Denosumab for the treatment of bone metastases in advanced breast cancer.

In women with advanced breast cancer, approximately three-quarters develop metastases to the bone, with a median survival after diagnosis of 2-3 years. Receptor activator of nuclear factor-κB (RANK) and RANK ligand (RANKL) belong to a signal pathway highly implicated in the development of bone metastases. Denosumab, a human monoclonal antibody with high affinity and specificity for RANKL, prevents the RANKL/RANK interaction and inhibits osteoclast formation and function, thereby decreasing bone resorption and increasing bone mass. Denosumab compared with zoledronic acid showed superior efficacy in delaying time to first-on study SRE and time to first- and subsequent-on study SREs as well as reduction in bone turnover markers. These results led to the approval of denosumab by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA), for the prevention of SREs in adults with bone metastases from solid tumors, including breast cancer.

Casas A ，Llombart A ，Martín M 《-》

Quantitative pharmacology of denosumab in patients with bone metastases from solid tumors.

Denosumab (XGEVA®) is a recombinant, fully human IgG2 monoclonal antibody directed against the receptor activator of nuclear factor kappa-B ligand (RANKL) that prevents differentiation of osteoclast precursors into mature osteoclasts and acceleration of bone resorption, resulting in the inhibition of osteoclast activation. Denosumab is indicated for the prevention of skeletal-related events (SREs) in adult patients with bone metastases from solid tumors at the dose of 120 mg administered subcutaneously (SC) every 4 weeks. This review is focused on describing its target-mediated disposition and direct inhibitory effect on bone resorption, as well as the modeling and simulation techniques used to integrate the PKPD information collected during clinical development of denosumab. In addition, this review further discusses the clinical relevance of patient covariate effects on denosumab systemic exposure, target engagement and downstream pharmacodynamics biomarkers, and the rationale for dosing regimen selection for Phase 3 studies. Phase 3 clinical studies demonstrated that denosumab was superior to zoledronic acid in inhibiting bone resorption and, consequently, delaying the time to first SRE by a median of 8.2 months in patients with bone metastases from solid tumors. Thus, denosumab may be considered a better alternative treatment than zoledronic acid for the prevention of SRE in patients with bone metastases from solid tumors.

Perez Ruixo JJ ，Doshi S ，Sohn W ，Chow A ... -  《-》

Denosumab in breast cancer treatment.

The bone is the most common site to which breast cancer metastasises. Recently, denosumab, a fully human monoclonal antibody that binds to receptor activator of nuclear factor kappa-B ligand (RANKL) has been developed as a new targeted bone therapy. In a large randomized phase III study with a head-to-head comparison of denosumab to zoledronic acid in patients with bone metastases of breast cancer, denosumab significantly delayed the time to first skeletal related event. In the adjuvant setting denosumab significantly increased bone mineral density compared to placebo in a phase III study in patients treated with aromatase inhibitors. Preclinical data suggest an effect of denosumab on tumour growth and even on carcinogenesis. This review describes the current indications for denosumab in the various settings of breast cancer treatment, with special attention for efficacy, short and long term toxicity and other relevant issues for clinical practice. Furthermore possible and necessary future research questions are proposed.

Drooger JC ，van der Padt A ，Sleijfer S ，Jager A ... -  《-》

Advances in prevention and treatment of bone metastases in prostate cancer. Role of RANK/RANKL inhibition.

Bone metastases are a common complication of prostate cancer, so treatment and prevention are essential to slow the progression of the disease and the occurrence of skeletal related events (SREs), which have devastating consequences for the quality of life of patients. Bone metastases are characterized by increased bone turnover and altered balance between osteogenesis and osteolysis, with activation of the RANK and its ligand (RANKL). In patients with metastatic prostate cancer, bisphosphonates have been the bone-targeted agents most commonly used to date. Zoledronic acid has demonstrated efficacy in the reduction and delay of SREs in patients with bone metastases. Denosumab, a RANKL inhibitor, has been demonstrated to be superior to zoledronic acid in the prevention of SREs in castration-resistant prostate cancer (CRPC). Both agents are being considered, along with other new bone-targeted agents, for the prevention of bone metastases in patients with nonmetastatic CRPC, where denosumab has already demonstrated superiority over placebo. Denosumab and zoledronic acid prevent SREs in patients with prostate cancer and bone metastases. Denosumab also has a potential role in delaying bone metastases in nonmetastatic patients. Advances in the treatment of CRPC include an increasing focus on prevention of the progression of bone disease.

Gomez-Veiga F ，Ponce-Reixa J ，Martinez-Breijo S ，Planas J ，Morote J ... -  《-》

[Anti-RANKL antibody for treatment of patients with bone metastasis from breast cancer].

Takahashi S 《-》