Oral Ibandronate Reduces Skeletal Complications of Cancer

ORLANDO—Daily doses of oral ibandronate (investigational, Hoffmann-La Roche, Basel, Switzerland), a highly potent third-generation bisphosphonate, significantly reduced the incidence of new skeletal complications in breast cancer patients with metastatic bone disease enrolled in a phase III trial. The mean number of new events per patient was 1.36 for women taking oral ibandronate at 20 mg/d and 1.43 at 50 mg/d, compared with 2.23 for women taking placebo.

The results were discussed at the American Society of Clinical Oncology 38th Annual Meeting (abstract 176) by the study’s lead investigator, Debu Tripathy, MD, of The University of Texas Southwestern Medical Center, Dallas.

Although the 20-mg and 50-mg doses of oral ibandronate produced similar results, the higher dose was more effective in reducing bone turnover and painful lesions requiring radiotherapy. According to the researchers, these results "indicate that ibandronate 50 mg/d is the most appropriate clinical dose."

Bisphosphonates inhibit osteoclast-mediated bone resorption and are increasingly being used to manage metastatic bone disease as an alternative to radiation and systemic palliative therapies that are associated with significant side effects. Although bisphosphonates for metastatic bone disease are usually delivered intravenously, the researchers postulated that "a simple oral treatment could enhance tolerability and convenience without compromising efficacy."

The 435 women in the study all had advanced breast cancer with confirmed metastases and adequate performance status. More than 69% of patients in all three arms had been treated with hormonal therapy and more than 63% had received chemotherapy. Patients were randomized to placebo (n = 143) or oral ibandronate at 20 mg/d (n = 144) or 50 mg/d (n = 148) for up to 96 weeks.

Compared with placebo, both iban-dronate arms had a significant reduction in the mean rates of skeletal events per patient year—for the ibandronate arms, the mean rates were 0.97 at 20 mg/d and 0.98 at 50 mg/d, compared with 1.20 for the placebo group (see Table 1). A reduction was seen for each event and reached statistical significance for painful lesions requiring radiotherapy—for the ibandro-nate arms, the mean rates were 0.81 at 20 mg/d and 0.77 at 50 mg/d, compared with 0.99 for the placebo group.

Benefits were also seen in secondary endpoints, including a rapid reduction in bone pain and a significant reduction in analgesic requirements (Table 2). Ibandronate, both arms combined, produced a significant, treatment-related sustained reduction in biochemical markers of bone turnover, compared with placebo (P = .0001) and a significant benefit was seen in the 50-mg group, compared with the 20-mg group (P = .0006).

Adverse events were similar in the ibandronate and placebo groups. The most frequent and serious adverse event in all groups was malignant disease progression. This was the major cause of treatment discontinuation, which occurred in 33.6% of the placebo group, 29.9% of the 20 mg/d ibandronate group, and 20.3% of the 50 mg/d ibandronate group. Ibandronate was not associated with an increased incidence of upper gastrointestinal events and had no significant effects on renal function.

"These data support that oral daily ibandronate is effective in the treatment of skeletal complications of malignancy and has an overall excellent safety profile," the researchers concluded. "Once- daily administration of oral ibandronate is predicted to offer substantial and meaningful clinical advantages over current bisphosphonate IV infusions in terms of convenience and cost."

Asked about possible future trials with ibandronate, Dr. Tripathy told ONI: "I think the most relevant trial is going to be a direct head-to-head comparison with zoledronic acid [Zometa]," to test if oral ibandronate can be as effective as intravenous zoledronic acid.

A recently approved bisphosphonate, zoledronic acid is "highly potent," Dr. Tripathy said, and "can be given as a shorter infusion, which is why it is gaining popularity and probably now is the bisphosphonate to which any newcomers should be compared." [See article on page 3 regarding recent trials of zole-dronic acid.]

In Europe, ibandronate is approved for hypercalcemia, and approval is being sought for treatment of bone metastases. However, it is not available in the United States, Dr. Tripathy said. He noted that there currently is no oral bisphosphonate approved for cancer treatment in the United States, although one—clodro-nate—has been approved in Europe and Canada for quite some time.