In the German phase III SUCCESS A trial reported in JAMA Oncology, Friedl et al found no differences in disease-free or overall survival with 5 vs 2 years of zoledronate treatment following adjuvant chemotherapy for early breast cancer.

Study Details

In the multicenter, open-label, 2 × 2 factorial design trial, 3,754 women with node-positive or high-risk node-negative disease (≥ pT2, histologic grade 3, hormone receptor–negative, or age ≤ 35 years) were randomly assigned between September 2005 and March 2007 to receive adjuvant chemotherapy with three cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by three cycles of docetaxel with vs without gemcitabine. After chemotherapy, patients were randomly assigned to receive either 2 years of zoledronate at 4 mg every 3 months (n = 1,447 included in analysis) or 5 years of zoledronate at 4 mg every 3 months for 2 years followed by 4 mg every 6 months for 3 years (n = 1,540 included in analysis).

The current report provides findings only for the zoledronate 2- vs 5-year randomization. The primary endpoint was disease-free survival. Survival times were measured from 2 years after the start of zoledronate in a landmark analysis. Multivariable analyses adjusted for age, body mass index, menopausal status, type of surgery, tumor size, nodal category, histologic grade, histologic type, hormone receptor status, HER2 status, and adjuvant chemotherapy. Final data analysis was performed between September 2019 and October 2020.

Survival Outcomes

Median follow-up from 2 years after the start of zoledronate treatment was 35.4 months for both 2-year landmark disease-free survival and distant disease–free survival and 36.0 months for 2-year landmark overall survival.

Disease-free survival events occurred in 129 patients in the 5-year group (8.4%) vs 121 in the 2-year group (8.4%). Hazard ratios (HRs) in the landmark analysis for 5 vs 2 years were 0.97 (95% confidence interval [CI] = 0.76–1.25, P = .83) on univariate analysis and 0.97 (95% CI = 0.75–1.25, P = .81) on multivariate analysis. HRs were 1.08 (95% CI = 0.77–1.52) among patients receiving FEC plus docetaxel and 0.86 (95% CI = 0.60–1.23) among those receiving FEC plus docetaxel and gemcitabine.

Overall survival events occurred in 59 patients in the 5-year group vs 57 in the 2-year group. HRs in the landmark analysis for 5 vs 2 years were 0.93 (95% CI = 0.65–1.34, P = .71) on univariate analysis and 0.98 (95% CI = 0.67–1.42,  P = .90) on multivariate analysis. HRs for 5 vs 2 years in landmark analysis of distant disease–free survival (total of 177 events) were 0.86 (95% CI = 0.64–1.16, P = .32) on univariate analysis and 0.87 (95% CI = 0.65–1.18, P = .38) on multivariate analysis.  

Adverse Events

Adverse events of any grade occurred in 46.2% of the 5-year group vs 27.2% of the 2-year group (P < .001), with grade 3 or 4 events occurring in 7.6% vs 5.1%. In both groups, the skeletal-related events of bone pain and arthralgia were the most common adverse events; both bone pain (8.3% vs 3.7%) and arthralgia (5.1% vs 3.1%) were more common in the 5-year group. Fractures were observed in 14 vs 3 patients. Osteonecrosis of the jaw was observed in 11 vs 5 patients.

The investigators concluded: “The results of this phase III randomized clinical trial indicate that extending the zoledronate treatment beyond 2 years does not improve the prognosis of high-risk patients with early breast cancer receiving chemotherapy, suggesting that the currently recommended bisphosphonate treatment duration of 3 to 5 years could be reduced.”

Thomas W.P. Friedl, PhD, of the Department of Gynecology and Obstetrics, University Hospital Ulm, is the corresponding author of the JAMA Oncology article.

Disclosure: The investigator-initiated trial was supported by grants from AstraZeneca, Chugai, Menarini Silicon Biosystems (formerly Veridex), Lilly, Novartis, and Sanofi-Aventis. For full disclosures of the study authors, visit jamanetwork.com.