In a former life, the drug elacestrant, also known as RAD1901, was supposed to treat dementia. Then it became a treatment for hot flashes in post-menopausal women. Fast forward 30 years and it is now an FDA-approved drug for hard-to-treat advanced breast cancers.
As the first and only treatment approved specifically to fight breast cancers with mutations in estrogen receptors that are resistant to standard hormone therapy, elacestrant addresses a significant unmet need.
But its hidden potential would have remained untapped had Professor Donald McDonnell not read about the results of the drug’s early clinical trials.
“At low concentrations, the drug was effective at reducing the number and severity of hot flashes,” said McDonnell, who is a Glaxo-Wellcome Distinguished Professor of molecular cancer biology with Duke’s Department of Pharmacology and Cancer Biology.
But when the drug was given in higher doses, instead of reducing the frequency and impact of hot flashes further, it made them worse.
“We would have expected that if ‘a little was good, more would be better’ but that was not the case,” he explained. “We were intrigued by this unusual pharmacology and began to figure out the mechanistic basis for this unexpected finding.”
Professor Donald McDonnell’s lab is focused on identifying and developing new hormone therapies to treat advanced breast cancer // Credit: Duke University School of Medicine
Taking up this challenge, Assistant Professor Suzanne Wardell, who joined the McDonnell lab in 2012, worked with then postdoctoral trainee Erik Nelson, now a professor of molecular and integrative physiology at the University of Illinois, to study the drug’s effect in human breast cell lines.
They found that the drug was effective at blocking estrogen from binding to its receptor in breast cancer cells, thereby arresting cell growth. It also reduced the expression of estrogen receptors in the cancer cells and inhibited the growth of estrogen-receptor-positive tumours in preclinical models of the disease.
“It turned out that the reason for its failure as a treatment for hot flashes was actually a useful property for a breast cancer drug,” added McDonnell, who is also the associate director of translational research at the Duke Cancer Institute.
Recognising the potential that RAD1901 offered as a breast cancer therapeutic, McDonnell and his team filed for patents covering the drug’s use in breast cancer. “We were concerned that if we did not give it new life in the form of these patents it would be forgotten,” he added.
Then they had to persuade the owners of the drug, Radius Health, a biopharmaceutical company primarily focused on addressing unmet medical needs in bone health to develop it for breast cancer. “It took nearly three years but finally, everyone bought into the concept,” recalled McDonnell.
In 2017, the team licensed their patents to Radius, kickstarting the drug’s clinical development for breast cancer.
Since the completion of the phase III clinical trial, also known as the EMERALD trial, the drug received approval under the FDA’s Priority Review and Fast Track designation when the trial demonstrated that elacestrant reduced the risk of progression or death in patients by 45 per cent, with a medial progression-free survival time of 8.6 months compared with 1.9 months for the standard of care treatment.
“We believe that elacestrant has the potential to become the hormone therapy of choice in late-stage breast cancer,” said McDonnell.
Adapted by Chua Li Min from New Therapy for Advanced Breast Cancer Has Roots in Duke Lab and “Luck favours the prepared mind”.