Experience with denosumab (XGEVA®) for prevention of skeletal-related events in the 10 years after approval

Abstract

Skeletal-related events (SREs) are complications of bone metastases and carry a significant patient and economic burden. Denosumab is a receptor activator of nuclear factor-κB ligand (RANKL) inhibitor approved for SRE prevention in patients with multiple myeloma and patients with bone metastases from solid tumors. In phase 3 trials, denosumab showed superiority to the bisphosphonate zoledronate in reducing the risk of first on-study SRE by 17% (median time to first on-study SRE delayed by 8.2 months) and the risk of first and subsequent on-study SREs by 18% across multiple solid tumor types, including some patients with multiple myeloma. Denosumab also improved pain outcomes and reduced the need for strong opioids. Additionally, a phase 3 trial showed denosumab was noninferior to zoledronate in delaying time to first SRE in patients with newly diagnosed multiple myeloma. Denosumab has a convenient 120 mg every 4 weeks recommended dosing schedule with subcutaneous administration. Rare but serious toxicities associated with denosumab include osteonecrosis of the jaw, hypocalcemia, and atypical femoral fracture events, with multiple vertebral fractures reported following treatment discontinuation. After a decade of real-world clinical experience with denosumab, we are still learning about the optimal use and dosing for denosumab. Despite the emergence of novel and effective antitumor therapies, there remains a strong rationale for the clinical utility of antiresorptive therapy for SRE prevention. Ongoing studies aim to optimize clinical management of patients using denosumab for SRE prevention while maintaining safety and efficacy.

Keywords: AFF, Atypical femoral fracture; BM, Bone metastasis; BMFS, BM-free survival; BP, Bisphosphonate; BTA, Bone-targeting agent; Bone metastasis; CI, Confidence interval; Denosumab; Efficacy; HR, Hazard ratio; HRQoL, Health-related quality of life; IMWG, International Myeloma Working Group; MM, Multiple myeloma; MVF, Multiple vertebral fracture; NSCLC, Non–small-cell lung cancer; ONJ, Osteonecrosis of the jaw; OPG, Osteoprotegerin; OS, Overall survival; PFS, Progression-free survival; Q12W, Every 12 weeks; Q4W, Every 4 weeks; RANKL, Receptor activator of nuclear factor-κB ligand; SC, Subcutaneous; SRE, Skeletal-related event; Safety; Skeletal-related events; uNTx/Cr, Urinary N-telopeptide normalized to urinary creatinine.

Fig. 1

Approval of BTAs in the US (blue boxes) and Europe (gray boxes) for prevention of SREs. BM, bone metastasis; BTA, bone-targeting agent; FDA, US Food and Drug Administration; MM, multiple myeloma; SRE, skeletal-related event. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Overview of (A) normal bone physiology, (B) tumor pathology, and (C) the mechanism of action of denosumab bone metastases. CSF, colony-stimulating factor; IL, interleukin; OPG, osteoprotegerin; RANK, receptor activator of nuclear factor-κB; RANKL, RANK ligand.

Fig. 3

SRE outcomes with denosumab versus zoledronate in patients with solid tumors or multiple myeloma , , , . *Events occurring ≥ 21 days apart. ^†Primary tumor types (n [%]) were non–small-cell lung cancer (denosumab, 350 [39%]; zoledronate, 352 [40%]), multiple myeloma (denosumab, 87 [10%]; zoledronate, 93 [10%]), and other (breast and prostate excluded; denosumab, 449 [51%]; zoledronate, 455 [50%]). CI, confidence interval; HR, hazard ratio; NR, not reached; SRE, skeletal-related event.

Fig. 4

Prespecified AEs of interest with denosumab versus zoledronate in patients with solid tumors or multiple myeloma , , , . AE, adverse event; MM, multiple myeloma; ONJ, osteonecrosis of the jaw; SAE, serious AE.