• 1.5 million patients in the U.S. are currently on endocrine therapies for breast cancer
• 270,000 invasive breast cancers are diagnosed annually in women in the U.S., with 70% to 80% being ER+ cancers
• 40% of patients with ER+ breast cancer go on to develop an ESR1 mutation

A Duke-patented drug originally intended for treating osteoporosis is now being studied as a possible endocrine therapy for metastatic breast cancer in patients with estrogen receptor 1 (ESR1) mutations.

Lasofoxifene, a selective estrogen receptor modulation that blocks the effects of estrogen in breast tissue, is at the center of an international, multisite, phase II open label study with Fast Track designation by the FDA. The “Evaluating LAsofoxIfeNe in ESR 1 Mutations,” or the ELAINE study, compares lasofoxifene to fulvestrant, the standard-of-care treatment for postmenopausal and premenopausal women with locally advanced or metastatic estrogen receptor (ER)-positive breast cancer.

Between 70% and 80% of the more than 270,000 invasive breast cancers diagnosed annually in women in the U.S. are estrogen receptor-positive (ER+), explains Donald McDonnell, PhD, associate director of Translational Research at Duke Cancer Institute. The potential for this new treatment is significant for the up to 40% of patients with ER+ breast cancer who go on to develop an ESR1 mutation. This mutation is especially prevalent in those who have been extensively pretreated with aromatase inhibitors, an estrogen synthesis suppressant.

“Lasofoxifene looks promising where other endocrine therapies have failed,” says McDonnell, who co-led the team that developed the drug in the early 1990s to treat osteoporosis in women as a result of estrogen loss in menopause. Because the drug was surpassed by another drug in clinical trials for treating osteoporosis, it was never registered, but since 2016, McDonnell’s team at Duke has patented and licensed it for use in metastatic breast cancer.

“In our research, we have found that lasofoxifene alone is effective against almost all of the ESR1 mutations,” he notes. “We know that if a patient develops an ESR1 mutation, they will be resistant to varying degrees to all the endocrine therapies we have, but lasofoxifene is different.”

More than 1.5 million women in the U.S. are currently on endocrine therapies for breast cancer—either as monotherapies or in combination with other drugs. These therapies have been found to work well, in some cases for many years, until they begin to lose their efficacy.

“The side effects of endocrine therapies can be really difficult on patients,” says Sarah Sammons, MD, Duke medical oncologist and the ELAINE study’s principal investigator. “Lasofoxifene is unique because it has the ability to improve dyspareunia in post-menopausal women with vaginal atrophy and strengthen bone, which most endocrine therapies markedly reduce.”

If the phase II ELAINE study yields positive results, Sammons explains, the next step will be to combine lasofoxifene with other targeted agents. This is already in progress with the ELAINE II trial combining lasofoxifene with the CDK4/6 inhibitor abemaciclib. Both studies are nearly fully enrolled and expect to have results soon in the coming year.

“We are very hopeful that these will be options for this high-need patient population in the future,” Sammons says.

McDonnell adds, “With lasofoxifene, we want people to understand that when you fail the standard-of-care endocrine therapy, that’s not the end of the line.”

McDonnell and Sammons are working together on several other trials looking at new options and novel therapies for this patient population, most notably the effect of endocrine therapy on the immune system.

“We are exploring how manipulating estrogen impacts both the body's immune system and its ability to fight breast cancer so that we can come up with immunotherapy regimens that would benefit these patients,” McDonnell says.