Role of denosumab in the management of skeletal complications in patients with bone metastases from solid tumors

Skeletal-related events (SREs) including pain, fractures, and hypercalcemia are a major source of morbidity for cancer patients with bone metastases. The receptor activator of NF-κB ligand (RANKL) is a key mediator of osteoclast formation and activity in normal bone physiology as well as cancer-induced bone resorption. The first commercially available drug that specifically targets and inhibits the RANKL pathway is denosumab, a fully human monoclonal antibody that binds and neutralizes RANKL, thereby inhibiting osteoclast function. In this review, we summarize the major studies leading to the US Food and Drug Administration-approval of denosumab for the prevention of SREs in patients with bone metastases from solid tumors. Further, we discuss the role of denosumab in the prevention and treatment of SREs and bone loss in cancer patients. As a monoclonal antibody, denosumab has several advantages over bisphosphonates, including improved efficacy, better tolerability, and the convenience of administration by subcutaneous injection. In addition, as denosumab has no known renal toxicity, it may be the preferred choice over bisphosphonates in patients with baseline renal insufficiency or receiving nephrotoxic therapies. However, other toxicities, including osteonecrosis of the jaw and hypocalcemia, appear to be class effects of agents that potently inhibit osteoclast activity and are associated with both denosumab and bisphosphonate use. The data presented highlight the differences associated with intravenous bisphosphonate and denosumab use as well as confirm the essential role bone-modifying agents play in maintaining the quality of life for patients with bone metastases

Changes in Bone Turnover Marker Levels and Clinical Outcomes in Patients With Advanced Cancer and Bone Metastases Treated With Bone Antiresorptive Agents

Purpose: Bone antiresorptive agents can significantly reduce bone turnover markers (BTMs) in patients with advanced cancer. We evaluated association of changes in BTMs with overall survival (OS), disease progression (DP), and disease progression in bone (DPB) in patients with advanced cancer and bone metastases following denosumab or zoledronic acid treatment. Experimental Design: This is an integrated analysis of patient-level data from three identically designed, blinded, phase III trials with patients randomized to subcutaneous denosumab or intravenous zoledronic acid. Levels of the BTMs urinary N-telopeptide (uNTx) and serum bone-specific alkaline phosphatase (sBSAP) measured at study entry and month 3 were analyzed. OS, DP, and DPB were compared in patients with BTMs {greater than or equal to} median vs < median based on month 3 assessments. Results: uNTx levels {greater than or equal to} the median of 10.0 nmol/mmol at month 3 were associated with significantly reduced OS compared with levels < median (HR for death 1.85, P<0.0001). sBSAP levels {greater than or equal to} median of 12.6 ng/mL were associated with significantly reduced OS compared with levels < median (HR 2.44, P<0.0001). uNTx and sBSAP levels {greater than or equal to} median at month 3 were associated with significantly greater risk of DP (HR 1.31, P<0.0001 and HR 1.71, P<0.0001, respectively) and DPB (HR 1.11, P=0.0407 and HR 1.27, P<0.0001, respectively). Conclusions: BTM levels {greater than or equal to} median after 3 months of bone antiresorptive treatment were associated with reduced OS and increased risk of DP and DPB. Assessment of uNTx and sBSAP levels after bone antiresorptive therapy may add to identification of patients at risk for worse clinical outcomes

Safety of long-term denosumab therapy: results from the open label extension phase of two phase 3 studies in patients with metastatic breast and prostate cancer

Purpose: Zoledronic acid (ZA) or denosumab treatment reduces skeletal-related events; however, the safety of prolonged therapy has not been adequately studied. Here, we describe safety results of extended denosumab therapy in patients with bone metastases from the open-label extension phase of two phase 3 trials. Methods: Patients with metastatic breast or prostate cancer received subcutaneous denosumab 120 mg Q4W or intravenous ZA 4 mg Q4W in a double-blinded fashion. Denosumab demonstrated superior efficacy in the blinded treatment phase; thus, patients were offered open-label denosumab for up to an additional 2 years. Results: Cumulative median (Q1, Q3) denosumab exposure was 19.1 (9.2, 32.2) months in the breast cancer trial (n = 1019) and 12.0 (5.6, 21.3) months in the prostate cancer trial (n = 942); 295 patients received denosumab for >3 years. No new safety signals were identified during the open-label phase, or among patients who switched from ZA to denosumab. During the blinded treatment phase, exposure-adjusted subject incidences of osteonecrosis of the jaw (ONJ) were 49 (1.9 %) and 31 (1.2 %) in the denosumab and ZA groups, respectively. In total, 32 (6.9 %) and 25 (5.5 %) new cases of ONJ (not adjusted for exposure) were reported for patients continuing and switching to denosumab, respectively. The incidences of hypocalcemia were 4.3 and 3.1 %, in patients continuing and switching to denosumab, respectively. Conclusion: These results describe the safety profile of denosumab after long-term exposure, or after switching to denosumab from ZA. No new safety signals were identified. Hypocalcemia rates were similar in the blinded treatment and open-label phases. ONJ rates increased with increasing exposure to antiresorptives, consistent with previous reports

Blood Plasma Derived Extracellular Vesicles (Bevs): Particle Purification Liquid Chromatography (PPLC) and Proteomic Analysis Reveals Bevs as a Potential Minimally Invasive Tool for Predicting Response to Breast Cancer Treatment

PURPOSE: Circulating blood plasma derived extracellular vesicles (BEVs) containing proteins hold promise for their use as minimally invasive biomarkers for predicting response to cancer therapy. The main goal of this study was to establish the efficiency and utility of the particle purification liquid chromatography (PPLC) BEV isolation method and evaluate the role of BEVs in predicting breast cancer (BC) patient response to neoadjuvant chemotherapy (NAC). METHODS: PPLC isolation was used to separate BEVs from non-EV contaminants and characterize BEVs from 17 BC patients scheduled to receive NAC. Using LC-MS/MS, we compared the proteome of PPLC-isolated BEVs from patients (n = 7) that achieved a pathological complete response (pCR) after NAC (responders [R]) to patients (n = 10) who did not achieve pCR (non-responders [NR]). Luminal MCF7 and basaloid MDA-MB-231 BC cells were treated with isolated BEVs and evaluated for metabolic activity by MTT assay. RESULTS: NR had elevated BEV concentrations and negative zeta potential (ζ-potential) prior to receipt of NAC. Eight proteins were enriched in BEVs of NR. GP1BA (CD42b), PECAM-1 (CD31), CAPN1, HSPB1 (HSP27), and ANXA5 were validated using western blot. MTT assay revealed BEVs from R and NR patients increased metabolic activity of MCF7 and MDA-MB-231 BC cells and the magnitude was highest in MCF7s treated with NR BEVs. CONCLUSION: PPLC-based EV isolation provides a preanalytical separation process for BEVs devoid of most contaminants. Our findings suggest that PPLC-isolated BEVs and the five associated proteins may be established as predictors of chemoresistance, and thus serve to identify NR to spare them the toxic effects of NAC