Superiority of denosumab to zoledronic acid for prevention of skeletal-related events: A combined analysis of 3 pivotal, randomised, phase 3 trials

Abstract

Background

Patients with bone metastases from advanced cancer often experience skeletal-related events (SRE), which cause substantial pain and morbidity. Denosumab, a fully human monoclonal antibody that inhibits RANK Ligand (RANKL), is a novel bone-targeted agent with a distinct mechanism of action relative to the bisphosphonate zoledronic acid, for prevention of SRE. This pre-planned analysis evaluates the efficacy and safety of denosumab versus zoledronic acid across three pivotal studies.

Methods

Patient-level data from three identically designed, randomised, double-blind, active-controlled, phase 3 trials of patients with breast cancer, prostate cancer, other solid tumours or multiple myeloma were combined. End-points included time to first SRE, time to first and subsequent (multiple) SRE, adverse events, time to disease progression and overall survival.

Findings

Denosumab was superior to zoledronic acid in delaying time to first on-study SRE by a median 8.21 months, reducing the risk of a first SRE by 17% (hazard ratio, 0.83 [95% confidence interval (CI): 0.76–0.90]; P < 0.001). Efficacy was demonstrated for first and multiple events and across patient subgroups (prior SRE status; age). Disease progression and overall survival were similar between the treatments. In contrast to zoledronic acid, denosumab did not require monitoring or dose modification/withholding based on renal status, and was not associated with acute-phase reactions. Hypocalcaemia was more common for denosumab. Osteonecrosis of the jaw occurred at a similar rate (P = 0.13).

Conclusion

Denosumab was superior to zoledronic acid in preventing SRE with favourable safety and convenience in patients with bone metastases from advanced cancer.

Introduction

Every year, over 400,000 patients will be affected by skeletal metastases in the US.¹ Bone metastases are common in patients with advanced cancer, arising in 70–80% of patients with breast or prostate cancer and 30–40% of patients with lung cancer or other solid tumours.² Patients with bone metastases may experience local irreversible skeletal complications including pathologic fracture, spinal cord compression and/or radiation or surgery to bone, known collectively as skeletal-related events (SRE). SRE are indicators of poor prognosis and cause substantial pain and morbidity frequently leading to hospitalisation, poor quality of life and increased medical resource utilisation.3, 4, 5, 6, 7 Bone metastases may also contribute to malignant hypercalcaemia. Patients with breast and prostate cancer may survive several years with bone metastases² during which time they are at risk for SRE. Indeed, long-term management of metastatic bone disease is increasingly relevant as new anticancer treatments extend the overall survival.

Over the last two decades, intravenous bisphosphonates, such as pamidronate8, 9 and zoledronic acid10, 11, 12 were developed as effective treatments to delay or prevent SRE in patients with bone metastases, marking an important step in the improvement of palliative cancer care. Despite treatment with bisphosphonates, about 50% of patients continue to experience SRE.8, 9, 10 Zoledronic acid, the most potent bisphosphonate for prevention of SRE, is associated with acute phase reactions, osteonecrosis of the jaw,¹³ and has the potential to cause renal insufficiency. The use of zoledronic acid is restricted in patients with renal impairment,¹³ a common condition in cancer patients.¹⁴ These issues underscore the need for additional options to manage the sequelae of bone metastases.

Crucial research in bone biology revealed a key pathway regulating the process of bone remodelling. Osteoprotegerin (OPG) and OPG-ligand (also known as RANK Ligand [RANKL]) were identified as the essential mediators of osteoclast differentiation, activation and survival leading to bone resorption.15, 16 Tumour cells exploit the RANKL/OPG axis17, 18 leading to osteolytic¹⁹ or osteoblastic bone metastases.¹⁷ In a murine model of established bone metastases, inhibition of RANKL prevented osteoclast-mediated bone destruction and growth of human breast cancer cells in bone.²⁰

The successful use of RANKL inhibition to interrupt the ‘vicious cycle’ of bone destruction and tumour proliferation in animal models suggested a potential new approach for the treatment of bone metastases. Denosumab, a fully human monoclonal antibody with high affinity and specificity for human RANKL inhibited bone resorption in early studies in patients with advanced cancer,21, 22, 23, 24 including those who failed prior bisphosphonate treatment.²³ In a large phase 3 programme, denosumab was superior to zoledronic acid in patients with breast cancer²⁵ or prostate cancer²⁶ and non-inferior to zoledronic acid in patients with solid tumours or multiple myeloma²⁷ for the prevention of SRE in metastatic bone disease.

Combined patient-level analyses offer enhanced power to a more fully evaluated safety and efficacy, particularly with respect to patient subpopulations. This planned combined analysis of the three identically designed pivotal denosumab trials in over 5700 patients with advanced cancer and bone metastases provides an unprecedented opportunity to discriminate the relative effects of the RANKL inhibitor denosumab and the bisphosphonate zoledronic acid for the prevention of SRE.