Prevention of Symptomatic Skeletal Events With Denosumab Administered Every 4 Weeks Versus Every 12 Weeks

Inclusion Criteria:

• Patient has given written informed consent.

• Histologically confirmed diagnosis of breast or prostate cancer beforerandomization.

• Patient has metastatic breast cancer (stage IV, all subtypes allowed) or prostatecancer (stage IV) and bone metastases and is planned to receive or is receivingantineoplastic treatment.

• Patients with prostate cancer must have evidence of disease progression oncontinuous androgen deprivation therapy (CRPC).

• Patients must have ≥ 3 bone metastases (lytic or blastic or mixed). The lesions mustbe documented by radiological evaluation within 12 weeks before randomization (byX-Ray, CT scan, PET-CT, MRI scan or bone scintigraphy).

• WHO performance status 0-2

• Age ≥ 18 years.

• Corrected serum calcium ≥ 2 mmol/l and ≤ 3 mmol/l (medical treatments to obtainserum calcium levels in the normal range are allowed, as far as no denosumab isused. Maximally 1 dose of bisphosphonates in the case of hypercalcemia is allowed,if the bisphosphonate was applied at least 3 weeks before the first dose ofdenosumab).

• Liver transaminases not more than 1.5 x ULN or not more than 3 x ULN with livermetastases. Serum total bilirubin ≤ 1.5 x ULN (≤ 2.0 x ULN in case of knownGilbert's disease)

• Women are not breastfeeding. Women with child-bearing potential are using effectivecontraception, are not pregnant and agree not to become pregnant duringparticipation in the trial and during the 12 months thereafter. A negative pregnancytest before inclusion (within 7 days) into the trial is required for all women withchild-bearing potential.

• Men agree not to father a child during participation in the trial and during 12months thereafter.

Exclusion Criteria:

• Definite contraindication for denosumab (e.g. hypocalcaemia [Albumin-corrected serumcalcium < 2.0 mmol/l]).

• History or current evidence of osteonecrosis of the jaw.

• Non-healed mucosa in oral cavity (by surgery or as a side effect of any othertreatment).

• Jaw or dental conditions that require oral surgery or if surgery or invasive dentalprocedures are planned.

• Prior use of denosumab for bone metastases (dose 120 mg every 4 weeks) orbisphosphonates to treat bone metastases. Patients treated with denosumab orbisphosphonates against osteopenia or osteoporosis are allowed to enter the trial ifthe last dose was more than 28 days before randomization.

• Patients with known osteoporosis (T-score ≤ -2.5) at study entry (since fracturesfrom osteoporosis are difficult to be discriminated from fractures through bonemetastases).

• Radiotherapy or surgery to the bone within the last two weeks before randomizationor planned within 6 weeks after randomization.

• Presence or history of CNS metastases or leptomeningeal disease. A MRI evaluationwithin 12 weeks before randomization must be performed in case of suspicioussymptoms.

• Psychiatric disorder precluding understanding of information on trial relatedtopics, giving informed consent, filling out QoL forms.

• Concurrent treatment in a clinical trial with SSE or SRE as primary endpoint.

• Known hypersensitivity to trial drug or hypersensitivity to any other component ofthe trial drug (e.g. fructose).

• Any concomitant drugs contraindicated for use with the trial drugs according to theapproved product information.

• Any psychological, familial, sociological or geographical condition potentiallyhampering compliance with the trial protocol.