Xgeva off-label and for prostate cancer – pro

Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Its indication is not very different from Zometa: Zometa is indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy.

For prostate4 cancer, Xgeva(denosumab) is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. In the pivotal study by Henry and Vadhan-Raj(2012), 1, 2 Denosumab was superior to zoledronic acid in delaying or preventing SREs in patients with breast cancer metastatic to bone and was generally well tolerated. With the convenience of a subcutaneous injection and no requirement for renal monitoring, denosumab represents a potential treatment option for patients with bone metastases.In general, Xgeva is only slightly better than Zometa 3. The thirteen member Oncologic Drugs Advisory Committee, reviewed a study funded by the manufacturer, Amgen on 1,435 patients with castration-resistant prostate cancer. They found that the drug did prevent metastasis for four months over placebo (29 months vs 25 months). However, Xgeva did not increase expected lifespan, and the side effects were severe and judged to be too common for routine use. A measurement of the drug’s effectiveness known as bone metastasis free survival (BMFS) was increased, but this was offset by the increase in serious reportable events (SRE) the worst classification of side effects. Side effects were notable for including a form of bone destruction called osteonecrosis of the jaw in 33 (4.6 percent) of the patients treated with Xgeva. Other side effects included hypocalcemia, rashes and several types of infections. 3, 4

NCCN lists Xgeva for prostate cancer. For men with castration-resistant metastatic prostate cancer, the NCCN panel now recommends denosumab (Xgeva, Amgen) as an alternative to zoledronic acid for the prevention of skeletal-related events based on a phase 3 study showed denosumab to be the superior agent in delaying the time to first skeletal-related event and other measures 5. NICE limited the use of Xgeva for prostate cancers and covers only Zometa.

According to the “fine print”, during consultation on the very first draft of guidance on the use of denosumab in England, NICE’s Appraisal Committee determined that

 … bisphosphonates should not be used as the comparator for denosumab in people with bone metastases from prostate cancer. This is because, according to NICE guidelines [on management of prostate cancer], bisphosphonates are recommended as a treatment for pain relief (a use which denosumab is not licensed for) and not to prevent skeletal-related events. Therefore, the Appraisal Committee concluded that the main comparator for this group of patients should be best supportive care.

Data submitted to the Appraisal Committee during the second consultation on this draft guidance did in fact suggest that

… bisphosphonates are prescribed for people with bone metastases from prostate cancer but the committee noted a wide variety of reasons for their use. The committee concluded that the data was not robust and there should continue to be regard for the recommendations included in the NICE guideline on prostate cancer.

NICE’s Appraisal Committee then concluded that best supportive care should remain the main comparator to denosumab and not bisphosphonates.

This is a decision based on cost-benefit and it has been vigorously contested.

1. David H. Henry, Luis Costa, Francois Goldwasser, Vera Hirsh, Vania Hungria, Jana Prausova,Giorgio Vittorio Scagliotti, Harm Sleeboom, Andrew Spencer, Saroj Vadhan-Raj, Roger von Moos, Wolfgang Willenbacher, Penella J. Woll, Jianming Wang, Qi Jiang, Susie Jun, Roger Dansey, and Howard Yeh, Zoledronic Acid in the Treatment of Bone Metastases in Patients With Advanced Cancer (Excluding Breast and Prostate Cancer) or Multiple Myeloma. JCO March 20, 2011 vol. 29 no. 9 1125-1132

2. S. Vadhan-Raj Clinical benefit in patients with metastatic bone disease: results of a phase 3 study of denosumab versus zoledronic acid, Ann Oncol (2012) 23 (12): 3045-3051.

3. Alison T. Stopeck, et al, Denosumab Compared With Zoledronic Acid for the Treatment of Bone Metastases in Patients With Advanced Breast Cancer: A Randomized, Double-Blind Study JCO November 8, 2010 JCO.2010.29.7101

4. Monica N. Fornier Denosumab: Second Chapter in Controlling Bone Metastases or a New Book? JCO Dec 10, 2010:5127-5131

5. NCCN, Prostate Cancer 2015

6. https://www.nice.org.uk/guidance/ta265


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