. Interim results of AZURE trial report Zometa added to standard adjuvant therapy did not show disease free survival advantage compared to standard therapy alone[1]
. In subgroup of women with well-established menopause, an improvement in disease free survival and overall survival was shown in Zometa arm[1]
. Current applications in the US and EU for adjuvant treatment in early breast cancer will be withdrawn; Novartis to evaluate future plans based on these new data
. Study results do not impact the current indications for Zometa in preventing SREs in patients with advanced cancers involving bone and multiple myeloma and treating HCM
Basel, December 9, 2010 - Results from the second interim analysis of the Phase III AZURE (Adjuvant Zoledronic acid to redUce REcurrence) trial show that Zometa® (zoledronic acid) did not demonstrate a disease-free survival (DFS) advantage when added to standard adjuvant (post-surgery) chemotherapy and/or hormonal therapy in pre- and postmenopausal women with early breast cancer. In a preplanned analysis based on menopausal status, a benefit in disease free survival and overall survival was seen in women with well-established menopause in the Zometa arm[1].

The AZURE trial was conducted to determine if Zometa as adjuvant therapy had a benefit in preventing recurrences in premenopausal and postmenopausal women with early breast cancer. The results were presented today at the 33rd Annual CTRC-AACR San Antonio Breast Cancer Symposium in San Antonio, Texas, US[1].

Zometa is currently approved for the reduction or delay of bone complications (skeletal-related events, or SREs) across a broad range of metastatic cancers (breast, prostate, lung and other solid tumors) involving bone and multiple myeloma, as well as for the treatment of hypercalcemia of malignancy (HCM) and is the most widely used bisphosphonate in the oncology setting.

"These trial results do not impact the current usage of Zometa, which continues to be a critical treatment for many patients with a broad range of metastatic cancers and multiple myeloma," said Hervé Hoppenot, President, Novartis Oncology. "Although we did not see an overall disease free survival advantage for early breast cancer patients receiving Zometa in the adjuvant setting, we're encouraged that a subset of postmenopausal patients in the trial experienced an improvement."

The potential anticancer benefit of Zometa was previously observed in a large, randomized, Phase III study from the Austrian Breast & Colorectal Cancer Study Group (ABCSG-12 study), which included more than 1,800 premenopausal women with hormone receptor-positive (HR+) early-stage breast cancer who, following curative surgery and hormone therapy, including goserelin treatment to suppress ovarian function and induce menopause, were treated with or without Zometa for three years[2]. The trial showed that the addition of three years of Zometa therapy to hormonal therapy following surgery improved disease-free survival by 32% (hazard ratio=0.68 [95% confidence interval 0.51-0.91], P=0.009)[3].

Last year, Novartis filed supplemental marketing authorization applications for the adjuvant treatment of premenopausal women with HR+ early breast cancer in conjunction with hormonal therapy in the US and European Union (EU) based on the results of ABSCG-12. Novartis is currently reviewing the data from the AZURE trial results, which were expected to be added to the submission. In the meantime, Novartis will withdraw the current marketing applications and discuss next steps with health authorities.

Zometa is approved in more than 100 countries for the reduction or delay of bone complications in multiple myeloma and across a broad range of metastatic cancers (breast, prostate, lung and other solid tumors) involving bone, as well as for the treatment of hypercalcemia of malignancy. It is the most widely used bisphosphonate in the oncology setting and has been used to treat more than 3.9 million patients worldwide.

AZURE study details
AZURE is a randomized, open-label, multicenter, parallel group trial that enrolled 3,360 women from 174 centers in seven countries[4],[1]. The study is run by the National Cancer Research Network in the United Kingdom with input from an international collaborative group[4]. Patients participate in a five-year treatment phase and a subsequent five-year follow-up phase[4]. A small subset of patients also received neo-adjuvant (pre-surgery) therapy[4].

The primary endpoint of DFS was to be determined after 940 disease events[4]. The data presented at SABCS are from a second interim analysis performed when at least 75% (752) of the final events had occurred[1]. Secondary endpoints included invasive DFS, overall survival, bone metastasis free survival safety, and other translational endpoints[4]. After a median follow up of 59 months (interquartile range 53-61), the hazard ratio (HR) for DFS in Zometa-treated (n=1681) compared to control patients (n=1678) was 0.98 (95% confidence interval [CI] [0.85-1.13], P=0.79), thus there was no clinically significant benefit between the treatment groups[1]. The trend toward improved overall survival in patients on the Zometa arm was not statistically significant (HR=0.85 [95% CI 0.72-1.01], P=0.0726)[1].

In a preplanned analysis of women based on menopausal status, a benefit of disease free survival and overall survival was seen in women with well-established menopause in the Zometa arm[1]. An adjusted analysis for imbalances in prognostic factors (estrogen receptor, lymph node status and tumor stage) showed this benefit was statistically significant (29% improvement in overall survival (HR=0.71 [95% CI 0.54-0.94]; P=0.017)[1]. No benefit was seen in premenopausal women[1].

The tolerability profile of Zometa is well-established and results from this study were found to be consistent with the known profile[1]. Generally, serious adverse events (SAE) were similar in both treatment arms[1]. There were 17 cases of osteonecrosis of the jaw confirmed in the Zometa arm[1]. This represents a rate of 1.16%, which is consistent with what has been seen in other well controlled trials[6].

About ZOMETA
Zometa is indicated for the prevention of skeletal related events (pathological fractures, spinal compression, radiation or surgery to bone, or tumor-induced hypercalcemia) in patients with multiple myeloma and advanced malignancies involving bone. An intravenous bisphosphonate, Zometa is the only approved therapy to demonstrate efficacy in reducing or delaying bone complications in multiple myeloma and across a broad range of malignancies such as breast, prostate, lung and renal cell cancers in patients with metastatic disease when administered monthly. Zometa offers patients, nurses and clinicians a 4 mg, 15-minute infusion.