Zometa(R) Helps Prevent Bone Loss In Breast Cancer Patients On Aromatase Inhibitors, Data Presented At SABCS

Main Category: Breast Cancer
Also Included In: Bones / Orthopaedics;  Women's Health / Gynecology
Article Date: 14 Dec 2007 - 1:00 PDT

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New 36-month data presented showed that hormone receptor-positive postmenopausal breast cancer patients taking an aromatase inhibitor as initial adjuvant therapy were significantly less likely to suffer from bone loss if they received treatment with twice-yearly Zometa® (zoledronic acid, 4mg) administered at the start of aromatase inhibitor therapy, compared with patients who received delayed treatment with Zometa.

These data from the Zometa-Femara Adjuvant Synergy Trial (Z-FAST) were announced during an oral presentation today at the 30th Annual San Antonio Breast Cancer Symposium (SABCS).

Study results demonstrated that mean increase in lumbar spine bone mineral density (BMD), the primary endpoint, was 3.72% in the upfront group versus a mean decline of 2.95% in the delayed treatment group, resulting in a significant difference of 6.7% in favor of upfront Zometa. Mean increase in total hip BMD was 1.66% in the upfront group versus a mean decline of 3.51% in the delayed treatment group, resulting in a significant difference of 5.2% in favor of upfront Zometa. These observed differences improved from year one through year three. Furthermore, fractures in the upfront group occurred in 5.6% versus 6.3% in the delayed group, and disease recurrences were less frequent in the upfront arm (3.5%) in comparison to the delayed arm (6.9%).

"In this study, early treatment with Zometa had a significant impact on the prevention of bone loss in postmenopausal breast cancer patients taking an aromatase inhibitor," said lead investigator Adam Brufsky, MD, PhD, Magee/UPCI Breast Program, University of Pittsburgh Cancer Center, Pittsburgh, PA. "Bone loss can be managed in this patient population. With heightened awareness, regular bone density screening and proper treatment, patients may benefit from optimal breast cancer therapy while maintaining bone health."

Aromatase inhibitors have demonstrated a significant reduction in the risk of breast cancer recurrence compared with tamoxifen. This class of drugs works by blocking the estrogen that fuels tumor growth. Reduced estrogen levels can affect bone health.

Aromatase inhibitors, like Femara® (letrozole tablets, 2.5mg), the therapy used in the Z-FAST trial, are increasingly used following surgery to reduce the risk of breast cancer recurrence in postmenopausal women with hormone-sensitive early breast cancer due to the therapy's significant benefit over tamoxifen in this treatment setting. Femara is the only aromatase inhibitor shown to significantly reduce the risk of distant metastases when this risk is the greatest - particularly two to three years following surgery.

"Novartis remains committed to cancer therapy research that aims to fill unmet patient needs," said Diane Young, MD, Vice President, Head, Global Medical Affairs, Novartis Oncology. "Zometa continues to be studied in other clinical settings. There are over 200 completed and active Zometa studies, with more than 24,000 patients having completed or currently enrolled in these studies."

Zometa is approved and indicated for the treatment of patients with multiple myeloma and patients with documented bone metastases from solid tumors, 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 tumor types such as breast, prostate, lung and renal cell cancers in patients with metastatic disease when administered every three or four weeks. Zometa offers patients, nurses and clinicians a convenient 4mg, 15-minute infusion.

Zometa effectively slows the bone-destroying effect that occurs with bone metastases, by fighting abnormal activation of osteoclasts. Osteoclasts are bone cells that normally break down old bone to allow replacement by new bone. The osteoclasts are abnormally activated by substances produced by cancer cells in bone. This causes excessive wearing away of bone, and also slows the abnormal build-up of new but unstable bone produced by related bone cells called osteoblasts.

About Z-FAST

The Z-FAST trial is an open label, randomized multi-center study of 602 postmenopausal women in the U.S. and Canada being treated for hormone-receptor positive early breast cancer following breast cancer surgery.

Beginning day one, all patients will be treated with Femara as their adjuvant therapy for a maximum of five years, or until disease progression. Patients were randomized to one of two Zometa treatment arms, receiving either an upfront 4mg, 15-minute infusion every six months starting on day one, or a delayed start 4mg, 15-minute infusion of Zometa every six months. The delayed start group received Zometa when researchers detected a post-baseline bone mineral density T-score below -2.0 SD (standard deviation) or after a bone fracture occurred. Patients are followed for bone complications including fractures, and disease recurrence.

At 36 months, Zometa was generally well tolerated with no serious renal adverse events in this setting. To date, there have been no confirmed cases of osteonecrosis of the jaw reported as part of the Z-FAST trial.

About 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. In prostate cancer, patients should have progressed after treatment with at least one hormonal therapy. Zometa also is indicated for the treatment of hypercalcemia of malignancy (HCM).

Zometa safety profile

Zometa is contraindicated in patients with hypersensitivity to zoledronic acid or other bisphosphonates, or any of the excipients in the formulation of Zometa. Hypersensitivity reactions, including rare cases of urticaria and angioedema and very rare cases of anaphylactic reaction/shock, have been reported.

Due to the risk of clinically significant deterioration in renal function in cancer patients, single doses of Zometa should not exceed 4 mg, and the duration of infusion should be no less than 15 minutes. Risk factors for the deterioration of renal function include impaired baseline renal function, prior to chemotherapy received, and multiple cycles of bisphosphonate treatment.

Zometa is not recommended in patients with bone metastases with severe renal impairment. In patients with mild to moderate renal impairment at baseline, lower doses of Zometa are recommended based on calculated creatinine clearance. Before each Zometa dose, serum creatinine should be measured and treatment should be withheld for renal deterioration until serum creatinine has returned to within 10% of the baseline value.

Zometa should not be used during pregnancy. Women of childbearing potential should be advised to avoid becoming pregnant. If the patient becomes pregnant while taking this drug, the patient should be apprised of the potential harm to the fetus.

Osteonecrosis of the jaw (ONJ) has been reported predominantly in cancer patients treated with intravenous bisphosphonates, including Zometa. Many of these patients were also receiving chemotherapy and corticosteroids, which may be risk factors for ONJ. Postmarketing experience and the literature suggest a greater frequency of reports of ONJ based on tumor type (advanced breast cancer, multiple myeloma) and dental status (dental extraction, periodontal disease, local trauma, including poorly fitting dentures). Many reports of ONJ involved patients with signs of local infection, including ostiomyelitis. Cancer patients should maintain good oral hygiene and should have a dental examination with preventive dentistry prior to treatment with bisphosphonates. While on treatment, these patients should avoid invasive dental procedures, if possible. No data are available as to whether discontinuation of bisphosphonate therapy reduces the risk of ONJ in patients requiring dental procedures. A causal relationship between bisphosphonate use and ONJ has not been established. Clinical judgment of the treating physician should guide the management plan of each patient based on individual benefit/risk assessment.

In postmarketing experience, severe and occasionally incapacitating bone, joint, and/or muscle pain has been reported infrequently in patients taking bisphosphonates.

In clinical trials in patients with bone metastases and hypercalcemia of malignancy (HCM), Zometa had an acceptable safety profile. The most commonly reported adverse events included flu-like syndrome (fever, chills, arthralgias, myalgias, skeletal pain), fatigue, gastrointestinal reactions, anemia, weakness, cough, dyspnea and edema. 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.

Caution is advised when bisphosphonates are administered with aminoglycosides, loop diuretics, and potentially nephrotixic drugs.

Zometa contains the zoledronic acid. Patients being treated with Zometa should not be treated with Reclast, as they both contain zoledronic acid as their active ingredient. Patients with Multiple myeloma and patients with document bone metastases from solid tumors should take an oral calcium supplement of 500 mg and a multiple vitamin containing 400 IU of vitamin D daily while on Zometa therapy.

About Femara

Femara is approved for the adjuvant (following surgery) treatment of postmenopausal women with hormone receptor-positive early breast cancer. The benefits of Femara in clinical trials are based on 24 months of treatment and 26 months of follow-up. Further follow-up will be needed to determine long-term outcomes.

Femara is also approved for the extended adjuvant treatment of early stage breast cancer in postmenopausal women who are within three months of completion of five years of adjuvant tamoxifen therapy. The benefits of Femara in the extended adjuvant setting are based on 24 months of treatment. Further follow-up will be needed to determine long-term results.

Femara is also approved for the first-line treatment of postmenopausal women with hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer. Femara is also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

Femara safety profile

Femara is a one-daily oral prescription medication. You should not take Femara if you are premenopausal. Your doctor should discuss the need for adequate birth control if you have the potential to become pregnant, if you are not sure of your postmenopausal status, or if you recently became postmenopausal. Femara is only indicated for postmenopausal women. Patients should talk to their doctor if they are allergic to Femara or any of its ingredients. Femara should be used with caution by nursing mothers. Patients should not take Femara if they are pregnant as it may cause fetal harm. Some women reported fatigue and dizziness with Femara. Until a patient knows if Femara affects them, they should use caution before driving or operating machinery. Some patients taking Femara had an increase in cholesterol. Additional follow-up is needed to determine the risk of bone fracture associated with long-term use of Femara.

In the adjuvant setting, commonly reported side effects are generally mild to moderate. Side effects that are comparable between Femara and tamoxifen include night sweats, weight gain, nausea, and tiredness. Side effects seen more often with tamoxifen vs. Femara were hot flashes and vaginal bleeding. Joint pain was experienced more often with Femara vs. tamoxifen. The incidence of stroke was 1.1% for women on Femara and 1.0% for women on tamoxifen, and the incidence of other cardiovascular events was 6.6% for Femara vs. 6.2% for tamoxifen. The percentage of women on Femara reporting bone fracture was 5.6% vs. 4% for women on tamoxifen. The percentage of women reporting osteoporosis was 2% for Femara vs. 1.1% for tamoxifen. Additional side effects for both Femara and tamoxifen were heart attack, thomboembolic events, endometrial cancer and second malignancies.

In the extended adjuvant setting, commonly reported side effects are generally mild to moderate. Those seen more often with Femara vs. placebo were hot flashes (50% vs. 43%), joint pain (22% vs. 18%) and muscle pain (7% vs. 5%). Other side effects, which were comparable to placebo, include fatigue (34% vs. 32%), swelling due to fluid retention (18% vs. 16%), headache (20% vs. 20%), increase in sweating (24% vs. 22%) and increase in cholesterol (16% vs. 16%). The percentage of patients on Femara vs. placebo reporting a fracture was 5.9% vs. 5.5%. The percentage of patients reporting osteoporosis was 6.9% vs. 5.5%. Bisphosphonates, drugs to increase bone strength, were given to 21.1% of Femara patients and 18.7% of placebo patients. Additional side effects seen in study were arthritis, dizziness, constipation, nausea and cardiovascular ischemic events.

In the metastatic setting, commonly reported side effects are generally mild to moderate and may include bone pain, hot flashes, back pain, nausea, joint pain, shortness of breath, fatigue, coughing, constipation, limb pain, chest pain, and headache.

Disclaimer

The foregoing release contains forward-looking statements that can be identified by terminology such as "likely," "may," "committed," "will," or similar expressions, or by express or implied discussions regarding potential new indications or labeling for Zometa or Femara or regarding potential future revenues from Zometa or Femara. Such forward-looking statements reflect the current views of the Company regarding future events, and involve known and unknown risks, uncertainties and other factors that may cause actual results with Zometa or Femara to be materially different from any future results, performance or achievements expressed or implied by such statements. There can be no guarantee that Zometa or Femara will be approved for any additional indications or labeling in any market. Nor can there be any guarantee that Zometa or Femara will achieve any particular levels of revenue in the future. In particular, management's expectations regarding Zometa and Femara could be affected by, among other things, unexpected clinical trial results, including unexpected new clinical data and unexpected additional analysis of existing clinical data; unexpected regulatory actions or delays or government regulation generally; competition in general; government, industry and general public pricing pressures; the company's ability to obtain or maintain patent or other proprietary intellectual property protection; and other risks and factors referred to in Novartis AG's current Form 20-F on file with the US Securities and Exchange Commission. Should one or more of these risks or uncertainties materialize, or should underlying assumptions prove incorrect, actual results may vary materially from those anticipated, believed, estimated or expected. Novartis is providing the information in this press release as of this date and does not undertake any obligation to update any forward-looking statements contained in this press release as a result of new information, future events or otherwise.

For more information

Additional information regarding Zometa, Femara or Novartis Oncology can be found on the websites http://www.zometa.com, http://www.femara.com or http://www.novartisoncology.com.

About Novartis

Novartis Pharmaceuticals Corporation researches, develops, manufactures and markets leading innovative prescription drugs used to treat a number of diseases and conditions, including those in the cardiovascular, metabolic, cancer, organ transplantation, central nervous system, dermatological, gastrointestinal and respiratory areas. The company's mission is to improve people's lives by pioneering novel healthcare solutions.

Located in East Hanover, New Jersey, Novartis Pharmaceuticals Corporation is an affiliate of Novartis AG (NYSE: NVS), 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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