Adjuvant Zoledronate Duration ‘Could Be Reduced’ For High-Risk Early Breast Cancer

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: The SUCCESS A trial findings indicate that 2 years of zoledronate therapy may be adequate for the treatment of early breast cancer patients undergoing adjuvant chemotherapy for high-risk disease regardless of menopausal status. 

“Based on our results, the recommended 3 to 5 years of adjuvant bisphosphonate treatment for patients with high-risk [early breast cancer] as published in current clinical guidelines could be reduced”, say Thomas Friedl, from University Hospital Ulm in Germany, and co-authors in JAMA Oncology. 

The phase III open-label study recruited women with node-positive or high-risk node-negative breast cancer, defined as tumour size of pT2 or greater, grade 3 histology, negative hormone receptor status, or patient age of 35 years or younger. 

After primary breast-conserving surgery or radical mastectomy, the participants were given three cycles of adjuvant chemotherapy and then randomly assigned to receive zoledronate 4 mg every 3 months for 2 years or to receive zoledronate 4 mg every 3 months for 2 years followed by a further 3 years of treatment at 6-month intervals. 

On completion of 2 years of zoledronate therapy, the patients were followed-up for a median 35.4 months for the landmark disease-free survival (DFS) and distant DFS endpoints, extending to 36.0 months for the landmark overall survival (OS) analysis, the researchers explain. 

The primary endpoint of DFS did not significantly differ for the 1447 patients in the 2-year zoledronate arm and the 1540 patients in the 5-year zoledronate arm, with a hazard ratio of 0.97 according to a multivariable Cox proportional hazard regression model.  

Nor did the rate of distant DFS or OS significantly differ between the treatment arms, and at 5-years a comparable proportion of patients in the 2-year and 5-year zoledronate therapy arms had circulating tumour cells (7.2 vs 10.5%), the investigators write. 

In addition, exploratory analysis did not detect a significant difference in the survival outcomes with duration of treatment when premenopausal and postmenopausal women were assessed separately. 

But after 2 years of zoledronate therapy, adverse events were significantly more common in patients who continued the treatment than in those who did not (46.2 vs 27.2%), and this included rates of grade 3 and 4 events (7.6 vs 5.1%). 

Patients in the 5-year arm were more likely to report bone pain (8.3 vs 3.7%) and arthralgia (5.1 vs 3.1%) than those in the 2-year arm. Fourteen patients given 5 years of treatment experienced fractures versus three patients given only 2 years of zoledronate therapy, and osteonecrosis of the jaw occurred in 11 and five patients, respectively. 

“Our results suggest that extended adjuvant bisphosphonate treatment with zoledronate 

for 5 years should not be considered in patients with [early breast cancer] in the absence of decreased bone density”, conclude Thomas Friedl et al. 

Ian Tannock, from the Princess Margaret Cancer Center in Toronto, Ontario, Canada, and co-authors of an accompanying editorial agree that the evidence indicates that “if zoledronate is included as a component of adjuvant therapy, a shorter duration of treatment is sufficient.” 

However, when considering the SUCCESS A trial findings and those from historical trials comparing bisphosphonates versus no bone-targeted therapy, the editorialists question the benefit of adjuvant bisphosphonates in a “contemporary breast cancer setting in which DFS events are infrequent.” 

They conclude: “It is time to reevaluate the guidelines.” 

References  

Friedl TWP, Fehm T, Muller 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; Advance online publication 24 June 2021. doi:10.1001/jamaoncol.2021.1854  

Desnoyers A, Amir E, Tannock IF. Adjuvant zoledronate therapy for women with breast cancer – effective treatment or fool’s gold? JAMA Oncol; Advance online publication 24 June 2021. doi:10.1001/jamaoncol.2021.1516