Denosumab (Prolia®, Xgeva®) is a fully human monoclonal antibody against the receptor activator of nuclear factor kappa-B ligand (RANKL), a protein that is essential for the formation, function, and survival of osteoclasts. Denosumab (Prolia, Xgeva) prevents RANKL from activating its receptor, receptor activator of nuclear factor κ B (RANK), on the surface of the osteoclasts and their precursors. Prevention of the RANKL/RANK interaction inhibits osteoclast formation, function and survival, thereby decreasing bone resorption and increasing bone mass and strength in both cortical and trabecular bone.

Denosumab (Prolia)

Denosumab (Prolia) may be considered medically necessary for ANY of the following indications:

• As treatment to increase bone mass in men receiving androgen deprivation therapy (ADT) for non-metastatic prostate cancer at high risk for fracture as defined by EITHER of the following:
  • Individual has T-score less than -1 in combination with multiple risk factors for fracture; or
  • Previous history of osteoporotic fracture; or
• As treatment to increase bone mass in women receiving adjuvant aromatase therapy for breast cancer at high risk for fracture as defined by EITHER of the following:
  • Individual has T-score less than -1 in combination with multiple risk factors for fracture; or
  • Previous history of osteoporotic fracture; or
• As treatment for postmenopausal women and to increase bone mass in men with osteoporosis who have a T-score of -2.5 or less and EITHER of the following:
  • The individual has had an adequate trial and failure of at least one bisphosphonate:
    • Trial and failure defined as a decrease in bone mineral density (BMD) despite trial of bisphosphonate therapy (e.g., alendronate, ibandronate, risedronate, zoledronic acid); or
  • The individual has a contraindication to all bisphosphonates:
    • Contraindications to bisphosphonate therapy include but are not limited to hypocalcemia, esophageal ulcerations, esophageal stricture, Barrett's esophagus, active ulcers, renal impairment, and an inability to stand or sit upright for 30 minutes; or
• As treatment to prevent fractures in men and postmenopausal women with T-score between -1 and -2.5, or as treatment of glucocorticoid-induced osteoporosis in men and women with the following:
  • The individual is at high risk for an osteoporotic fracture as substantiated by EITHER of the following:
    • The individual has a history of previous osteoporotic fracture; or
    • The individual has a 10-year risk of a major osteoporotic fracture greater than or equal to 20%; or
    • The individual has a 10-year risk of hip fracture greater than or equal to 3%; and
  • The individual has had an adequate trial and failure of at least one bisphosphonate:
    • Trial and failure defined as a decrease in BMD despite trial of bisphosphonate therapy (e.g., alendronate, ibandronate, risedronate, zoledronic acid); or
  • The individual has a contraindication to all bisphosphonates:
    • Contraindications to bisphosphonate therapy include but are not limited to hypocalcemia, esophageal ulcerations, esophageal stricture, Barrett's esophagus, active ulcers, renal impairment, and an inability to stand or sit upright for 30 minutes.

Denosumab (Prolia) is considered experimental/investigational when all of the criteria specified above are not met, or for the treatment of all other indications, and therefore non-covered. There is a lack of evidence based literature to confirm the efficacy and safety for any other indication.

Denosumab (Xgeva)

Food and Drug Administration (FDA) Indications

Denosumab (Xgeva) may be considered medically necessary for ANY of the following indications:

• As treatment for prevention of skeletal-related events in individuals:
  •  With EITHER:
    • Multiple myeloma; or
    • Bone metastases from solid tumors; and
  • Prior treatment with an IV bisphosphonate (e.g. pamidronate or zoledronic acid) has been ineffective, contraindicated, or not tolerated;  or
• For the treatment of giant cell tumor of the bone (GCTB) that is unresectable or where surgical resection is likely to result in severe morbidity in both individuals 18 years of age and older and skeletally mature adolescents (e.g., at least one (1) mature long bone); or
• As treatment of hypercalcemia of malignancy (HCM) refractory to intravenous bisphosphonate therapy when the following criteria are met:
  • Prior treatment with an IV bisphosphonate (e.g. pamidronate or zoledronic acid) has been ineffective, contraindicated, or not tolerated.

National Comprehensive Cancer Network (NCCN) Indications

Denosumab (Xgeva) may be considered medically necessary for ANY of the following indications:

• For the prevention of skeletal-related events in men with castration resistant prostate cancer who have documented bone metastases and creatinine clearance greater than 30 mL/min; or
• For the prevention or treatment of osteoporosis during ADT for individuals with prostate cancer who have a high fracture risk; or
• For use as second-line therapy for osteopenia or osteoporosis in individuals with systemic mastocytosis with bone pain not responding to bisphosphonates, or for individuals who are not candidates for bisphosphonates due to renal insufficiency; or
• As treatment for bone metastases of papillary carcinoma, follicular carcinoma, Hürthle cell carcinoma, or medullary carcinoma of the thyroid; or
• As palliative care for bone metastases for anaplastic carcinoma of the thyroid; or
• As supportive therapy in individuals with bone metastases for non-small cell lung cancer; or
• As a component of best supportive care for bony metastases for kidney cancer; or
• For treatment of GCTB when therapy is used as a:
  • Single agent or combined with interferon alfa or radiation therapy for localized disease; or
  • Single agent for metastatic disease; or
• As treatment to maintain or improve BMD, and reduce the risk of fractures in natural or induced postmenopausal women receiving adjuvant endocrine therapy for invasive breast cancer along with calcium and vitamin D supplementation; or
• As treatment in combination with calcium and vitamin D supplementation in addition to chemotherapy or endocrine therapy for bone metastasis in individuals with invasive breast cancer with expected survival of 3 months or greater and adequate renal function;
• For the treatment of multiple myeloma when used in combination with primary myeloma therapy.

Denosumab (Xgeva) is considered experimental/investigational when all of the criteria specified above are not met, or for the treatment of all other indications, and therefore non-covered. There is a lack of evidence based literature to confirm the efficacy and safety for any other indication.

Note: NCCN recognizes that the use of a bisphosphonate (oral/IV) or denosumab is acceptable to maintain or improve bone mineral density and reduce risk of fractures in postmenopausal (natural or induced) individuals receiving adjuvant endocrine therapy.

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Note: Therapy with denosumab (Prolia, Xgeva) is appropriate for continuation when an individual shows stability or improvement in their condition.

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NOTE: In addition to the above criteria, product specific dosage and/or frequency limits may apply in accordance with the U.S. Food and Drug Administration (FDA)-approved product prescribing information, national compendia, Centers for Medicare and Medicaid Services (CMS) and other peer reviewed resources or evidence-based guidelines. Highmark may deny, in full or in part, reimbursement for utilization that does not fall within the applicable dosage and/or frequency limits.

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All individuals should be monitored for hypocalcemia and denosumab (Prolia, Xgeva) is contraindicated for individuals with hypocalcemia.