Three Trials Support Evidence Of Zometa(R) Anticancer Benefit In Pre- And Post-Menopausal Women With Early-stage Breast Cancer

Main Category: Breast Cancer
Also Included In: Cancer / Oncology;  Women's Health / Gynecology;  Clinical Trials / Drug Trials
Article Date: 17 Sep 2008 - 3:00 PDT

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New data from three clinical trials show Zometa® (zoledronic acid) reduced the risk of local and distant recurrence in pre- and post-menopausal women with early-stage breast cancer. Investigators reported on the studies this week in Stockholm at the 33rd Annual Congress of the European Society for Medical Oncology (ESMO), the primary European professional organization representing medical oncologists.

The new data add to a growing body of research suggesting that Zometa® may help protect patients against the return and spread of early-stage cancer. They include results from the Austrian Breast & Colorectal Cancer Study Group Trial 12 (ABCSG-12), a Phase III study in which the addition of Zometa® to endocrine therapy demonstrated a 33% reduction in risk of disease-free survival events in premenopausal patients (P = 0.02),1 and the Phase III Z-FAST/ZO-FAST trial, which studied the effect of Zometa® on aromatase inhibitor-associated bone loss in postmenopausal women who were receiving Femara® (letrozole) after surgery for early breast cancer.2 Results of a pilot study in patients receiving a variety of presurgical and postsurgical therapies also were presented.

"The evidence for the anticancer effect of zoledronic acid is building," said Hugh O'Dowd, Oncology Business Unit Head for Novartis in the UK. "These data further suggest that zoledronic acid significantly reduces the risk of breast cancer recurrence in this patient population and may represent a new treatment option."

According to Cancer Research UK, each year approximately 12,000 women die from breast cancer in the UK each year.3 Moreover, the incidence of breast cancer in the UK has risen by 13% in the last ten years.3

Approximately one-third of women with hormone-sensitive, early breast cancer experience a recurrence with the majority appearing in other organs and tissues. These distant recurrences, or metastases, are the primary cause of death from breast cancer, with 60% of women dying within five years.

Zometa® is a treatment for the prevention or delay of skeletal-related events (SREs) in patients with advanced malignancies involving bone across a broad range of tumours. Laboratory research had suggested that Zometa® may also help protect patients from the spread of cancer to other parts of the body (distant metastatic sites) and help keep patients recurrence-free.

Laboratory research has suggested that Zometa® may also have anticancer effects, including helping to protect against the return and spread of cancer before it reaches an advanced stage. A tumour passes through six stages on its path to metastasising (spreading). In the laboratory, Zometa® has been shown to make passage through these stages more difficult by inhibiting angiogenesis (formation of blood vessels that grow and feed cancer cells), stimulating cancer-fighting T-cells, inducing tumour cell apoptosis (programmed cell death) and increasing the activity of anticancer agents that target tumour cell metastases.4

A growing number of clinical studies are examining the potential anticancer impact of Zometa®. One of the largest of these studies, AZURE (Adjuvant Zoledronic acid to redUce REcurrence), has completed enrollment. The study will evaluate the impact of Zometa® in reducing risk of cancer recurrence in 3,360 premenopausal and postmenopausal women with Stage II/III breast cancer.

References

1. Gnant M, Mlineritsch B, Schippinger W, et al. Zoledronic acid improves disease-free and recurrence-free survival in premenopausal women with early breast cancer (ERBC) receiving adjuvant endocrine therapy: multivariate analysis of efficacy data from ABCSG-12. [ABSTRACT # 690, ESMO DATA]

2. Frassoldati A, Brufsky A, Bundred N, et al. The effect of Zoledronic acid on aromatase inhibitor associated bone loss in postmenopausal women with early breast cancer (EBC) receiving adjuvant letrozole: 24 months integrated follow-up of the Z-FAST/ZO-FAST trials. [ABSTRACT # 185PD, ESMO DATA]

3. Cancer Research UK (last visited 27/05/08). http://info.cancerresearchuk.org/cancerstats/types/breast/

4. Mundy, GR, et al. Metastases to bone: causes, consequences and therapeutic opportunities. Nature Reviews Cancer. 2002;2:584-593.

5. Lin AY, Park JW, Scott J, et al. Adjuvant zoledronic acid therapy decreases the prevalence of disseminated tumor cells in bone marrow of patients with early-stage breast cancer: 2-year results. J Clin Oncol 26: 2008: abstract # 559

Study details

Results from the Austrian Breast & Colorectal Cancer Study Group Trial 12 (ABCSG-12), demonstrated that Zometa® improved disease-free and recurrence-free survival in 1,801 premenopausal women with early breast cancer receiving adjuvant (post-surgery) endocrine therapy with goserelin in combination with anastrozole or tamoxifen. This new multivariate analysis showed that the addition of Zometa® to endocrine therapy significantly reduced the risk of disease-free survival (DFS) events by 33% (P = 0.02) and recurrence-free survival events by 32% (P = 0.03) compared with endocrine therapy alone.1 These results differ from an analysis presented at the American Society of Clinical Oncology (ASCO) annual meeting in June, which did not evaluate the impact of specific factors (tumor stage, tumor grade, lymph node involvement and progesterone receptor status) on the treatment groups.

Results from the Z-FAST/ZO-FAST trial further support the conclusion that Zometa® may reduce the risk of recurrence. The study examined the effect of Zometa® on aromatase inhibitor-associated bone loss in 1,667 postmenopausal women with early breast cancer receiving letrozole after surgery. Participants were randomized to receive either upfront therapy with Zometa® or delayed treatment with Zometa® after researchers detected bone loss. The primary endpoint of the study was change in lumbar spine bone mineral density after one year. Patients were also followed for disease recurrence (secondary endpoint), among other variables. In this 24-month integrated analysis of the trials, 3.6% of women who received upfront Zometa® before symptoms of bone loss experienced disease recurrence (defined as local recurrence, distant metastasis or death), versus 5.5% of women who received delayed Zometa® after showing symptoms of bone loss. In a stratified analysis, upfront Zometa® significantly decreased the risk of DFS events by 43% (P = .0183).2

Data from the third clinical trial, a pilot study in 45 women with early-stage breast cancer, suggested that Zometa® therapy decreases the prevalence of disseminated tumor cells in the bone marrow. At the two-year follow-up, 71% (12/17) of evaluable patients had a decrease in disseminated cancer cells (P = 0.01). In patients with early-stage breast cancer, disseminated tumour cells in the bone marrow are associated with distant recurrence and death.5 The study is ongoing and additional data will be necessary to determine if the results become statistically significant.

About Zometa®

Zometa® is indicated for the treatment of prevention of skeletal related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumour-induced hypercalcaemia) in patients with advanced malignancies involving bone. Zometa® is approved and indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumours, in conjunction with standard antineoplastic therapy. An intravenous bisphosphonate, Zometa® is the only therapy to demonstrate efficacy in reducing or delaying bone complications across a broad range of tumour types such as breast, prostate, lung and renal cell cancers in patients with metastatic disease when administered monthly. Zometa® offers patients, nurses and clinicians a convenient 4 mg, 15-minute infusion.

Important safety information

In clinical studies, the safety profile with Zometa® was similar to that of pamidronate. Zometa® has been associated with reports of renal insufficiency. Patients should have serum creatinine assessed prior to receiving each dose of Zometa®. Caution is advised when Zometa® is used in aspirin-sensitive patients, or with aminoglycosides, loop diuretics, and other potentially nephrotoxic drugs. Due to the risk of clinically significant deterioration in renal function, single doses of Zometa® should not exceed 4 mg and the duration of infusion should be no less than 15 minutes in 100 ml of diluent.

In clinical trials in patients with bone metastases and hypercalcaemia of malignancy (HCM), Zometa® had a safety profile similar to other intravenous bisphosphonates. The most commonly reported adverse events included flu-like syndrome (fever, arthralgias, myalgias, skeletal pain), fatigue, gastrointestinal reactions, anaemia, weakness, cough, dyspnoea and oedema. Zometa® should not be used during pregnancy. Zometa® is contraindicated in patients with clinically significant hypersensitivity to zoledronic acid or other bisphosphonates, or any of the excipients in the formulation of Zometa®.

Osteonecrosis of the Jaw (ONJ): ONJ has been reported in patients with cancer receiving treatment including bisphosphonates, chemotherapy, and/or corticosteroids. The majority of reported cases have been associated with dental procedures such as tooth extraction. A dental examination with appropriate preventive dentistry should be considered prior to treatment with bisphosphonates in patients with concomitant risk factors. While on treatment, these patients should avoid invasive dental procedures if possible. No data are available to suggest whether discontinuation of bisphosphonate therapy reduces the risk of ONJ in patients requiring dental procedures.

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About Novartis

Novartis AG (NYSE: NVS) is a world leader in offering medicines to protect health, cure disease and improve well-being. Our goal is to discover, develop and successfully market innovative products to treat patients, ease suffering and enhance the quality of life. We are strengthening our medicine-based portfolio, which is focused on strategic growth platforms in innovation-driven pharmaceuticals, high-quality and low-cost generics, human vaccines and leading self-medication OTC brands. Novartis is the only company with leadership positions in these areas. In 2006, the Group's businesses achieved net sales of USD 37.0 billion and net income of USD 7.2 billion. Approximately USD 5.4 billion was invested in R&D. Headquartered in Basel, Switzerland, Novartis Group companies employ approximately 100,000 associates and operate in over 140 countries around the world.

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