Amgen today announced results from a randomized, double-blind, placebo-controlled, multicenter Phase 3 study evaluating the treatment effect of adjuvant Prolia® (denosumab), 60 mg once every six months, therapy in postmenopausal women with early hormone receptor positive (HR+) breast cancer receiving aromatase inhibitor therapy. The trial met its primary endpoint of time from randomization to first clinical fracture (HR=0.5, 95 percent CI 0.39-0.65, p<0.0001). The observed 50 percent reduction in fractures between the Prolia and placebo arms, 92 versus 176, respectively, was similar in patients with normal bone health at baseline (n=1,872, HR=0.44, p<0.0001) and in patients who started the trial with early signs of bone loss (n=1,548, HR=0.57, p=0.0021). The data will be presented at the 51st Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago today at 9:12 a.m. CT (abstract no. 504).

This is the first Prolia trial to enroll patients independent of baseline bone mineral density (BMD) and with the majority in the normal BMD range.

“Fracture is a common side effect of aromatase inhibitors, which are an important first-line therapy for postmenopausal women with non-metastatic breast cancer,” said principal investigator Michael Gnant, professor of surgery at Medical University of Vienna. “These encouraging data demonstrate the potential benefit of initiating Prolia simultaneously with aromatase inhibitor therapy, regardless of the patient’s baseline BMD, to decrease the risk of fracture.”

Evaluation of key secondary endpoints showed that Prolia reduced the incidence of new vertebral and new or worsening of pre-existing vertebral fractures at 36 months (p<0.01). Statistically significant increases in BMD of the lumbar spine, total hip and femoral neck were observed in the Prolia-treated group at 36 months. The other secondary endpoints of disease-free survival, bone metastasis-free survival and overall survival have not read out yet.

The safety profile of Prolia therapy was similar to placebo, and no major safety events were reported. The most frequently reported adverse events in this study included arthralgia, hot flush, back pain, osteoarthritis and bone pain.

“Our continued research into Prolia reinforces Amgen’s ongoing commitment to exploring the potential role this medicine can have in breast cancer treatment,” said Sean E. Harper, M.D., executive vice president of Research and Development at Amgen. “Breast cancer patients can be affected by bone loss and its repercussions, and this study provides new evidence of the clinical profile for Prolia in this important setting.”

About Prolia® (denosumab)
Prolia is the first approved therapy that specifically targets RANK Ligand, an essential regulator of bone-removing cells (osteoclasts).

Prolia is approved in the U.S. for the treatment of postmenopausal women with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy. Prolia is also approved for treatment to increase bone mass in men with osteoporosis at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy.

Prolia is approved in the EU plus Switzerland, Norway, Iceland and Liechtenstein for the treatment of osteoporosis in postmenopausal women and in men at increased risk of fractures. Prolia is also approved in the EU for the treatment of bone loss associated with hormone ablation in men with prostate cancer at increased risk of fractures.

Prolia is also indicated as a treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer and in men at high risk for fracture receiving androgen deprivation therapy for non-metastatic prostate cancer.

Prolia is administered as a single subcutaneous injection of 60 mg once every six months. Please see the Important Safety Information below.

Important Safety Information (U.S.)
Prolia is contraindicated in patients with hypocalcemia. Preexisting hypocalcemia must be corrected prior to initiating Prolia. Prolia is contraindicated in women who are pregnant and may cause fetal harm. Prolia is contraindicated in patients with a history of systemic hypersensitivity to any component of the product. Reactions have included anaphylaxis, facial swelling and urticaria. Prolia contains the same active ingredient (denosumab) found in XGEVA®. Patients receiving Prolia should not receive XGEVA®.

Clinically significant hypersensitivity including anaphylaxis has been reported with Prolia. Symptoms have included hypotension, dyspnea, throat tightness, facial and upper airway edema, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue further use of Prolia. Hypocalcemia may worsen in patients taking Prolia, especially in patients with severe renal impairment. In patients predisposed to hypocalcemia and disturbances of mineral metabolism, clinical monitoring of calcium and mineral levels is highly recommended within 14 days of Prolia injection. Adequately supplement all patients with calcium and vitamin D.

Osteonecrosis of the jaw (ONJ), which can occur spontaneously, is generally associated with tooth extraction and/or local infection with delayed healing and has been reported in patients receiving Prolia. A routine oral exam should be performed by the prescriber prior to initiation of Prolia. A dental examination with appropriate preventive dentistry is recommended prior to treatment with Prolia in patients with risk factors for ONJ such as invasive dental procedures, diagnosis of cancer, concomitant therapies (e.g., chemotherapy, corticosteroids, angiogenesis inhibitors), poor oral hygiene, and co-morbid disorders. Good oral hygiene practices should be maintained during treatment. For patients requiring invasive dental procedures, clinical judgment should guide the management plan of each patient. Patients who are suspected of having or who develop ONJ should receive care by a dentist or an oral surgeon. Extensive dental surgery to treat ONJ may exacerbate the condition. Discontinuation of Prolia therapy should be considered based on individual benefit-risk assessment.

Atypical low-energy or low trauma fractures of the shaft have been reported in patients receiving Prolia. Causality has not been established as these fractures also occur in osteoporotic patients who have not been treated with antiresorptive agents. During Prolia treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be evaluated to rule out an incomplete femur fracture. Interruption of Prolia therapy should be considered, pending a risk/benefit assessment, on an individual basis.

In a clinical trial (N= 7800) in women with postmenopausal osteoporosis, serious infections leading to hospitalization were reported more frequently in the Prolia group than in the placebo group. Serious skin infections, as well as infections of the abdomen, urinary tract and ear were more frequent in patients treated with Prolia. Endocarditis was also reported more frequently in Prolia-treated patients. The incidence of opportunistic infections and the overall incidence of infections were similar between the treatment groups. Advise patients to seek prompt medical attention if they develop signs or symptoms of severe infection, including cellulitis. Patients on concomitant immunosuppressant agents or with impaired immune systems may be at increased risk for serious infections. In patients who develop serious infections while on Prolia, prescribers should assess the need for continued Prolia therapy.

In the same clinical trial in women with postmenopausal osteoporosis, epidermal and dermal adverse events such as dermatitis, eczema and rashes occurred at a significantly higher rate with Prolia compared to placebo. Most of these events were not specific to the injection site. Consider discontinuing Prolia if severe symptoms develop.

Severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported in patients taking Prolia. Consider discontinuing use if severe symptoms develop.  Suppression of Bone Turnover In clinical trials in women with postmenopausal osteoporosis, Prolia resulted in significant suppression of bone remodeling as evidenced by markers of bone turnover and bone histomorphometry. The significance of these findings and the effect of long-term treatment are unknown. Monitor patients for these consequences, including ONJ, atypical fractures, and delayed fracture healing.

It is not known whether Prolia is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Prolia, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

The most common adverse reactions (>5% and more common than placebo) in women with postmenopausal osteoporosis are back pain, pain in extremity, musculoskeletal pain, hypercholesterolemia, and cystitis. The most common adverse reactions (> 5% and more common than placebo) in men with osteoporosis are back pain, arthralgia, and nasopharyngitis. Pancreatitis has been reported with Prolia. In women with postmenopausal osteoporosis, the overall incidence of new malignancies was 4.3% in the placebo group and 4.8% in the Prolia groups. In men with osteoporosis, new malignancies were reported in no patients in the placebo group and 4 (3.3%) patients in the Prolia group. A causal relationship to drug exposure has not been established. Denosumab is a human monoclonal antibody. As with all therapeutic proteins, there is potential for immunogenicity. The most common (per patient incidence ≥ 10%) adverse reactions reported with Prolia in patients with bone loss receiving ADT for prostate cancer or adjuvant AI therapy for breast cancer are arthralgia and back pain. Pain in extremity and musculoskeletal pain have also been reported in clinical trials. Additionally, in Proliatreated men with nonmetastatic prostate cancer receiving ADT, a greater incidence of cataracts was observed.

 

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