Bisphosphonates turn 50

Trying to reconcile disparate findings

Those findings left his group with a dilemma, said Dr. Coleman. “Do we start again and run trials, and wait another 10 years, or is there a shortcut to [understanding] what’s going on?” he asked.

In a meta-analysis of all trials from the Early Breast Cancer Trialists’ Collaborative Group in 2015 examining adjuvant bisphosphonate treatment and placebo in patients with early-stage breast cancer, intent-to-treat analyses did not show significant benefit after therapy, but postmenopausal women (11,767 women in 36 trials) saw a clear benefit in all recurrence (rate ratio, 0.86; 95% CI, 0.78-0.94), bone recurrence (RR, 0.72; 95% CI, 0.60-0.86), and breast cancer–related mortality (RR, 0.82; 95% CI, 0.73-0.93; Lancet. 2015 Jul 23. doi: 10.1016/S0140-6736[15]60908-4). The effect seemed to be similar, regardless of bisphosphonate type, with other results seen across trials that used clodronate, zoledronic acid, pamidronate, or ibandronate.

“Although those outcome differences might look quite small for a common disease, that’s a really big effect. Reducing one-sixth of breast cancer deaths at 10 years is the equivalent of saving 10,000 lives across the [European Union], and about half that in the United States,” said Dr. Coleman, noting that guidelines in North America from the American Society of Clinical Oncology and the European Society for Medical Oncology now support adjuvant bisphosphonates in postmenopausal patients with breast cancer.

However, bisphosphonates’ effect on breast cancer does not extend to other cancers, such as non–small cell lung cancer or prostate cancer. In other absorption inhibitors such as denosumab, there also seems to be no benefit for patients with breast cancer, including in postmenopausal patient subgroups, said Dr. Coleman. “In my view, osteoclast inhibition is only part of the story,” he noted.

In the AZURE trial, secondary outcomes examined how the transcription factor MAF interacted with menopausal status and treatment with zoledronic acid. The 79% of patients with tumors that were negative for MAF fluorescence in situ hybridization had improved overall survival (0.69; 95% CI, 0.50-0.94), regardless of menopause status (J Bone Oncol. 2018. doi: 10.1016/j.jbo.2018.09.008). “There’s probably a need to merge the treatment: in this case, the bisphosphonate, the biology of the cancer, and the environment the cancer finds itself in,” noted Dr. Coleman.

“From the cancer perspective, bisphosphonates have transformed the experience for many of our patients with advanced disease, and now we’re working to see great improvements, at least in common diseases such as postmenopausal breast cancer,” he concluded.

Dr. Coleman reports being a paid employee of prIME Oncology (until March 2019); is a consultant for Amgen, Astellas, Boehringer Ingelheim, Scandell, and Biocon; is on the speakers bureau for Amgen and Eisai; holds intellectual property rights for a biomarker being developed by Inbiomotion; and is on the scientific advisory board for Inbiomotion.