Denosumab In Breast Cancer Research Articles

Long-Term Outcomes of Adjuvant Denosumab in Breast Cancer

BackgroundAdjuvant aromatase inhibitors increase osteoporosis and fractures in patients with hormone receptor–positive breast cancer. We have previously reported outcomes of the ABCSG-18 (study 18 from the Austrian Breast & Colorectal Cancer Study Group) trial showing that adjuvant anti–receptor activator of nuclear factor-κB ligand denosumab treatment counteracts these adverse effects and may improve outcomes. We report here the final long-term outcomes.MethodsABCSG-18 is a prospective, double-blind, placebo-controlled, phase 3 trial in which 3425 postmenopausal patients with early hormone receptor–positive breast cancer receiving aromatase inhibitor therapy were randomly assigned in 58 trial centers to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months. The primary end point was the time to first clinical fracture after randomization. Secondary disease outcome–related end points were disease-free survival (DFS), bone metastasis–free survival (BMFS), and overall survival (OS).ResultsFor this final protocol-defined analysis, median follow-up is 8 years (interquartile range, 6 to 9.6 years). There were 309 versus 368 DFS events (hazard ratio, 0.83; 95% confidence interval [CI], 0.71 to 0.97) in the denosumab versus the placebo group, respectively, resulting in an absolute 9-year DFS benefit of 3.5 percentage points (79.4 vs. 75.9%). Adjuvant denosumab improved BMFS by 2.5 percentage points (88.9 vs. 86.4%; hazard ratio, 0.81; 95% CI, 0.65 to 1.00) and OS by 1.0 percentage point (90.9 vs. 89.9%; hazard ratio, 0.80; 95% CI, 0.64 to 1.01). No new toxicities for this dose of adjuvant denosumab were observed.ConclusionsDFS, BMFS, and OS continued to show benefit in this final long-term analysis of ABCSG-18. There were no new toxicities. (Funded by Amgen; ClinicalTrials.gov number, NCT00556374.)

207 (PB-031) Poster - Efficacy and safety of the biosimilar QL1206 compared with denosumab in breast cancer with bone metastases: subgroup analyses of a phase III study

Background: The prevalence of bone metastases in advanced breast cancer is high (>70%). QL1206 is a biosimilar for denosumab (Xgeva®, Amgen Inc.) and has demonstrated equivalence to the reference product in previous Ph I bioequivalence trial and Ph III trial. Here we present the results of these analyses in breast cancer subgroup.

Long-term outcomes of adjuvant denosumab in breast cancer: Fracture reduction and survival results from 3,425 patients in the randomised, double-blind, placebo-controlled ABCSG-18 trial.

507 Background: State-of-the-art adjuvant endocrine therapy with aromatase inhibitors (AI) compromises bone health in postmenopausal patients with hormone receptor-positive (HR+) breast cancer, increasing fracture incidence. Adjuvant treatment with the anti-RANK ligand denosumab (Dmab) counteracts these side effects and may improve outcomes. We here report the final long-term outcomes of the ABCSG-18 trial (ClinicalTrials.gov NCT00556374). Methods: In this prospective, double-blind, placebo-controlled, phase 3 trial, 3,425 postmenopausal patients with early HR+ breast cancer on AI therapy were randomised in 58 trial centers between 2006 and 2013 to receive either Dmab 60 mg or placebo s.c. every 6 months (q6m). The primary endpoint was time to first clinical fracture, secondary disease outcome-related endpoints were disease-free survival (DFS), bone-metastasis free survival (BMFS), and overall survival (OS). In addition to the main endpoint analyses reported previously, exploratory long-term follow-up was conducted in ABCSG-18. Main time-to-event analyses were based on stratified Cox models. Sensitivity analyses accounting for treatment cross-over associated with a late Dmab open-label phase, as well as for receiving any anti-resorptive agents were performed. Results: For this final protocol-defined analysis, median follow-up is 8 years (Q1,3: 6, 9.6), and all patients had ended their randomly assigned double-blind treatment (Dmab 60mg s.c. q6m n = 1711; placebo s.c. q6m n = 1709) for a median of 5 years. DFS was improved in the Dmab group versus the placebo group (309 versus 368 DFS events, hazard ratio (HR) 0.83, 95% CI 0.71-0.97, p = 0.016), resulting in an absolute 9-year DFS difference of 3.5% (79.4% vs 75.9%, respectively). When censoring for late cross-over and use of anti-resorptive agents, the DFS difference was confirmed (HR 0.82, p = 0.010). BMFS was improved by 19 per cent (HR 0.81, 95% CI 0.65-1.00, p = 0.047) in the Dmab group, and OS was improved by 20 per cent in the uncensored analysis (127 versus 158 OS events, HR 0.80, 95% CI 0.64-1.01, p = 0.065), and 26 per cent after censoring (HR 0.74, 95% CI 0.58-0.94, p = 0.013). The previously reported marked reduction in clinical fractures persisted even long-term, with 201 fractures in the Dmab and 255 fractures in the placebo group (HR 0.76, 95% CI 0.63-0.92, p = 0.004). No new toxicities for this (low) bone-protective dose of adjuvant Dmab were reported, particularly no ONJ occured.. Conclusions: Adjuvant Dmab 60mg every 6 months during AI therapy is safe, and markedly reduces treatment-induced clinical fractures even in the long-term. DFS, BMFS, and OS are improved in this descriptive final long-term analysis of ABCSG-18. Adjuvant denosumab should be considered for routine clinical use in postmenopausal patients with HR+ breast cancer. Clinical trial information: NCT00556374.

Abstract PD5-06: The immunomodulatory potential of denosumab in breast cancer: results from D-BEYOND, a window of opportunity trial evaluating a RANK-ligand (RANKL) inhibitor and its biological effects in young pre-menopausal women diagnosed with early breast cancer

Abstract Background Breast cancer (BC) in young women has unique biology and poor prognosis. Previous reports suggest that they often express RANKL, which was also shown to play a role in mammary tumorigenesis and various immune processes. Here, we present the primary results of D-BEYOND, a window study investigating the biological activity of the RANKL inhibitor; denosumab in pre-menopausal BC patients. Methods D-BEYOND is a prospective, phase Iia, single-arm, multicenter study assessing the effect of denosumab on BC biology in premenopausal women with early BC (NCT01864798). Patients received two subcutaneous injections of denosumab (120mg), one week apart, followed by breast surgery. The primary endpoint was geometric mean change in tumor Ki67 assessed by immunohistochemistry (IHC). Blood, tumor and normal adjacent breast tissue were collected pre- and post-treatment. Serum levels of RANKL, OPG and CTX were assessed by ELISA. RNA was extracted from fresh-frozen tissue and RNAseq was performed. DESeq2 was used for differential expression analysis, GAGE was used for pathway analysis and CIBERSORT was used to infer immune cell subsets between pre- and post-treatment. Ki67, CD4/Foxp3 and CD4/CD8 IHC were performed on FFPE tissue to further assess the immune microenvironment. The percentage of TILs was independently evaluated by two pathologists on H&E slides. Pre- and post-treatment values were compared using a paired t-test. Results A total of 27 patients were enrolled in the study between October 2013 and July 2016. The median age was 45 years (range 35-51 years). Tumors of 21 patients were hormone receptor positive (77.8%), 4 were HER2 positive (14.8%) and 2 were triple negative (7.4%). No serious adverse events were reported, the most frequent non-serious adverse event being arthralgia (14.8%). After treatment, serum levels of CTX and RANKL decreased in all patients (P < 0.001) whereas OPG increased in 76.9% of patients (P = 0.009, 95% CI 0.56-0.91). There was no significant reduction of Ki67 values from baseline (geometric mean [GM] change after treatment; 0.98, 95% CI 0.76-1.26; P = 0.90). Twenty-four pre- and post-treatment tumor pairs were available for RNAseq, IHC and TILs evaluation. There was a significant increase in the percentage of stromal TILs after treatment (GM change of 1.75, 95% CI 1.28–2.39; P = 0.001). 1084 differentially expressed genes were identified and pathway analysis revealed enrichment of several immune processes. CIBERSORT revealed an enrichment of CD8+ T cells (GM change 1.72, 95% CI 1.19–2.48; P = 0.006) and a decrease of Treg cells (0.71, 95% CI 0.52–0.98, P = 0.040). These results were confirmed by IHC of CD8+ and CD4+/Foxp3+ cells (GM change 1.59, 95% CI 1.14–2.21; P = 0.008 and 0.63, 95% CI 0.49–0.83, P = 0.001, respectively). Conclusion Short course of denosumab did not reduce tumor proliferation rate. However, it induced a significant increase in TILs and CD8 cytotoxic T cells, while Treg infiltration decreased. These findings suggest an immunomodulatory role for denosumab in young breast cancer and that its use in combination could boost immunotherapy efficacy. Citation Format: Nguyen B, Marion M, Salgado R, Venet D, Vuylsteke P, Polastro L, Wieldiers H, Simon P, Lindeman G, Larsimont D, Van den Eynden G, Velghe C, Rothe F, Garaud S, Michiels S, Willard-Gallo K, Azim Jr HA, Loi S, Piccart M, Sotiriou C. The immunomodulatory potential of denosumab in breast cancer: results from D-BEYOND, a window of opportunity trial evaluating a RANK-ligand (RANKL) inhibitor and its biological effects in young pre-menopausal women diagnosed with early breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD5-06.

In postmenopausal women with breast cancer treated with aromatase inhibitors, denosumab reduced fractures.

Source Citation Gnant M, Pfeiler G, Dubsky PC, et al; Austrian Breast and Colorectal Cancer Study Group. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015 May 29. Epub ahead of print. 26040499

Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial

Adjuvant endocrine therapy compromises bone health in patients with breast cancer, causing osteopenia, osteoporosis, and fractures. Antiresorptive treatments such as bisphosphonates prevent and counteract these side-effects. In this trial, we aimed to investigate the effects of the anti-RANK ligand antibody denosumab in postmenopausal, aromatase inhibitor-treated patients with early-stage hormone receptor-positive breast cancer. In this prospective, double-blind, placebo-controlled, phase 3 trial, postmenopausal patients with early hormone receptor-positive breast cancer receiving treatment with aromatase inhibitors were randomly assigned in a 1:1 ratio to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months in 58 trial centres in Austria and Sweden. Patients were assigned by an interactive voice response system. The randomisation schedule used a randomly permuted block design with block sizes 2 and 4, stratified by type of hospital regarding Hologic device for DXA scans, previous aromatase inhibitor use, and baseline bone mineral density. Patients, treating physicians, investigators, data managers, and all study personnel were masked to treatment allocation. The primary endpoint was time from randomisation to first clinical fracture, analysed by intention to treat. As an additional sensitivity analysis, we also analysed the primary endpoint on the per-protocol population. Patients were treated until the prespecified number of 247 first clinical fractures was reached. This trial is ongoing (patients are in follow-up) and is registered with the European Clinical Trials Database, number 2005-005275-15, and with ClinicalTrials.gov, number NCT00556374. Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled into the trial, of whom 3420 were randomly assigned to receive denosumab 60 mg (n=1711) or placebo (n=1709) subcutaneously every 6 months. Compared with the placebo group, patients in the denosumab group had a significantly delayed time to first clinical fracture (hazard ratio [HR] 0·50 [95% CI 0·39-0·65], p<0·0001). The overall lower number of fractures in the denosumab group (92) than in the placebo group (176) was similar in all patient subgroups, including in patients with a bone mineral density T-score of -1 or higher at baseline (n=1872, HR 0·44 [95% CI 0·31-0·64], p<0·0001) and in those with a bone mineral density T-score of less than -1 already at baseline (n=1548, HR 0·57 [95% CI 0·40-0·82], p=0·002). The patient incidence of adverse events in the safety analysis set (all patients who received at least one dose of study drug) did not differ between the denosumab group (1366 events, 80%) and the placebo group (1334 events, 79%), nor did the numbers of serious adverse events (521 vs 511 [30% in each group]). The main adverse events were arthralgia and other aromatase-inhibitor related symptoms; no additional toxicity from the study drug was reported. Despite proactive adjudication of every potential osteonecrosis of the jaw by an international expert panel, no cases of osteonecrosis of the jaw were reported. 93 patients (3% of the full analysis set) died during the study, of which one death (in the denosumab group) was thought to be related to the study drug. Adjuvant denosumab 60 mg twice per year reduces the risk of clinical fractures in postmenopausal women with breast cancer receiving aromatase inhibitors, and can be administered without added toxicity. Since a main side-effect of adjuvant breast cancer treatment can be substantially reduced by the addition of denosumab, this treatment should be considered for clinical practice. Amgen.

Adjuvant denosumab in breast cancer: Results from 3,425 postmenopausal patients of the ABCSG-18 trial.

504 Background: Adjuvant endocrine therapy compromises bone health in pre- and postmenopausal breast cancer (BC) patients. Treatment-induced osteopenia, osteoporosis, and fractures are frequent sid...

Denosumab for the treatment of bone metastases in breast cancer: evidence and opinion

Denosumab, a fully human monoclonal antibody, targets the receptor activator of nuclear factor-kappaB (RANK) ligand, a protein essential for osteoclast differentiation, activity and survival. Loss of osteoclasts from the bone surface reduces bone turnover and bone loss in malignant and benign diseases. In breast cancer, bone metastases are frequently observed; cancer treatment-induced bone loss (CTIBL) may result as a consequence of endocrine treatment or chemotherapy. Furthermore, preclinical studies suggest a direct role of the RANK/RANK-ligand pathway in breast tumorigenesis. This paper reviews preclinical and clinical data on denosumab in breast cancer. Studies were identified through the Medline database. Key search terms included: AMG-162, bisphosphonates, denosumab, RANK-ligand and zoledronic acid. Information available in abstract form only was retrieved from major oncology meetings, such as the American Society of Clinical Oncology (ASCO) annual meeting, ASCO breast meeting, European Cancer Organization, European Society of Medical Oncology and the San Antonio Breast Cancer Symposium. Denosumab was consistently well tolerated throughout clinical trials, although the observed incidence of osteonecrosis of the jaw was comparable to that with bisphosphonates. Efficacy as determined by a reduction of skeletal-related events was at least equal to zoledronic acid, and superior in one phase III study conducted in patients with metastatic breast cancer. Clinical trials investigating the role of denosumab for the prevention of CTIBL and breast cancer recurrences are currently ongoing. In conclusion, denosumab appears to be an effective and safe treatment option in patients with bone metastases from breast cancer with the potential of also preventing CTIBL.

Denosumab in Breast Cancer

Bone destruction is mediated by osteoclasts, whose formation, function, and survival requires the receptor activator of NF-kB ligand (RANKL). Denosumab is a fully human monoclonal antibody to RANKL, thereby inhibiting osteoclast-mediated bone destruction, and blocks the vicious cycle of cancer-mediated bone disease. In breast cancer patients with bone metastases, denosumab was superior to zoledronic acid in delaying time to first on-study skeletal-related event (SRE; HR=0.82; P=0.01 superiority) and time to first and subsequent on-study SREs (HR=0.77; P=0.001). Overall survival, disease progression, and serious adverse events were similar between groups.

Role of denosumab in breast cancer

Recent advances in adjuvant treatment have improved progression-free and overall survival in patients with early stage breast cancer. However, up to one third of women will experience tumour recurrence, with bone being a common metastatic site. Current treatment options for metastases to bone comprise systemic antitumour therapy, irradiation, surgery and biphosphonates. As osteoclast activation is mediated by the receptor activator of NF-κB (RANK)/RANK ligand pathway and inhibited by osteoprotegerin (OPG), it was suggested that inhibition of this system may treat bone metastases. Recombinant Fc-OPG was evaluated in women with osteoporosis and malignant bone disease. The fully human antibody denosumab has demonstrated superior activity in reducing markers of bone turnover; therefore this drug was further developed in clinical settings. In advanced breast cancer, denosumab reduced urinary-N-telopeptide:creatinine ratio with potentially fewer side effects compared with bisphosphonates. Proof of direct antitumor activity is missing. Here we review the development and current status of denosumab in breast cancer. Data were obtained by searching the Medline database and abstracts from the American Society for Clinical Oncology (ASCO) annual meeting, European Cancer organization (ECCO), European Society for Medical Oncology (ESMO) and the San Antonio Breast Cancer Symposium, using search terms including bone metastases, bisphosphonates, breast cancer, denosumab, osteoprotegerin, RANK and skeletal-related events.