Extending the Use of Adjuvant Zoledronate Past 2 Years Does Not Improve Prognosis in High-Risk Early Breast Cancer


Patients with high-risk early breast cancer who received zoledronate for over 2 years did not experience an improvement in prognosis.

Utilizing zoledronate (Reclast) for over 2 years did not appear to improve in the prognosis in a cohort of patients with high-risk early breast cancer, according to the results of the phase 3 SUCCESS A (NCT02181101) study published in JAMA Oncology.

Disease-free survival (DFS; HR, 0.97; 95% CI, 0.75-1.25; P = .81), overall survival (OS; HR, 0.98; 95% CI, 0.67-1.42; P = .90), and distant DFS (HR, 0.87; 95% CI, 0.65-1.18; P = .38) did not differ significantly between the 2 treatment arms. Findings from the study indicate that it may be possible to reduce the current recommended bisphosphonate treatment duration of 3 to 5 years.

“There is clearly a lack of data regarding the optimal adjuvant treatment duration of bisphosphonates. To our knowledge, the SUCCESS A trial reported herein is the first randomized clinical trial filling this gap. The results of this large, multicenter phase 3 trial indicate that there is no benefit with regard to DFS, OS, and DDFS for extending adjuvant zoledronate treatment beyond 2 years in patients with high-risk [early breast cancer] receiving chemotherapy, independent of their menopausal status,” the investigators wrote.

Investigators enrolled 3754 patients on the randomized trial, 91.1% of whom were assigned to receive adjuvant zoledronate after chemotherapy. Among this group, 195 patients had a DFS event and 239 patients were lost to follow-up during the first 2 years of zoledronate treatment. A total of 1447 patients enrolled on the 2-year zoledronate arm and 1540 enrolled on the 5-year zoledronate arm.

Patients had a median age of 53 years and 65.0% of patients had node-positive disease. Both of the zoledronate treatment cohorts were considered to be well balanced by investigators.

Two years after the start of treatment with zoledronate, the median follow-up was 35.4 months for DFS and 36.0 months for 2-year OS. A total of 250 DFS events and 116 deaths were noted during the follow-up period.

The subgroup analysis according to menopausal status revealed no statistically significant difference in DFS (HR, 1.21; 95% CI, 0.81-1.81; P = .35), OS (HR, 0.93; 95% CI, 0.57-1.53; P = .78), or distant DFS (HR, 1.03; 95% CI, 0.65-1.63; P = .90), compared with postmenopausal women (DFS: HR, 0.85; 95% CI, 0.62-1.16; P = .30; OS: HR, 0.96; 95% CI, 0.67-1.39; P = .84; distant DFS: HR, 0.76; 95% CI, 0.52-1.12; P = .16).

Additionally, there was no significant 2-way interaction between duration of zoledronate treatment and menopausal status of adapted DFS (P = .17), adapted OS (P = .74), and adapted distant DFS (P = .33). Investigators stated that there is not evidence of a survival benefit associated with extended treatment in postmenopausal or menopausal women.

After 5 years, circulating tumor cells (CTC) were assessed in 714 patients. In 43 of 410 patients, at least 1 CTC was identified in the 5-year zoledronate arm vs 22 out of 304 patients in the 2-year zoledronate arm, a difference that was not considered to be significant (P = .14).

Additionally, 53 patients with bone recurrence as their first distant recurrence, with or without other concurrent recurrences were observed, with 25 reported events in the 5-year zoledronate arm and in 28 events in the 2-year zoledronate arm. Investigators did not report a statically significant difference between the 2 arms in terms of bone recurrence-free survival (HR, 0.80; 95% CI, 0.47-1.38; P = .43).

In terms of safety, investigators reported 2845 adverse effects (AEs) of any grade, including 1954 in the 2-year zoledronate arm and 891 in the 5-year zoledronate arm. A total of 159 grade 3/4 AEs were reported in the 5-year zoledronate arm and 98 in the 2-year zoledronate arm. The most common AEs were bone pain (8.3% vs 3.7%) and arthralgia (5.1% vs 3.1%), in the 5-year and 2-year zoledronate arms, respectively.

Fractures were observed in 14 patients who received 5-year zoledronate and 3 patients who received 2-year zoledronate. Additionally, 11 patients in the 5-year zoledronate arm and 5 patients in the 2-year zoledronate arm developed osteoporosis.

“[T]here was no statistically significant difference between 5 and 2 years of zoledronate treatment with respect to bone recurrences as first distant recurrence. These results are corroborated by the fact that we found no statistically significant differences between the 2 treatment arms with regard to the presence of CTCs 5 years after adjuvant chemotherapy, which is a prognostic factor for late recurrences in hormone receptor–positive disease,” the investigators concluded.


Friedl TWP, Fehm T, Müller V, et al. Prognosis of patients with early breast cancer receiving 5 years vs 2 years of adjuvant bisphosphonate treatment: A phase 3 randomized clinical trial. JAMA Oncol. 2021;7(8):1149-1157. doi:10.1001/jamaoncol.2021.1854

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