Études pivotales

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Denosumab Oncology Phase 3 Studies

Denosumab (120 mg Q4W; XGEVA®) to prevent skeletal complications and delay pain progression

    The superiority of denosumab (120 mg Q4W; XGEVA®) versus zoledronic acid in the prevention and delay of skeletal related events (SREs) of bone metastases from solid tumors has been demonstrated in three identically designed pivotal studies.
  • Study 136: Breast cancer with bone metastases
  • Study 103: Prostate cancer with bone metastases
  • Study 244: Other solid tumors with bone metastases and multiple myeloma*
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Integrated analysis of denosumab SRE trials – results
On top of the primary efficacy endpoint showing a reduction of SREs, denosumab reduced pain progression and reduced the progression from no/low analgesic use to strong opioid use.
The slide deck includes the results of the integrated analyses for the solid tumor population.

Denosumab in breast cancer patients with bone metastases


This video shows and discusses all relevant information regarding the denosumab pivotal trial in the prevention of skeletal complications in breast cancer patients with bone metastases (Stopeck A, et al. J Clin Oncol 2010), and the data about the prevention of symptomatic skeletal related events (SSE) from the ESMO Meeting 2016 (Body JJ, et al.).

Denosumab in prostate cancer patients with bone metastases

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Denosumab pivotal trial in prostate cancer patients with bone metastases
Further materials to other tumor entities (breast, prostate, lung) can be found in the Materials for download section.

Denosumab is indicated for the treatment of Giant Cell Tumors of the Bone (GCTB).

GCTB slide deck can be found in the Materials for Download section

Denosumab is not licensed in Switzerland for the treatment of bone lesions in patients with multiple myeloma. The results of the phase III study can be viewed in the congress section (Raje N, et al. Lancet Oncol 2018).

Denosumab (XGEVA®) safety and risk factors

Hypocalcaemia and Osteonecrosis of the jaw (ONJ) are known adverse events of a denosumab therapy and are explained with their respective precautions in these slides.
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The slide deck shows the incidence of hypocalcaemia during the pivotal trial, with a special focus on the higher risk in the prostate cancer population, and what precautions can be taken. (also see XGEVA Professional Information, Switzerland). The risk of ONJ can be reduced by specific measures and should be communicated by the treating physician to the patients. Dentists should be made aware of a patient's denosumab therapy by either the physician or the patient directly. Brochures and flyers are available to facilitate this communication.

Denosumab (60mg Q6M; Prolia®) against cancer treatment-induced bone loss (CTIBL)

Two pivotal phase 3, placebo-controlled studies demonstrated a significant increase in bone mineral density with denosumab as concomitant treatment to hormone ablation therapy in women with breast cancer (Ellis GK, et al. J Clin Oncol 2008) and men with prostate cancer (Smith MR, et al. N Engl J Med 2009).
Additionally, the ABCSG-18 study showed that concomitant denosumab significantly delayed the time to first clinical fractures compared to placebo (HR 0.50 [95% CI 0.39–0.65], p<0·0001) in early-stage, hormone receptor-positive postmenopausal breast cancer patients receiving aromatase inhibitors (Gnant M, et al. Lancet 2015; http://dx.doi.org/10.1016/S0140-6736(15)60995-3)
An exploratory Disease-Free Survival analysis from the ABCSG-18 study has been presented at ASCO 2018 and can be found in the congress section.

Denosumab therapy management in CTIBL

The Swiss Association against Osteoporosis (SVGO/ASCO) recommends a therapy with denosumab in patients with high risk of fracture. This high risk is defined as: prevalent fracture (hip, spine or multiple fractures before or during therapy); low T-score (femoral neck T-score <˗2.5 SD if age <65 years, <-2.0 SD if age >65 years and/or frequent falls); continuing hormone ablative therapy (e.g., aromatase inhibition, androgen deprivation therapy); secondary osteoporosis, continuing glucocorticoid therapy.
When the fracture risk is estimated as low at the end of the hormone ablation therapy, the SVGO recommends the use of a bisphosphonate for 12 to 24 months after denosumab therapy discontinuation.
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Denosumab therapy management in AIBL
Meier C et al., Osteoporosis drug treatment: duration and management after discontinuation. A position statement from the Swiss Association against Osteoporosis (SVGO/ASCO). Swiss Med Wkly. 2017;147:w14484.
    At the ASBMR (American Society of Bone Mineral Research) 2018, G. Pfeiler et al. presented the «rebound-associated fracture» analysis after discontinuation of denosumab (Prolia) in early-stage breast cancer patients of the ABSCG-18 study. They analysed clinical fractures in the off-treatment period, starting at 6 months after the last dose of denosumab/placebo (n=1613/n=1576) with a median follow-up of 36 months. Abstract (LB-1167) for download here. Conclusions of the authors (oral presentation):
  • There was no difference in overall fracture risk observed in patients who stopped denosumab compared to patients who stopped placebo.
  • After stopping denosumab there was a significant increase in clinical vertebral (1.4% vs. 0.6% ≈2.5-fold) and clinical multiple vertebral fractures (0.7% vs 0.2%; 3.5-fold), even though the (absolute) numbers were small.
  • There was no signal for an increase in clinical vertebral fractures in patients who ended AI treatment within 6 months of stopping denosumab.
ECTS (European Calcified Tissue Society) issued a recommendation in 2017 based on literature research: Discontinuation of Denosumab therapy for osteoporosis: A systematic review and position statement by ECTS. Tsourdi E, et al. Bone. 2017 Dec;105:11-17. doi: 10.1016/j.bone.2017.08.003. Epub 2017 Aug 5.
Several observational studies documented that the application of iv zoledronic acid after denosumab discontinuation could reduce the bone mineral density loss but could not permanently stop it.1
    The administration of a single dose following a longer interval than 6 months after the last denosumab dose seemed to have a favourable effect. This report showed that 5mg iv zoledronic acid approximately 8 months after the last denosumab dose has been associated with a relatively high maintenance of bone mineral density.2
  1. Reid IR, et al. Bone Loss After Denosumab: Only Partial Protection with Zoledronate. Calcif Tissue Int. 2017 Oct;101(4):371-374
  2. Horne AM, et al. Bone Loss After Romosozumab/Denosumab: Effects of Bisphosphonates. Calcif Tissue Int. 2018 Jul;103(1):55-61
The current data situation of denosumab management in AIBL is summarized here.
*Denosumab is not licensed in Switzerland for the treatment of bone lesions in patients with Multiple Myeloma
Abbreviations: Overall Survival (OS); Progression Free Survival (PFS); months (mo); Hazard Ratio (HR); versus (vs); weeks (we)

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