence of SRE. Data on the associations between BMA use and overall survival (OS) and the development of SRE among patients with mNSCLC treated with immune checkpoint inhibitors (ICI) is limited. Methods: We conducted a retrospective study of patients with mNSCLC treated with first line pembrolizumab or pembrolizumab plus chemotherapy at The Ohio State University from 2017-2020. The associations between SRE and categorical variables were studied using Fisher’s exact test and with continuous variables using the Kruskal-Wallis test. The association between BMA and risk of osseous progression was studied using Fisher’s exact test. The association between BMA and OS was examined using a Cox proportional hazard model. Median OS was estimated using the Kaplan-Meier method with 95% CI. OS was calculated from date of ICI initiation to death from any cause or last follow up. Results: We identified a cohort of 228 patients: 107 (47%) treated with pembrolizumab and 121 (53%) treated with pembrolizumab plus chemotherapy; 48 (21%) had squamous histology and 179 (79%) had nonsquamous histology (1 had NSCLC histology not specified); median age 62.6 years; median OS was 26.8 months (95% CI: 17.2 – 34.5 months). A total of 95/228 (42%) patients had bone metastases at time of ICI initiation; 45/95 (42%) had treatment with BMA and 50/95 (58%) were not treated with BMA. Among patients with bone metastases at time of ICI, 45 (42%) developed SRE after ICI initiation and BMA use was not associated with risk of SRE (p = 1). BMA use was not significantly associated with risk of osseous progression (p = 0.21). For patients with baseline bone metastases prior to ICI, the use of BMA was not associated with OS (p = 0.24); the type of BMA used (bisphosphonate vs RANK ligand inhibitor) was also not associated with OS (p = 0.13). Conclusions: In patients with metastatic NSCLC treated with first line pembrolizumab alone or with chemotherapy, bone modifying agents were not associated with OS, decreased risk of osseous progression, or development of SRE in patients with baseline bone metastases prior to ICI initiation. The type of BMA used was also not associated with survival. Further studies evaluating the utility and impact of BMA use in this patient population are needed.

Assessment of Bone Health Education in US Multiple Myeloma and Solid Tumor Patients at Risk for Skeletal-Related Events.

PurposeCancer patients with bone metastasis (BM) from solid tumors or multiple myeloma (MM) have an increased risk of painful skeletal-related events (SREs), which can decrease quality of life and increase mortality. Bone targeting agents (BTAs) can help delay or prevent SREs; however, a significant portion of eligible patients are not receiving BTA therapy. This study was conducted to understand patient awareness of cancer-related bone health and to identify opportunities to improve bone health education in cancer patients at risk of SREs.MethodsThe online BonE heAlth eduCatiOn Needs assessment (BEACON) survey included questions about patient demographics, cancer diagnosis and treatments (including BTA usage), and extent and satisfaction with bone health education received. Direct-to-patient outreach was used to recruit patients. Eligible patients were US adults with a diagnosis of self-reported MM or BM from a solid tumor (breast, lung, or prostate cancer) within the past three years.ResultsOf 125 patients, 71% were diagnosed with solid tumors with BM and 29% with MM. At least one prior SRE was experienced by 57% of patients (38% radiation to bone, 32% bone fracture, 22% spinal cord compression, and 19% surgery to bone), and 74% were currently receiving BTA therapy. Awareness of cancer bone health, protection strategies, and screening tests was low to moderate; patients were least informed of the impact of lifestyle changes (38%) and specific cancer treatments (≤35%) on bone health. Sixty-two percent of patients were not completely satisfied with the bone health education received. Patients generally wanted more information (58%) and to receive information by more than one mode of communication.ConclusionNotable gaps in bone health education were observed in cancer patients at risk for SREs indicating an important need for improved communication and education strategies to promote better health outcomes.

Safety of concomitant therapy with radium-223 and abiraterone or enzalutamide in a real-world population.

Real-world utilization and outcomes of combination therapy for men with metastatic castrate-resistant prostate cancer (mCRPC) are largely unknown. We evaluated the overall survival (OS) and skeletal-related events (SREs) among men who received radium-223 with or without concomitant abiraterone or enzalutamide in the Veterans Affairs (VA) Health System. We reviewed charts of all mCRPC patients who received radium-223 in the VA from January 2013 to September 2017. We used Cox models to test the association between concomitant therapy versus radium-223 alone on OS and SRE. Sensitivity analyses were performed for concomitant use of denosumab/bisphosphonates. Three hundred and eighteen patients treated with radium-223 were identified; 116/318 (37%) received concomitant abiraterone/enzalutamide. Two hundred and seventy-seven (87%) patients died during follow-up. Patients who received concomitant therapy were younger at radium-223 initiation (median age 68 vs. 70, p = .027) and had a longer follow-up (median 29.5 vs. 17.9 months, p = .030). There was no OS benefit for those on concomitant therapy (hazard ratio [HR]: 0.87, 95% confidence interval [CI]: 0.67-1.12, p = .28). There was a trend for an increased SRE risk for patients on concomitant therapy (HR: 1.87, 95% CI: 0.96-3.61, p = .066), but this was not significant. When analyses were limited to men using bone heath agents, similar results were seen for OS (HR: 0.86, 95% CI 0.64-1.15, p = .30) and SRE (HR: 2.36, 95% CI: 0.94-5.94, p = .068). Despite the common use of concomitant therapy in this real-world study, there was no difference in OS among mCRPC patients. A nonsignificant increased SRE risk was observed. Further work needs to evaluate the optimal sequence, timing, and safety of combination therapies.

P09.13 Bone Metastases and Overall Survival in Patients with Metastatic Non-Small Cell Lung Cancer Treated with Pembrolizumab

Bone metastases (BM) and skeletal-related events (SRE) are a common cause of morbidity in patients with metastatic non-small cell lung cancer (mNSCLC). Data on the impact of BM on overall survival (OS) in patients treated with immune checkpoint inhibitors (ICI) is limited. Here we report the incidence, impact on survival, and risk factors for SRE in patients with mNSCLC treated with first-line pembrolizumab monotherapy or pembrolizumab plus chemotherapy. We conducted a retrospective study of patients with mNSCLC treated with first-line pembrolizumab or pembrolizumab plus chemotherapy at our institution from 2017-2020. The associations between SRE and categorical variables were studied using Fisher’s exact test and with continuous variables using the Kruskal-Wallis test. Kaplan-Meier plots were used to visualize survival curves. The association between baseline BM and OS was examined using a Cox proportional hazard model. OS was calculated from date of ICI initiation to death from any cause or last follow-up. We identified a cohort of 202 patients: 93 (46%) treated with pembrolizumab and 109 (54%) treated with pembrolizumab plus chemotherapy; 39 (19%) had squamous histology and 163 (81%) had nonsquamous histology; median age 62.7; median OS 33.7 months (95% CI: 17.2 – NR). In our cohort, 87 (43%) patients had BM at time of ICI initiation and 47 (23%) developed SRE after ICI initiation. Patients who developed SRE were more likely to have baseline BM than those without SRE (91.5% vs 28.4%, p<0.001). Development of BM during treatment with ICI and performance status were also significantly associated with SRE (p<0.001 and p=0.006, respectively). Patients with BM at time of ICI, or development of new or progression of existing BM while on ICI, had shorter survival than those without (Figure 1a and Figure 1b, respectively). In multivariate survival analysis, the hazard of death for patients with baseline BM was 2.85 times those without (HR=2.85, 95% CI: 1.53, 5.29, p-value=0.0009) after controlling for age, BMI, performance status, histology, PD-L1 expression, smoking, and SRE. The use of bone-modifying agents (BMA) was not associated with OS, osseous progression, or risk of SRE. The presence of BM at time of ICI was associated with shorter survival after controlling for multiple clinical characteristics. These patients represent a high-risk cohort for worse outcomes when treated with ICI alone or in combination with chemotherapy. In our cohort BMA were not associated with increased OS or decreased risk of osseous progression or SRE.

Abstract PS9-69: Findings from the BonE heAlth eduCatiOn needs assessment (BEACON) study: A survey of bone metastatic breast cancer patients at risk for skeletal-related events

Abstract PURPOSE Nearly 40% of patients with bone metastases from breast cancer experience a skeletal-related event (SRE) such as fracture, spinal cord compression, bone surgery, or radiation to bone, within 1 year of diagnosis (1). Bone-targeting agents (BTAs) significantly reduce the risk of SREs, but real-world data indicates that only 58% (Commercial) and 67% (Medicare) of eligible metastatic breast cancer patients receive treatment with a BTA (2, 3). We surveyed U.S. patients with bone metastases from breast cancer to ascertain their awareness regarding bone health, to describe the source and amount of bone health education received, and to identify potential gaps in bone health education. METHODS The BonE heAlth eduCatiOn Needs assessment (BEACON) survey was developed through a collaboration between GRYT Health Inc. and Amgen Inc. The online survey consisted of treatment-related questions, cancer-related bone health educational questions, and open-ended questions. U.S. adult patients who consented to participate, with self-reported bone metastasis from breast cancer, were recruited using a unique IRB-approved direct-to-patient approach pioneered by GRYT Health, which incorporates digital outreach, advocacy partnerships, and virtual app and conference-based communication. RESULTS Seventy-four breast cancer patients with bone metastasis completed the online survey. Thirty-eight (51%) had experienced at least one SRE, defined as bone fracture (n=19; 26%), spinal cord compression (n=11; 15%), or radiation (n=28; 38%) or surgery (n=9; 12%) on a bone. While the majority of patients were aware that bones are more fragile in individuals with cancer (n=48; 65%) and that treatments are available to help prevent broken bones caused by cancer (n=50; 68%), fewer understood that bones are more fragile after receiving chemotherapy (n=20; 27%) and radiation (n=28; 38%), or that lifestyle changes can help to prevent broken bones (n=23; 31%). Similarly, when asked about bone protection, the majority of patients had knowledge about calcium and/or vitamin D supplements (n=55; 74%) and BTAs (n=53; 72%), but only 24% had knowledge of lifestyles changes as a bone health protection strategy (n=18). Oncologist and nurses were the most commonly reported HCPs to provide cancer-related bone health information. Patient-reported satisfaction with the amount of bone cancer education was “low” or “moderate” (n=46; 62%); “low” satisfaction was more common in patients not receiving a BTA (n=6/13; 46%) compared to those currently receiving a BTA (n=17/61; 28%). More than half of patients reported receiving either no bone health information (n=8; 11%) or less information than desired (n=35; 47%). CONCLUSION Despite potential limitations in patient recall and population selection biases, there appears to exist important gaps in knowledge and education related to bone health and SRE prevention among metastatic breast cancer patients. Patient- and provider-oriented interventions that increase opportunities for communication and education on bone health may help ensure optimal SRE prevention strategies including appropriate BTA use. REFERENCES 1. Clemons M, Gelmon KA, Pritchard KI, Paterson AH. Curr Oncol 2012 Oct; 19(5):259-268. 2. Hernandez RK, Adhia A, Wade SW, et al. Clin Epidemiol 2015 Jul; 7:335-345. 3. McGrath LJ, Overman RA, Reams D, et al. Clin Epidemiol 2018 Sep; 10:1349-1358. Citation Format: Darcy R Flora, Katherine B Carlson, Kimberly Lowe, Benoit Cadieux, Guy Boike, Basia Bachmann, David C Fuehrer. Findings from the BonE heAlth eduCatiOn needs assessment (BEACON) study: A survey of bone metastatic breast cancer patients at risk for skeletal-related events [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-69.

Beta-Adrenergic Antagonists and Cancer Specific Survival in Patients With Advanced Prostate Cancer: A Veterans Administration Cohort Study

To interrogate the National Veterans Health Administration (VA) database to determine if beta-blocker use at time of initiation of androgen therapy deprivation (ADT) would result in improved oncological outcomes in advanced prostate cancer (PCa). All men diagnosed with high risk PCa (PSA >20) from 2000-2008 who were on ADT ≥ 6 months were identified. Patients receiving ADT concurrently with primary radiation therapy were excluded. Pharmacy data was interrogated for all beta-blockers, but then focused on the selective beta-1 blocker metoprolol. Cox proportional hazards ratios were calculated for overall survival (OS), PCa specific survival (CSS) and skeletal related events (SREs). In 39,198 patients with high risk PCa on ADT, use of any beta-blocker was not associated with improvement in OS, CSS, or SREs. Further analyses focusing on metoprolol found that 10,224 (31.9%) had used metoprolol while 21,834 had no beta-blocker use. Multivariable analysis with Inverse Propensity Score Weighting, adjusted for factors including PSA, Gleason score, and duration ADT, found that utilization of metoprolol was not associated with improvement in OS (hazard ratio [HR] 0.97, P=.19), CSS (HR 0.94, P=.23) or SREs (HR 0.98, P=.79). In this large cohort, metoprolol use in conjunction with ADT in high risk PCa was not associated with improvement in OS, CSS, or risk of SRE. In contrast to a recent smaller clinical study, our data strongly suggests no cancer specific benefit to beta-blocker use in advanced PCa.

Review of Bone Modifying Agents in Metastatic Breast Cancer.

Bone is the most common site for distant metastases in breast cancer and can cause significant morbidity and mortality. Bone modifying agents (BMAs) that include bisphosphonates (BPAs) and denosumab help in decreasing and delaying skeletal-related events (SREs) associated with metastatic breast cancer. BPAs approved for use by the Food and Drug Administration (FDA) in bone metastases (BM) in the United States are pamidronate and zolendronic acid, while clodronate and ibandronate are licensed for use in other countries. Current American Society of Clinical Oncology (ASCO) guidelines recommend denosumab 120 mg subcutaneously every four weeks, or zolendronic acid 4 mg every four weeks or every 12 weeks, or intravenous pamidronate 90 mg every four weeks. Current guidelines do not recommend one BMA over another, however, zolendronic acid and denosumab were the most commonly used BMAs in population-based studies. Side effects of BMAs include acute phase reactions, hypocalcemia, nephrotoxicity, osteonecrosis of jaw, etc. While other side effects are common with both BPAs and denosumab, the latter has less nephrotoxic potential and is preferred for use in patients with renal failure. Current ASCO guidelines recommend continuing BMAs indefinitely, however, in clinical practice, this decision needs to be individualized, especially since there is no data on the impact of long-term use of BMAs. Further studies would need to be developed to develop an algorithm of SRE risk assessment and to determine which patients would benefit from BMAs.

Safety and Feasibility of Outpatient Rehabilitation in Patients With Secondary Bone Cancer: A Preliminary Study

Background: Because of fear of skeletal complications, physicians often avoid referring patients with secondary bone cancer (SBC) to physical rehabilitation. However, there is little evidence on the risk of skeletal-related events (SREs) and pathological fracture (PF) during rehabilitation therapies. Objective: To determine the risk of PF following physical rehabilitation in people with SBC. Design: Single-group, single-centered interventional clinical trial. Setting: University-based outpatient rehabilitation clinic. Patients: Forty-eight patients with confirmed diagnosis of SBC were enrolled. Interventions: Participants were prescribed a multidisciplinary rehabilitation program. Participants and rehabilitation therapists were trained to detect and report symptoms that would indicate PF. Radiographs were used to confirm the presence of PF. Measurements: The primary outcomes were safety and feasibility of an outpatient rehabilitation program for patients with SBC. Safety was measured by the rate of SREs. Feasibility was measured by the ability to successfully complete the program. Secondary outcome measures included Short Form Health Survey (SF-36) and numeric rating scale (NRS) scores to assess pain intensity. Results: One PF was detected, which occurred outside of rehabilitation therapy. Two other SREs occurred, resulting in a total event rate of 11.8 for every 10 000 hours of exposure. There was a significant improvement in NRS (95% CI, 1.41-3.08, P &lt; .001) and SF-36 measures (95% CI, 80.35-158.11, P &lt; .001). Limitations: Twenty participants (42%) did not complete the rehabilitation program due to clinical complications or death. Conclusions: Rehabilitation interventions may not increase the risk of SREs or PF in patients with SBC. Further research is indicated to verify these findings.

Extending Dosing Intervals of Denosumab As a Maintenance Strategy in Multiple Myeloma: A Real-World Experience at a Large Academic Cancer Center

Introduction: Osteolytic bone destruction is a defining characteristic of multiple myeloma (MM) and patients with MM have an increased risk of skeletal related events (SREs) - including pathologic fractures, spinal cord compression, and the need for radiation therapy or surgery to bone - which is a significant source of impaired quality of life and mortality. Bone modifying agents (BMAs), such as bisphosphonates or denosumab, have shown to substantially decrease or delay onset of new SREs. Optimal duration or frequency of a BMA, however, is less clear. Data supporting zoledronic acid administered at an extended dosing interval of every 3 months compared to the traditional 3-4 weeks interval in patients with MM have been previously reported in the Z-MARK study (Raje N, et al. Clin Cancer Res. 2016). Denosumab, an anti-RANKL monoclonal antibody, received approval for the prevention of SREs in patients with MM in early 2018, but there is a paucity of data for extending denosumab dosing intervals as maintenance. Herein, we report real-world observations by characterizing our use, safety and efficacy, and other practical considerations of denosumab administered at extended dosing intervals. Methods: In this retrospective study, patients with MM at Massachusetts General Hospital Cancer Center who received at least two doses of denosumab at extended intervals (&amp;gt;3 months) as a maintenance strategy between January 1, 2018 and September 30, 2019 were identified. The corresponding electronic medical records (EMRs) were reviewed for incidences of new SREs, hypocalcemia, and disease progression including those with bone-related progression requiring change in therapy. Incidences of new SREs were captured by reviewing radiologic reports/EMRs for pathologic and compression fractures and radiation/surgery to treat bone lesions while on treatment. Evaluation of hypocalcemia included the need for intravenous calcium repletion. Results: Over the 21-month period, a total of 194 patients received denosumab at various extended dosing intervals as maintenance. All patients had received monthly BMA preceding the maintenance therapy. Extended dosing intervals were: 3 months, between 3-6 months, and ≥6 months (58.8%, 26.8%, 14.4%, respectively). Majority of the patients (171, 88.1%) had received bisphosphonates prior to denosumab and evidence of bone disease at diagnosis was seen in 169 (87.1%) patients. Time from diagnosis of MM ranged from 0.3 - 17 years; 51.5% and 16.5% were ≥4 years and ≥8 years since diagnosis, respectively. New SREs while on denosumab maintenance occurred in 6 (3.1%) patients; these consisted of vertebral compression fractures and pathologic fractures of humerus and femur requiring surgical interventions or radiation. These SRE events were associated with disease progression and average time from MM diagnosis to these events was 7.9 years (range 6.2 - 9.5 years). Hypocalcemia (≥grade 1) was seen in 29 (14.9%) patients, and among these, only 6 required intravenous calcium repletion. Disease progression requiring change in therapy occurred in 46 (23.7%) patients and 34 (17.5%) patients had bone-related progression. Conclusions: Our data support the use of denosumab extended dosing during maintenance. However, our study has several limitations including retrospective nature of analysis, heterogeneity in the patient pool, and exclusion of patients with more frequent dosing of denosumab. Our experience therefore underscores the need to study denosumab extended dosing prospectively. Disclosures Branagan: Sanofi: Other: Advisory Board; Pharmacyclics: Other: Advisory Board. Yee:GSK: Consultancy; Celgene: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Oncopeptide: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Sanofi: Consultancy; Takeda: Consultancy, Research Funding. Raje:Celgene: Consultancy; Janssen: Consultancy; Bluebird Bio: Consultancy; BMS: Consultancy; Amgen: Consultancy. O'Donnell:Celgene: Consultancy.

Precautions For Yoga Practice Are Necessary In Cancer Patients With Spinal Metastasis

Yoga has been promoted for cancer patients as a tool for symptom management and improving quality of life. Many cancer patients have bone metastasis, are not fully aware of its impact. Improper movements during exercise and yoga can increase the risk for skeletal-related events. This short commentary alerts clinician and yoga teacher to assess bone integrity prior to recommending and teaching yoga.

Safety and Efficacy of Long-Term Zoledronic Acid in Advanced Breast Cancer with Bone Metastasis in South China.

Background This retrospective study aimed to characterize the long-term (>24 months) safety profile of zoledronic acid (ZA). We aimed to investigate whether long-term ZA treatment had greater benefits than short-term treatment in patients from southern China with advanced breast cancer (ABC) with bone metastasis. Patients and Methods. A total of 566 metastatic breast cancer cases were included and divided into two groups according to the duration of ZA treatment. The included patients had at least one lytic bone lesion and had no skeletal-related events (SREs) prior to ZA therapy. The primary endpoint was to analyze the safety and long-term adverse effects, which covered osteonecrosis of jaws (ONJ), renal impairment, and hearing impairment. The second objective was to determine the efficacy of long-term ZA treatment by the incidence of SREs. Results Fifteen patients were diagnosed with ONJ (2.7%): nine in the short-term group (3.1%) and six in the long-term group (2.2%, P = 0.606). Five cases (0.9%) had renal function impairment: two in the short-term group (0.7%) and four in the long-term group (1.1%, P = 0.676). One patient (0.2%) in the long-term group had hearing impairment after 23 months of ZA treatment (0.4%, P = 0.482). In total, 103 cases in the short-term group (35.2%) and 138 cases in long-term group (50.5%) developed SREs (P < 0.001). The mean annual SRE rate was 0.3 in the short-term group (range, 0–3.1) versus 0.2 in the long-term group (0–1.0, P = 0.269). Subgroup analysis suggested that cases with non-load-bearing bone involvement and those who received systematic anticancer therapy without chemotherapy might benefit from long-term ZA treatment. Cox regression analysis indicated poor performance status, and nonvisceral organ involvement predicted high risk for SRE. Conclusions The extension of ZA treatment did not increase the long-term adverse events and reduced the annual incidence of SREs beyond 24 months. Although longer treatment of ZA over 24 months appeared to be safe, further prospective investigation is required.

A Systematic Review and Meta-Analysis about the Effect of Bisphosphonates on the Risk of Skeletal-Related Event in Men with Prostate Cancer.

Although the adjuvant therapy of bisphosphonates in prostate cancer is effective in improving bone mineral density, it is still uncertain whether bisphosphonates could decrease the risk of Skeletal- Related Event (SRE) in patients with prostate cancer. We reviewed and analyzed the effect of different types of bisphosphonates on the risk of SRE, defined as pathological fracture, spinal cord compression, radiation therapy to the bone, surgery to bone, hypercalcemia, bone pain, or death as a result of prostate cancer. A systemic literature search was conducted on PubMed and related bibliographies. The emphasis during data extraction was laid on the Hazard Ratio (HR) and the corresponding 95% Confidence Interval (CI) from every eligible Randomized Controlled Trial (RCT). HR was pooled with the fixed effects model, and preplanned subgroup analyses were performed. 5 RCTs (n = 4651) were included and analyzed finally after screening 51 articles. The meta-analysis of all participants showed no significant decrease in the risk of SRE when adding bisphosphonates to control group (HR = 0.968, 95% CI = 0.874 - 1.072, p = 0.536) with low heterogeneity (I2 = 0.0% (d.f. = 4) p = 0.679). There was no significant improvement on SRE neither in the subgroups with Metastases (M1) or Castration-Sensitive Prostate Cancer (CSPC) (respectively HR = 0.968, 95% CI = 0.874 - 1.072, p = 0.536, I2 = 0.0% (d.f. = 4) p = 0.679; HR = 0.954, 95% CI = 0.837 - 1.088, p = 0.484, I2 = 0.0% (d.f. = 3) p = 0.534). Our study demonstrated that bisphosphonates could not statistically significantly reduce the risk of SRE in patients with prostate cancer, neither in the subgroups with M1 or CSPC.

Risk factors of skeletal-related events in patients with bone metastasis from non-small cell lung cancer undergoing treatment with zoledronate-a post hoc analysis of a randomized clinical trial.

Skeletal-related events (SREs) are critical events for patients with bone metastasis from non-small cell lung cancer (NSCLC). Thus, bone-modifying agents are recommended in this population. However, the baseline risk factors of SREs in patients with bone metastasis from NSCLC are not well established. We analyzed the patient-level data from the zoledronate arm of a clinical trial comparing denosumab with zoledronate in patients with bone metastasis ( ClinicalTrial.gov ID: NCT00330759) available at Project Data Sphere, a broad-access research platform. The primary endpoint was the first SRE from the inclusion to the trial, and the time to the first SRE was analyzed using Cox proportional hazards model. We analyzed 302 patients with NSCLC without a documented history of osteopenia or osteoporosis included in the zoledronate arm of the trial. Ninety-eight patients (32%) had at least one SRE. The univariate analysis showed that low serum albumin and elevated serum alkaline phosphatase (ALP) are significant baseline risk factors for SREs (hazard ratio (HR) [95% confidence interval (CI)]; 2.27 [1.43-3.61], and 1.91 [1.26-2.90], respectively). Additionally, osteoblastic and mixed type of bone metastasis showed a significantly lower risk of SREs compared with the osteolytic lesion (HR [95% CI]; 0.39 [0.21-0.72], and 0.31 [0.15-0.63], respectively). These factors also showed a significant association with the risk of SREs in multivariate analysis. We revealed that osteolytic bone metastasis, low serum albumin, and elevated serum ALP are risk factors for SREs in patients with bone metastasis from NSCLC.