HORMONE RECEPTOR-POSITIVE BREAST CANCERS represent more than 67% of breast cancer diagnoses, and estrogen-targeted therapies are a mainstay of treatment. For people with advanced or metastatic hormone receptor-positive breast cancer that is also HER2-negative, doctors commonly prescribe an aromatase inhibitor, which is a type of hormonal therapy, along with a CDK 4/6 inhibitor, which blocks two growth-signaling proteins. Aromatase inhibitors lower estrogen levels in postmenopausal women and men by stopping an enzyme in fat tissue from converting other hormones into estrogen. Over time, though, many breast cancers become resistant to aromatase inhibitors.

If that happens, treatment could move on to Faslodex (fulvestrant), a selective estrogen response degrader (SERD) first approved in 2002. SERDs bind tightly to estrogen receptors and break them down, blunting the effect of estrogen. Unlike other hormonal therapies, which are taken by mouth, Faslodex requires a series of injections into the buttocks.

After receiving Food and Drug Administration (FDA) approval in January 2023, Orserdu (elacestrant) is now the first SERD available in pill form. To be eligible, patients must test positive for an ESR1 gene mutation, measured by a genomic profiling blood test. Roughly 40% of advanced hormone receptor-positive, HER2-negative breast cancers will develop this mutation, which is associated with resistance to aromatase inhibitors. Orserdu’s approval was based on a global clinical trial called EMERALD, which showed that the medication improved progression-free survival over the standard of care, especially for those with an ESR1 mutation.

“This was practice-changing for women and men with this type of breast cancer,” says Kathleen Harnden, a breast medical oncologist at Inova Schar Cancer Institute in Fairfax, Virginia. “After the results were published, they began to impact treatment decisions right away.” Harnden was a principal investigator on the phase III trial and co-author of the study published October 2022 in the Journal of Clinical Oncology.

EMERALD enrolled 477 patients with hormone receptor-positive, HER2-negative advanced breast cancer that had progressed after one or two rounds of treatment with hormonal therapy plus a CDK 4/6 inhibitor. Some patients also had one line of chemotherapy. They were randomly assigned to take Orserdu or their physician’s choice of standard hormonal therapy: Faslodex or one of the three aromatase inhibitors.

Updated findings presented at the San Antonio Breast Cancer Symposium in December 2022 looked at patients who had taken CDK 4/6 inhibitors for 12 months or longer. Researchers found that the median progression-free survival on Orserdu was 3.8 months versus 1.9 months for those on standard hormonal therapy. For the roughly 48% of participants in this group with an ESR1 mutation, the impact on median progression-free survival was more dramatic: 8.6 months for Orserdu versus 1.9 months for standard hormonal therapy, reflecting a 59% reduction in risk for disease progression or death. Although nausea and vomiting were more common with Orserdu than with other hormonal therapies, these side effects were not severe for most people, and there were no other serious side effects.

“For patients, this is a big win in terms of quality of life,” Harnden says. “Fulvestrant [Faslodex] requires going to the infusion suite and getting an injection into each buttock muscle. Patients can be super sore and may not be able to sit down for a while, and some get sciatic pain. Doing that every month over the course of years can be quite bothersome.”

Looking longer term, experts hope that Orserdu and other oral SERDs now under investigation—such as camizestrant, giredestrant and imlunestrat, among others—may be able to overcome the challenge of hormonal therapy resistance. One theory is that oral SERDs are absorbed better by the body than Faslodex and have a stronger impact on inhibiting estrogen receptors.

While the EMERALD trial focused on Orserdu as a single therapy, ongoing and future trials will look at it in combination with other therapies for metastatic breast cancer, such as the CDK 4/6 inhibitor Verzenio (abemaciclib) and targeted therapies such as PI3K inhibitors.

“The EMERALD trial speaks to the fact that we are now regularly doing genomic testing on metastatic breast cancer when anticipating a change in treatment,” says Pallav Mehta, a breast medical oncologist with MD Anderson at Cooper in Camden, New Jersey, who was not involved with the study. “ESR1 is a mutation that comes up a lot. And until now, all we could really offer was Faslodex.”

Mehta is a co-investigator on a clinical trial called SERENA-6, which is testing patients regularly for an ESR1 mutation and randomly assigning those who test positive to continue standard care or switch to the oral SERD camizestrant. “When you think how trials are being done, the presence or absence of certain mutations via liquid biopsy genomic testing is becoming more important,” he says.

“There’s excitement because if oral SERDs can overcome the ESR1 mutation, we may be able to overcome the most important mechanism that estrogen receptor-positive breast cancer has to escape aromatase inhibitors,” Harnden notes. Another important question, she adds, is whether Orserdu might be more effective than an aromatase inhibitor in early-stage breast cancers. “This is a breakthrough in a new drug class, and it will probably have applications in many stages,” Harnden says.