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by Dr. C.H. Weaver M.D. updated 4/2021

Metastatic cancer refers to cancer that has spread to distant sites in the body. Several types of cancer have a tendency to spread to the bone. Bone metastases can lead to serious problems such as fractures and spinal cord compression and may require treatment with surgery or radiation therapy.

Preventing or delaying skeletal-related events (SREs) can preserve quality of life and reduce healthcare costs. Bisphosphonate drugs such as Zometa were historically used to reduce the risk of complications from bone metastases.

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XGEVA (Denosumab) targets a protein known as the RANK ligand that regulates the activity of osteoclasts (cells that break down bone) and is approved for the prevention of bone complications such as fracture in patients with lung, breast and other cancers prone to develop bone metastases.

What Does The Research Show?

Multiple Myeloma- XGEVA improves treatment of Multiple Myeloma

Lung Cancer

Approximately 30 to 40 percent of patients with non-small cell lung cancer (NSCLC) develop bone metastases.

Patients with advanced lung cancer experienced modest improvement in survival when they received bone-targeted therapy with Xgeva® (denosumab) instead of Zometa® (zoledronic acid), according to the results of a study published in the Journal of Thoracic Oncology.

A large, randomized, phase III trial compared Xgeva to Zometa for the treatment of bone metastases from solid tumors or multiple myeloma. Patients were randomized to receive subcutaneous Xgeva or intravenous Zometa. The trial included a subset of 811 patients with lung cancer—702 with NSCLC and 109 with small-cell lung cancer (SCLC).

In an analysis of all lung cancer patients, Xgeva was associated with improved median overall survival compared to Zometa—8.9 months versus 7.7 months. For patients with NSCLC who received Xgeva, the median overall survival was 9.5 months compared to 8.0 months for those who received Zometa. When the researchers further analyzed NSCLC by histological type, they found that patients with squamous cell carcinoma who received Xgeva had a median survival of 8.6 months compared to 6.4 for those who received Zometa. In the subgroup of patients with SCLC, there was a trend toward improved survival in those treated with Xgeva (5.1 months) compared to those treated with Zometa (2.5 months). The rate and severity of adverse events was similar between the two groups.

The researchers concluded that Xgeva was associated with improved overall survival compared with Zometa in patients with metastatic lung cancer.

Prostate Cancer

Xgeva Delays Bone Metastases in Men with Aggressive Prostate Cancer

Among men with prostate cancer that has aggressive characteristics and has stopped responding to hormonal therapy, Xgeva™ delayed the onset of bone metastases by more than seven months.

Androgen deprivation therapy (ADT) often plays an important role in the treatment of prostate cancer. ADT slows or stops prostate cancer growth by reducing the exposure of the prostate to testosterone. Eventually, however, prostate cancer can become resistant to ADT. This is known as hormone-refractory prostate cancer.

To evaluate the effect of Xgeva on the occurrence of bone metastases, researchers conducted a Phase III clinical trial among 1,432 men with hormone-refractory prostate cancer. The men had rapidly rising prostate-specific antigen (PSA) levels and/or high PSA levels but were free of bone metastases at the start of the study. Patients received either Xgeva or a placebo.

Earlier reports from this study indicated that Xgeva delayed the occurrence of bone metastases by more than four months. In the current analysis, researchers focused on the subset of patients who had a short PSA doubling time at the start of the study. A short PSA doubling time (defined in this case as PSA levels that double in six months or less) means that PSA levels are rising rapidly; this may indicate more aggressive disease.

  • Men with a short PSA doubling time developed bone metastases more quickly than other men. This confirms that these men are at particularly high risk of bone metastases.
  • Among the men with a short PSA doubling time, Xgeva delayed the onset of bone metastases by more than seven months.

These results indicate that Xgeva significantly delays the development of bone metastases among men at high risk of bone metastases.

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Breast Cancer

Xgeva® appears to delay the time to cancer progression and improve survival among early stage breast cancer patients treated with aromatase inhibitors.

Hormone-positive (HR+) breast cancer refers to breast cancer that is stimulated to grow when exposed to the female hormones estrogen and/or progesterone. The majority of breast cancers are HR+, and an effective and standard therapeutic approach for the treatment of HR+ breast cancers is hormone therapy to block the cancer cells from being exposed to the hormones that cause their excessive growth.

A common place for breast cancer to spread is the bones, and researchers continue to evaluate whether bone strengthening agents used for the treatment of osteoporosis can have a positive effect on reducing the risk of breast cancer spreading to the bones.

Researchers conducted a clinical trial to evaluate the potential effects of Xgeva in women with early stage breast cancer treated with hormone therapy in 3,425 postmenopausal women with HR+ early stage breast cancer. They were all treated with endocrine therapy consisting of aromatase inhibitor and with either Xgeva or a placebo (inactive substitute) and directly compared. The study revealed that Xgeva improved disease-free survival by 1% after 3 years, 2% after 5 years, and 3% at 7 years.5

Xgeva Delays Bone Complications in Women with Metastatic Breast Cancer

In a study of women with bone metastases from breast cancer, Xgeva delayed bone complications for five months longer than Zometa® (zoledronic acid).

To directly compare Xgeva to Zometa among breast cancer patients with bone metastases, researchers conducted a Phase III clinical trial among more than 2,000 patients. Study participants were assigned to receive either Xgeva or Zometa. Zometa is given intravenously, and Xgeva is given as a subcutaneous (under-the-skin) injection.

The objective of the study was to determine whether the occurrence of bone complications (“skeletal related events”) differed between the two study groups. The bone complications that were evaluated were fracture, radiation to the bone, surgery to the bone, and spinal cord compression.

The results of this study suggest that Xgeva is more effective than Zometa at delaying or preventing skeletal complications in breast cancer patients with bone metastases.

  • Patients treated with denosumab remained free of bone complications longer than patients treated with Zometa.
  • Overall survival and time to cancer progression were similar among patients treated with Zometa and patients treated with denosumab.
  • Osteonecrosis of the jaw (an uncommon but serious side effect) was seen infrequently in both study groups (2% of patients treated with denosumab and 1.4% of patients treated with Zometa).

The results of this study suggest that denosumab may be more effective than Zometa at delaying or preventing skeletal complications in breast cancer patients with bone metastases.

XGEVA Active Against Bone Metastases from Breast Cancer

According to the results of a Phase II clinical trial among women with breast cancer-related bone metastases, the experimental drug denosumab appears to reduce bone turnover and the risk of problems such as fractures to a similar extent as bisphosphonate treatment. These results were published in the Journal of Clinical Oncology.

To evaluate the effects of denosumab in women with breast cancer-related bone metastases, researchers conducted a Phase II clinical trial. The trial enrolled 255 women from North America, Australia, and Europe. None of the women had previously received bisphosphonate therapy.

Study participants were assigned to one of five different dosing schedules of subcutaneous denosumab, or to treatment with an intravenous bisphosphonate.

  • By 13 weeks the percent of patients who achieved a specified reduction in bone turnover was 74% among patients treated with denosumab and 63% among patients treated with a bisphosphonate.
  • Skeletal-related events (fracture, surgery or radiation to bone, or spinal cord compression) occurred among 9% of women treated with denosumab and 16% of women treated with a bisphosphonate.
  • There were no serious adverse effects of treatment among patients treated with denosumab.

The researchers conclude that the ability of denosumab to suppress bone turnover and to reduce the risk of skeletal-related events such as fractures may be similar to that of bisphosphonates. Phase III clinical trials of denosumab are underway and will provide additional information.

Answers to Frequently Asked Questions About XGEVA

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  1. Lipton A, Steger GG, Figueroa J et al. Randomized active-controlled phase II study of denosumab efficacy and safety in patients with breast cancer-related bone metastases. Journal of Clinical Oncology. 2007;25:4431-4437.
  2. Saad F, Smith MR,ShoreNDet al.Effect of denosumab on prolonging bone-metastasis free survival (BMFS) in men with nonmetastatic castrate-resistant prostate cancer (CRPC) presenting with aggressive PSA kinetics. Paper presented at: 2012 Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012;Chicago,IL. Abstract 4510.
  3. Scagliotti GV, Hirsh V, Siena S, et al. Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: Subgroup analysis from a randomized phase 3 study. Journal of Thoracic Oncology. 2012; 7(12): 1823-1829.
  4. Stopeck AT, Lipton A, Body J-J et al. Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. Journal of Clinical Oncology [early online publication]. November 8, 2010.
  5. Gnant M, Pfeiler G, Dubsky PC, et al. The impact of adjuvant Xgeva on disease-free survival: Results from 3,425 postmenopausal patients of the ABCSG-18 trial. Proceedings from the 2015 annual meeting of the San Antonio Breast Cancer Symposium. Abstract S2-02.