No Clinical Benefit With Adjuvant Ibandronate in Postmenopausal Breast Cancer

Sabine Linn, MD, PhD

Adjuvant ibandronate (Boniva) added to hormone therapy did not provide a clinical benefit to postmenopausal patients with HR-positive, early-stage breast cancer, according to findings from the phase III TEAM IIB trial.

Postmenopausal women treated with ibandronate for 3 years along with their hormone therapy, demonstrated an improved disease-free survival (DFS) rate of 94.3% compared with 90.8% in the control group, but the difference was not deemed clinically significant, reported Sabine Linn, MD, PhD, during a press conference at the 2016 San Antonio Breast Cancer Conference (SABCS).¹

The TEAM IIB trial investigated the addition of ibandronate to adjuvant endocrine therapy to see if it improved patient outcomes, following on a recent meta-analysis of 26 trials of adjuvant bisphosphonate treatment in patients with early breast cancer which reported a moderate improvement in survival when patients received bisphosphonates as part of their therapy, especially if the women were postmenopausal.²

Overall, 1116 postmenopausal women with early-stage, HR-positive breast cancer were enrolled in the trial, conducted across 37 hospitals in the Netherlands between 2007 and 2014. Accrual was slower than anticipated, Linn noted, so the protocol was changed to allow for a smaller group of participants. She added that when accrual for TEAM IIB was launched, ibandronate was part of a new class of bisphosphonates that was 100 times more potent than the classic bisphosphonate clodronate in this patient population.

Participants were randomized to either a standard adjuvant endocrine therapy control group (exemestane only, or tamoxifen followed by exemestane) for at least 5 years, or to the experimental arm, which added ibandronate 50 mg once daily to the regimen for 3 years. The primary endpoint of the study was DFS; secondary endpoints included time to and rate of bone metastases and safety.

At data cutoff, 73 patients remained on ibandronate therapy. Median follow-up was 4.6 years, and 67% of patients adhered to ibandronate.

Both the control group and ibandronate group had similar rates of all-cause mortality (47 and 48 events, respectively). The ibandronate group showed a lower rate of breast cancer—related mortality at 17 events, compared with 29 events in the control group. However, 14 secondary malignancy–related events were noted in the ibandronate group, compared with 9 in the control arm.

The hazard ratio (HR) for DFS rate between the 2 arms was 0.80 (95% CI, 0.58-1.10), which was not statistically significant. The rate of bone metastases—1.6% in the ibandronate arm versus 4.7% in the control group—also was not statistically significant (HR, 0.65; 95% CI, 0.38-1.11).

Linn indicated that the drug was safe, with only 20% of patients discontinuing treatment due to side effects, not all of which were ibandronate-related. The ibandronate group showed a higher rate of stomach- and reflux-related symptoms compared with controls (8.3% vs 2.2%, respectively).

There were 36 serious adverse events (SAEs) reported in 31 patients from the ibandronate arm and 51 SAEs reported in 39 patients from the control arm. Four patients in the ibandronate arm developed osteonecrosis of the jaw, which went away upon treatment discontinuation, Linn reported. Renal failure was also noted in 2 patients, although this may not have been related to the study drug.

Although the ibandronate failed to provide additional clinical benefit in the patient population, Linn questioned whether the analysis was premature, as a number of patients were still on treatment.

“It might be that this analysis was too early, especially for this type of breast cancer, luminal A breast cancer,” Linn said. “We might need a much longer formula to see the true effect of the addition of ibandronate.”

When compared with the EBCTCG meta-analysis, Linn noted that the HR rates were similar. “I think it’s in concordance with what we already know and that’s reassuring. It also means that apparently it does not matter so much what type of bisphosphonate you choose.”

Ultimately, treatment with bisphosphonates will depend upon individual patient characteristics, such as bone-mineral density, panelists suggested during the press conference.

Further analyses of the data are planned as soon as the last patient reaches the 3-year follow-up period (May 2017), and the investigators plan to follow the patients for up to 10 years to analyze the long-term effects.

References:

1. Vliek SB, Kranenbarg EM-K, van Rossum AGJ, et al. Adjuvant ibrandronate in postmenopausal women with early breast cancer: first results of the TEAM IIB trial. Presented at: 2016 San Antonio Breast Cancer Symposium; December 6-10, 2016; San Antonio, TX. Abstract S6-02.
2. Coleman R, Powles T, Paterson A, et al. Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomized trials. Lancet. 2015;386(10001):1353-1361.

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View more from the 2016 San Antonio Breast Cancer Symposium

“In the Netherlands it’s clinical practice [to use bisphosphonates], although there is debate among physicians whether you should use it in all postmenopausal breast cancer patients or only in those with a higher risk, because the relevant risk reduction is about 18% to 20% in breast cancer—specific survival,” Linn said. “If someone already has a very good prognosis, the actual benefit from this drug will be minimal, so it’s really weighing the costs and benefits of adding this drug.”