SABCS Interview Series

Alison Stopeck, MD, Rowan T. Chlebowski, MD, PhD, and Hugues Bourgeois, MD
Published: Friday, May 14, 2010
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The San Antonio Breast Cancer Symposium (SABCS) is held in Texas each year and brings together experts from all over the globe who present the latest research on breast disease. It is held jointly by the Cancer Therapy & Research Center at University of Texas Health Science Center in San Antonio and the American Association for Cancer Research. The 32nd annual SABCS meeting was held December 9-13, 2009, and was the largest to date. Next year’s SABCS will be held December 8-12, 2010.

Alison Stopeck, MD

Breast cancer commonly metastasizes to the bone, where it can cause a number of complications, such as fractures, spinal cord compression, hypercalcemia, and pain. The prognosis for women with breast cancer whose disease has spread to the bone has greatly improved as a result of advances in medical and surgical treatments. The most common treatment used for bone metastases today is a bisphosphonate, a drug originally developed as a therapy for osteoporosis.

Denosumab (Prolia), a monoclonal antibody, is being studied in breast and other cancers for its ability to reduce bone damage and has already been approved to treat postmenopausal women with osteoporosis and some men with prostate cancer. We discussed denosumab and the Denosumab 136 study with Alison Stopeck, MD, associate professor of medicine at the University of Arizona and director of the Clinical Breast Cancer Program at the Arizona Cancer Center.

OBTN: Can you describe the trial protocol for the Denosumab 136 study?

STOPECK: The 136 study was an international, phase III, randomized, double-blind study comparing denosumab with Zometa [zoledronic acid] in the treatment of bone metastases in patients with advanced breast cancer. This is the first phase III head-to-head trial versus Zometa in advanced breast cancer. Patients enrolled in the study were randomized in a 1:1 ratio to receive either 120 mg of denosumab subcutaneously every 4 weeks or Zometa administered intravenously at a dose of 4 mg in a 15-minute infusion every 4 weeks as per the label instructions.

What were the primary and secondary endpoints of the trial?

The primary endpoint was to evaluate if denosumab is noninferior to Zometa with respect to the time to first, on-study skeletal-related event (SRE) in patients with advanced breast cancer and bone metastases. Key secondary endpoints were to evaluate if denosumab was superior to Zometa with respect to the first on-study SRE, as well as the first-and-subsequent on-study SREs, and to assess the safety and tolerability of denosumab compared with Zometa.

Did the women in the study have a specific histological subtype of advanced breast cancer?

The participants in the study were women and men with histologically or cytologically confirmed breast adenocarcinoma. Patients with all subtypes of breast cancer were eligible. They had current or prior radiographic evidence of at least one bone metastases and an Eastern Cooperative Oncology Group performance status of 0, 1, or 2.

Is there a relationship between type of breast cancer and risk of bone metastases?

Bone metastases are the most common site of metastatic disease in breast cancer. Tumors that are estrogen receptor–positive seem to have the highest propensity to metastasize to bone, but all subtypes of breast cancer commonly metastasize to bone

How do you measure the success of drugs for bone metastases?

In clinical trials testing new medications for bone metastases, treatment success is measured by whether bone complications, or SREs, caused by the tumor are reduced or delayed. Pain relief is also an important endpoint.

Did denosumab meet its endpoints in this study?

Denosumab met both primary and secondary endpoints and demonstrated superiority over Zometa. All results were statistically significant. Importantly, patients on denosumab also had better pain control and fewer serious adverse events or toxicities.

What is the mechanism of action of denosumab in preventing SREs?

When cancer metastasizes to the bone, it triggers a vicious cycle of bone destruction and tumor growth. Denosumab is the first fully human monoclonal antibody that specifically targets RANK Ligand, the essential regulator of osteoclasts (the cells that break down bone), thereby reducing bone absorption, inhibiting tumor growth, and specifically interrupting this vicious cycle.

What are some of the most common SREs in breast cancer patients and how effective was denosumab at preventing them compared with zoledronic acid?

The most common SREs in patients with breast cancer include fractures or broken bones and radiation to the bone to manage pain or prevent fracture. Denosumab was 18% more effective than Zometa in delaying the time to the first on-study SRE and 23% more effective in delaying the time to the first and subsequent SREs.

Denosumab was also 26% more effective at specifically preventing those SREs related to radiation to bone. This is an objective measure consistent with the patients’ questionnaire results, [and] demonstrat[es] that denosumab controlled bone pain more effectively than Zometa.

Were there any other benefits seen with denosumab compared with zoledronic acid?

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