Skeletal Events Research Articles

Lutetium-177–PSMA-617 for Metastatic Castration-Resistant Prostate Cancer

BackgroundMetastatic castration-resistant prostate cancer remains fatal despite recent advances. Prostate-specific membrane antigen (PSMA) is highly expressed in metastatic castration-resistant prostate cancer. Lutetium-177 (177Lu)–PSMA-617 is a radioligand therapy that delivers beta-particle radiation to PSMA-expressing cells and the surrounding microenvironment.MethodsWe conducted an international, open-label, phase 3 trial evaluating 177Lu-PSMA-617 in patients who had metastatic castration-resistant prostate cancer previously treated with at least one androgen-receptor–pathway inhibitor and one or two taxane regimens and who had PSMA-positive gallium-68 (68Ga)–labeled PSMA-11 positron-emission tomographic–computed tomographic scans. Patients were randomly assigned in a 2:1 ratio to receive either 177Lu-PSMA-617 (7.4 GBq every 6 weeks for four to six cycles) plus protocol-permitted standard care or standard care alone. Protocol-permitted standard care excluded chemotherapy, immunotherapy, radium-223 (223Ra), and investigational drugs. The alternate primary end points were imaging-based progression-free survival and overall survival, which were powered for hazard ratios of 0.67 and 0.73, respectively. Key secondary end points were objective response, disease control, and time to symptomatic skeletal events. Adverse events during treatment were those occurring no more than 30 days after the last dose and before subsequent anticancer treatment.ResultsFrom June 2018 to mid-October 2019, a total of 831 of 1179 screened patients underwent randomization. The baseline characteristics of the patients were balanced between the groups. The median follow-up was 20.9 months. 177Lu-PSMA-617 plus standard care significantly prolonged, as compared with standard care, both imaging-based progression-free survival (median, 8.7 vs. 3.4 months; hazard ratio for progression or death, 0.40; 99.2% confidence interval [CI], 0.29 to 0.57; P<0.001) and overall survival (median, 15.3 vs. 11.3 months; hazard ratio for death, 0.62; 95% CI, 0.52 to 0.74; P<0.001). All the key secondary end points significantly favored 177Lu-PSMA-617. The incidence of adverse events of grade 3 or above was higher with 177Lu-PSMA-617 than without (52.7% vs. 38.0%), but quality of life was not adversely affected.ConclusionsRadioligand therapy with 177Lu-PSMA-617 prolonged imaging-based progression-free survival and overall survival when added to standard care in patients with advanced PSMA-positive metastatic castration-resistant prostate cancer. (Funded by Endocyte, a Novartis company; VISION ClinicalTrials.gov number, NCT03511664.)

Review of Myeloma Therapies and Their Potential for Oral and Maxillofacial Side Effects.

Simple SummaryMyeloma is a common cancer involving the bone marrow. Some of the medications used in the treatment of myeloma, including those that reduce the risk of bone fractures, can increase the chance of side effects occurring in the jawbone. The most serious complication in the jawbone is called medication-related osteonecrosis, meaning part of the jawbone dies. The aim of this review is to highlight some of the medications that are implicated and other risk factors that can contribute to osteonecrosis. Suggestions to prevent this complication from occurring are described. Conventional methods of treating established medication-related osteonecrosis of the jawbone are outlined as well as emerging new treatments.Myeloma is a common haematological malignancy in which adverse skeletal related events are frequently seen. Over recent years, treatment for myeloma has evolved leading to improved survival. Antiresorptive therapy is an important adjunct therapy to reduce the risk of bone fractures and to improve the quality of life for myeloma patients; however, this has the potential for unwanted side effects in the oral cavity and maxillofacial region. Osteonecrosis of the jaw related to antiresorptive medications and other myeloma therapies is not uncommon. This review serves to highlight the risk of osteonecrosis of the jaw for myeloma patients, with some suggestions for prevention and management.

Myeloma Bone Disease: The Osteoblast in the Spotlight.

Lytic bone disease remains a life-altering complication of multiple myeloma, with up to 90% of sufferers experiencing skeletal events at some point in their cancer journey. This tumour-induced bone disease is driven by an upregulation of bone resorption (via increased osteoclast (OC) activity) and a downregulation of bone formation (via reduced osteoblast (OB) activity), leading to phenotypic osteolysis. Treatments are limited, and currently exclusively target OCs. Despite existing bone targeting therapies, patients successfully achieving remission from their cancer can still be left with chronic pain, poor mobility, and reduced quality of life as a result of bone disease. As such, the field is desperately in need of new and improved bone-modulating therapeutic agents. One such option is the use of bone anabolics, drugs that are gaining traction in the osteoporosis field following successful clinical trials. The prospect of using these therapies in relation to myeloma is an attractive option, as they aim to stimulate OBs, as opposed to existing therapeutics that do little to orchestrate new bone formation. The preclinical application of bone anabolics in myeloma mouse models has demonstrated positive outcomes for bone repair and fracture resistance. Here, we review the role of the OB in the pathophysiology of myeloma-induced bone disease and explore whether novel OB targeted therapies could improve outcomes for patients.

Two-year results of a randomised trial comparing 4- versus 12-weekly bone-targeted agent use in patients with bone metastases from breast or castration-resistant prostate cancer

BackgroundWe present the 2-year results of a randomised trial comparing 4- versus 12-weekly bone-targeting agents (BTAs) in patients with bone metastases from breast or castration-resistant prostate cancer (CRPC). Patients and MethodsPatients with bone metastases from breast or CRPC, who were going to start or were already receiving BTAs, were randomised to 4- or 12-weekly BTA treatment for 2 years. The endpoints were: symptomatic skeletal events (SSE) rates, time to SSEs, toxicity and cost-effectiveness. ResultsOf 263 patients (160 breast cancer, 103 CRPC), 133 (50.6%) and 130 (49.4%) were randomised to the 4- and 12-weekly groups, respectively. BTAs included denosumab (56.3%), zoledronate (24.0%) and pamidronate (19.8%). After 2 years, the cumulative incidence rate (95% CI) of SSEs was 32.7% (24.6% to 41.1%) and 28.1% (20.3% to 36.4%) for the 4- and 12-weekly intervention groups respectively. The hazard ratio for time to first SSE was 0.96 (95% CI = 0.63 to 1.47). However, in a post hoc analysis, those patients who had an on-study SSE, there was a small non-statistical increased risk of subsequent SSEs among patients on the 12-weekly dosing arm (HR = 1.14; 95% CI – 0.90–1.44). BTA-related toxicity rates were similar between study arms. A cost-utility analysis showed that 12-weekly BTA is cost-effective from a public payer’s perspective. ConclusionThese results in addition to those previously reported for de-escalating zoledronate, would support that de-escalation of commonly used BTAs is a reasonable and economically valid treatment option. While not statistically significant, the increase in subsequent SSEs in the 12-weekly arm requires further exploration.

1327P Impact of bone targeted agents (BTA) in advanced non-small cell lung cancer (aNSCLC) patients (pts) with high bone tumor burden (HBTB) treated with PD(L)1 inhibitors (ICIs)

BTA use in cancer pts with bone metastases (BM) can prevent skeletal related events. A subgroup analysis of aNSCLC pts showed an overall survival (OS) benefit with denosumab (DN) compared to zoledronic acid (ZA), while in the SPLENDOUR trial the addition of DN to 1st line chemotherapy did not improve OS. Currently, the impact of BTA in ICI treated BM aNSCLC remains unclear.

New Functions of Vav Family Proteins in Cardiovascular Biology, Skeletal Muscle, and the Nervous System.

Simple SummaryIn this review, we provide information on the role of Vav proteins, a group of signaling molecules that act as both Rho GTPase activators and adaptor molecules, in the cardiovascular system, skeletal muscle, and the nervous system. We also describe how these functions impact in other physiological and pathological processes such as sympathoregulation, blood pressure regulation, systemic metabolism, and metabolic syndrome.Vav proteins act as tyrosine phosphorylation-regulated guanosine nucleotide exchange factors for Rho GTPases and as molecular scaffolds. In mammals, this family of signaling proteins is composed of three members (Vav1, Vav2, Vav3) that work downstream of protein tyrosine kinases in a wide variety of cellular processes. Recent work with genetically modified mouse models has revealed that these proteins play key signaling roles in vascular smooth and skeletal muscle cells, specific neuronal subtypes, and glia cells. These functions, in turn, ensure the proper regulation of blood pressure levels, skeletal muscle mass, axonal wiring, and fiber myelination events as well as systemic metabolic balance. The study of these mice has also led to the discovery of new physiological interconnection among tissues that contribute to the ontogeny and progression of different pathologies such as, for example, hypertension, cardiovascular disease, and metabolic syndrome. Here, we provide an integrated view of all these new Vav family-dependent signaling and physiological functions.

MP24-04 LONG-TERM OUTCOMES OF PHASE 1 STUDY ON CYTOREDUCTIVE RADICAL PROSTATECTOMY: IS CURE POSSIBLE?

You have accessJournal of UrologyProstate Cancer: Advanced (including Drug Therapy) II (MP24)1 Sep 2021MP24-04 LONG-TERM OUTCOMES OF PHASE 1 STUDY ON CYTOREDUCTIVE RADICAL PROSTATECTOMY: IS CURE POSSIBLE? Joshua Sterling, Arnav Srivastava, Bertram Yuh, Seok Soo Byun, Shigeo Horie, and Isaac Kim Joshua SterlingJoshua Sterling More articles by this author , Arnav SrivastavaArnav Srivastava More articles by this author , Bertram YuhBertram Yuh More articles by this author , Seok Soo ByunSeok Soo Byun More articles by this author , Shigeo HorieShigeo Horie More articles by this author , and Isaac KimIsaac Kim More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002015.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Roughly 4% of new prostate cancer (Pca) patients will be diagnosed with metastatic disease. Traditional treatments for these patients have focused on symptomatic relief and prevention of skeletal events. The dogma that there is no role for surgery in this population has started to be questioned. Here we report long-term outcomes of a phase 1 clinical trial on cytoreductive radical prostatectomy. METHODS: This is a multicenter phase 1 trial (NCT02458716). The major inclusion criteria was biopsy proven Pca with evidence of metastasis by MRI, CT, bone scan, or histologic confirmation. Primary end point was the major complication rate. Secondary outcomes were biochemical progression and overall survival. RESULTS: The patient characteristics of the 33 patients are included in this analysis are shown in table 1. With the median follow-up of 46 months, 25 out of the 33 patients (75%) are still alive at time of last contact. Kaplan Meier curve for overall survival is seen in figure 1. 15 patients still have an undetectable PSA. Among these men, seven were switched to intermittent androgen deprivation therapy and five remain free of any evidence of disease after more than two years off all systemic therapy and normalization of testosterone. Long term pad-free rate was 30.3%. CONCLUSIONS: Overall survival with a median follow-up of 46 months was 75% following cytoreductive radical prostatectomy. Importantly, 15% remain free of any evidence of disease off all systemic therapy for more than two years with normalization of testosterone. This observation suggest that the combination of surgery with systemic therapy may be curative in a minority of men who present with metastatic prostate cancer. However, long-term continence rate was only 30.3%. Source of Funding: This work is supported in part by the cancer center support grant from the National Cancer Institute (P30CA072720) © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e412-e413 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Joshua Sterling More articles by this author Arnav Srivastava More articles by this author Bertram Yuh More articles by this author Seok Soo Byun More articles by this author Shigeo Horie More articles by this author Isaac Kim More articles by this author Expand All Advertisement Loading ...

Real-world incidence of symptomatic skeletal events and bone-modifying agent use in castration-resistant prostate cancer – an Australian multi-centre observational study

IntroductionBone metastases occur frequently in castration-resistant prostate cancer (CRPC) and may lead to skeletal-related events (SREs), including symptomatic skeletal events (SSEs). Bone-modifying agents (BMAs) delay SREs and SSEs. However, the real-world use of BMAs is debated given the absence of demonstrated survival advantage and potential adverse events (AEs). Our retrospective study examined BMA use and SSE rates in Australian patients with CRPC. MethodsPatients with CRPC and bone metastases were identified from the electronic CRPC Australian Database. Patient characteristics, treatment patterns and AEs were analysed. Descriptive statistics reported baseline characteristics, SSE rates and BMA use. Comparisons between groups used t-tests and Chi-square analyses. Overall survival was calculated by the Kaplan-Meier method. ResultsA total of 532 eligible patients were identified with a median age of 73 years (range: 44–97 years). BMAs were prescribed in 232 men (46%), 183 of whom received denosumab. Patients receiving first-line docetaxel for CRPC were more likely to commence BMAs than those receiving abiraterone or enzalutamide (51% vs 31% vs 38%; p = 0.004). SSEs occurred in 148 men (28%), most commonly symptomatic lesions requiring intervention (75%). At the time of initial SSEs, only 28% were receiving BMAs. Patients treated at sites with lower BMA use (<median) had higher SSE rates (32% vs 22%, p = 0.019). ConclusionIn our real-world cohort, SSEs occurred in almost one-third of patients with CRPC and bone metastases, whereas less than half of patients received BMAs. The lower rate of SSEs in treatment sites with increased BMA use supports their benefit in this setting.

Skeletal adverse events in childhood cancer survivors: An Adult Life after Childhood Cancer in Scandinavia cohort study.

The dynamic growth of the skeleton during childhood and adolescence renders it vulnerable to adverse effects of cancer treatment. The lifetime risk and patterns of skeletal morbidity have not been described in a population-based cohort of childhood cancer survivors. A cohort of 26 334 1-year cancer survivors diagnosed before 20 years of age was identified from the national cancer registries of Denmark, Finland, Iceland and Sweden as well as a cohort of 127 531 age- and sex-matched comparison subjects randomly selected from the national population registries in each country. The two cohorts were linked with data from the national hospital registries and the observed numbers of first-time hospital admissions for adverse skeletal outcomes among childhood cancer survivors were compared to the expected numbers derived from the comparison cohort. In total, 1987 childhood cancer survivors had at least one hospital admission with a skeletal adverse event as discharge diagnosis, yielding a rate ratio (RR) of 1.35 (95% confidence interval, 1.29-1.42). Among the survivors, we observed an increased risk for osteonecrosis with a RR of 25.9 (15.0-44.5), osteoporosis, RR 4.53 (3.28-6.27), fractures, RR 1.27 (1.20-1.34), osteochondropathies, RR 1.57 (1.28-1.92) and osteoarthrosis, RR 1.48 (1.28-1.72). The hospitalization risk for any skeletal adverse event was higher among survivors up to the age of 60 years, but the lifetime pattern was different for each type of skeletal adverse event. Understanding the different lifetime patterns and identification of high-risk groups is crucial for developing strategies to optimize skeletal health in childhood cancer survivors.

CORR Insights®: Which Bone-Modifying Agent is Associated with Better Outcomes in Patients with Metastatic Bone Disease from Lung Cancer? A Systematic Review and Network Meta-Analysis.

CORR Insights®: Which Bone-Modifying Agent is Associated with Better Outcomes in Patients with Metastatic Bone Disease from Lung Cancer? A Systematic Review and Network Meta-Analysis.

Fat-Bone Relationship in Chronic Kidney Disease-Mineral Bone Disorders: Adiponectin Is Associated with Skeletal Events among Hemodialysis Patients.

Background: The risk of skeletal events is rising in parallel with the burden of chronic kidney disease and mineral bone disorder (CKD-MBD), whilst the role of the fat-bone axis in CKD-MBD remains elusive. Adiponectin derived from adipocytes has emerged as a valid biomarker of low bone mineral density and increased marrow adiposity. We aimed to explore the association between adiponectin and bone fracture (BF) risks in patients with maintenance hemodialysis (MHD). Methods: Serum concentrations of adiponectin and bio-clinical data were determined at study entry. The Cox proportional hazard regression analyses were used to assess unadjusted and adjusted hazard ratios (aHRs) of adiponectin and various clinical predictors for BF risks. The predictive accuracy of adiponectin for BF events was evaluated by receiver operating characteristic (ROC) curve analysis. Results: Age and serum concentrations of adiponectin, phosphate, and intact parathyroid hormone were significantly associated with higher risks of BF. With respect to the risk of BF events, the cumulative event-free survival curves differed significantly between the high and low concentration groups of adiponectin (p = 0.02). In multivariable analysis, higher adiponectin levels were associated with an incremental risk of BF (adjusted hazard ratios (aHRs): 1.08 (95% confidence interval (CI): 1.01–1.15, p < 0.05). The ROC analysis of adiponectin cutoff point concentration (18.15 ug/mL) for prediction of BF showed 0.66 (95% CI = 0.49 to 0.84). Conclusion: Adiponectin was associated with an incremental risk of BF that could serve as a potential predictor of BF in MHD patients. In the high-risk population with hyperphosphatemia, an elevated adiponectin level could alert clinicians to the urgent need to correct mineral dysregulation and undertake further bone survey.

Circulating p-Cresyl Sulfate, Non-Hepatic Alkaline Phosphatase and Risk of Bone Fracture Events in Chronic Kidney Disease-Mineral Bone Disease.

Patients with chronic kidney disease (CKD), especially those undergoing hemodialysis, are at a considerably high risk of bone fracture events. Experimental data indicate that uremic toxins intricately involved in bone-related proteins exert multi-faced toxicity on bone cells and tissues, leading to chronic kidney disease–mineral and bone disorder (CKD-MBD). Nonetheless, information regarding the association between p-cresyl sulfate (PCS), non-hepatic alkaline phosphatase (NHALP) and skeletal events remains elusive. We aim to explore the association between PCS, NHALP and risk of bone fracture (BF) in patients with hemodialysis. Plasma concentrations of PCS and NHALP were ascertained at study entry. Cox proportional hazard regression analyses were used to determine unadjusted and adjusted hazard ratios (aHRs) of PCS for BF risk. In multivariable analysis, NHALP was associated with incremental risks of BFs [aHR: 1.06 (95% CI: 1.01–1.11)]. The association between the highest PCS tertile and BF risk remained robust [aHR: 2.87 (95% CI: 1.02–8.09)]. With respect to BF events, the interaction between NHALP and PCS was statistically significant (p value for the interaction term < 0.05). In addition to mineral dysregulation and hyperparathyroidism in hemodialysis patients, higher circulating levels of PCS and NHALP are intricately associated with incremental risk of BF events, indicating that a joint evaluation is more comprehensive than single marker. In light of the extremely high prevalence of CKD-MBD in the hemodialysis population, PCS may act as a pro-osteoporotic toxin and serve as a potential surrogate marker for skeletal events.

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.

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.

Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION).

LBA4 Background: Despite recent therapeutic advances, metastatic castration-resistant prostate cancer (mCRPC) remains invariably fatal. Prostate-specific membrane antigen (PSMA) is highly expressed in mCRPC lesions. 177Lu-PSMA-617 is a targeted radioligand therapy that delivers ß-particle radiation to PSMA-expressing cells and surrounding microenvironment. Method: VISION was an international, randomized, open-label phase III study evaluating 177Lu-PSMA-617 in men with PSMA-positive mCRPC previously treated with next-generation androgen receptor signaling inhibition and 1–2 taxane regimens. PSMA positivity (threshold greater than liver) was determined by central review of 68Ga-PSMA-11 scans. Patients were randomized 2:1 to 177Lu-PSMA-617 (7.4 GBq every 6 weeks x 6 cycles) plus standard of care (SOC) versus SOC alone. SOC was investigator determined but excluded cytotoxic chemotherapy and radium-223. The alternate primary endpoints were radiographic progression-free survival (rPFS) using PCWG3 criteria by independent central review (ICR) and overall survival (OS). Under the null hypothesis, median rPFS was assumed to be 4 months and OS 10 months for 177Lu-PSMA-617 + SOC for a hazard ratio (HR) of 1.00. Under the alternative hypothesis, median rPFS was assumed to be 6 months for a HR of 0.67 and median OS was assumed to be 13.7 months for a HR of 0.7306. Key secondary endpoints were objective response rate (ORR; RECIST v1.1), disease control rate (DCR), and time to first symptomatic skeletal event (SSE). Results: Between 4 June 2018 and 23 October 2019, 831 of 1179 screened patients were randomized 2:1 to receive 177Lu-PSMA-617 + SOC (n = 551) or SOC only (n = 280). Median study follow-up was 20.9 months at the data cut-off (27 January 2021). Treatment groups were balanced in terms of demographics and baseline characteristics. 177Lu-PSMA-617 + SOC significantly improved rPFS versus SOC alone (median rPFS, 8.7 vs 3.4 months; HR, 0.40 [99.2% CI: 0.29, 0.57]; p &lt; 0.001, one-sided). The alternate primary endpoint of OS was also significantly improved versus SOC alone (median OS, 15.3 vs 11.3 months; HR, 0.62 [95% CI: 0.52, 0.74]; p &lt; 0.001, one-sided). All key secondary endpoints were statistically significant between the treatment arms in favor of 177Lu-PSMA-617 + SOC, including ICR-determined ORR (29.8% vs 1.7%), ICR-determined DCR (89.0% vs 66.7%) and time to first SSE (median time, 11.5 vs 6.8 months; HR, 0.50). While a higher rate of high-grade treatment-emergent adverse events was observed with 177Lu-PSMA-617 (52.7% vs 38.0%), therapy was well tolerated. Conclusions: 177Lu-PSMA-617 plus SOC treatment is a well-tolerated regimen that improves rPFS and prolongs OS compared with SOC alone in men with advanced-stage PSMA-positive mCRPC, supporting its adoption as a standard of care. Clinical trial information: NCT03511664.

UPAR PET/CT for Prognostication and Response Assessment in Patients with Metastatic Castration-Resistant Prostate Cancer Undergoing Radium-223 Therapy: A Prospective Phase II Study.

The aim of this Phase II study was to investigate the potential for response assessment and prognostication of positron emission tomography (PET) using the ligand 68Ga-NOTA-AE105 targeting the urokinase-type plasminogen activator receptor (uPAR) in patients receiving Radium-223-dichloride therapy (223RaCl2). A combined whole-body uPAR PET and computed tomography (CT) was performed before initiation of 223RaCl2 and after two cycles of therapy. Standardized uptake value (SUV) in selected bone metastases was measured and the lesion with the highest SUVmax was considered the index lesion. Clinical outcomes were overall survival (OS), radiographic progression free survival (rPFS) and occurrence of symptomatic skeletal event (SSE). A total of 17 patients were included and 14 patients completed both baseline and follow-up uPAR-PET/CT. Baseline SUVmax of the index lesion was associated with OS; hazard ratio 2.51 (95% CI: 1.01–6.28, p = 0.05) per unit increase in SUVmax. No association between changes in SUVmax from baseline to follow-up and OS, progression during therapy, or rPFS was found. Baseline SUVmax was a significant predictor of SSE with receiver operating characteristics (ROC) area under the curve (AUC) = 0.81 (95% CI: 0.58–1.00, p = 0.034). A cut-off for tumor SUVmax could be established with an odds ratio of 14.0 (95% CI: 1.14–172.6, p = 0.023) for occurrence of SSE within 12 months. Although based on a small number of patients, uPAR-PET SUVmax in bone metastases was predictive for OS and risk of SSE in mCRPC patients receiving 223RaCl2. However, a relatively low uptake of the uPAR ligand in bone metastases impedes visual evaluation and requires another modality for lesion delineation.

Morphological Verification Of Malignant Neoplasm Of The Urinary System With Multiple Bone Metastases

In metastatic renal cell carcinoma (mRCC), bone is the second most common site of metastases, occurring in one third of patients. Most bone metastases are found in the sacrum, pelvis, spine and proximal limbs. In addition, the majority of bone metastases are osteolytic with elements of destruction; mixed metastases also occur. This predisposes patients to skeletal events such as pathological fracture, spinal cord compression, which implies the prescription of radiation therapy or bone surgery.

Perceptions around bone-modifying agent use in patients with bone metastases from breast and castration resistant prostate cancer: a patient survey.

BackgroundOptimal use of bone-modifying agent (BMA) therapy in patients with bone metastases from breast and castrate-resistant prostate cancer (CRPC) is evolving.MethodsPatients receiving BMA for bone metastases from breast or CRPC were surveyed. Information was collected on patient and disease characteristics, BMA treatments and perceptions regarding BMA benefits and side effects. Interest in participation in trials of de-escalated BMA therapy was also gauged.ResultsOf 220 patients contacted, 172 eligible patients responded (response rate 78%). Median age was 67 (range: 21–91); 137 (80%) had breast cancer and 35 (20%) CRPC. Symptomatic skeletal events (SSEs) occurred prior to starting BMAs in 61% (84/137) of breast and 48% (17/35) of CRPC patients. Among breast cancer patients, 47, 33 and 13% received zoledronate, pamidronate and denosumab, respectively. Eighty-five percent (30/35) of CRPC patients received denosumab. De-escalation of therapy was more common among breast cancer patients. Although most patients correctly reported the goals of BMA therapy were to “help stop fractures” (62%) and “[improve] quality of life” (63%), 46.5% felt it prolonged survival and 54% felt it reduced bone progression. Most respondents (102/129, 79%) were comfortable with de-escalating to 6-monthly treatment after 2 years of BMA therapy. Patients considered the most important endpoints of de-escalation studies to be “stability of bone metastases” (45%), “quality of life” (22%) and “SSE rates” (14%).ConclusionTwelve weekly BMA was more common in breast than in prostate cancer. There remain misconceptions about the benefits of BMAs, highlighting potential gaps in patient education. Patients were interested in further BMA de-escalation after 2 years of prior BMA and provided study endpoints that were most important to them.Supplementary InformationThe online version contains supplementary material available at 10.1007/s00520-021-06238-1.

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.