Aditya Bardia, MD, MPH, on Elacestrant vs Standard-of-Care Endocrine Therapy in ER-Positive, HER2-Negative Breast Cancer

Endocrine therapy with a CDK4/6 inhibitor is the preferred first line treatment for patients with hormone receptor positive metastatic breast cancer, but patients eventually have disease progression. Endocrine resistance could be due to development of mutations in the estrogen receptor, the ESR1 mutations. In the second, third line setting we tend to use Fulvestrant as the endocrine therapy, but Fulvestrant is given as an intramuscular shot and different studies have shown that the duration of response, the median progression-free survival with Fulvestrant in the post-CDK4/6 setting is about two to three months, so clinically, there's an unmet need for better endocrine therapy options for patients with metastatic hormone receptor positive breast cancer. The EMERALD trial was designed to look at a novel oral selective estrogen receptor degrader SERD called Elacestrant. It was compared with standard endocrine therapy Fulvestrant or choice of aromatase inhibitor depending on what patients received previously. If a patient had received AI plus a CDK4/6 in first line, in the second line setting they could receive Fulvestrant if randomized to the control arm. The primary endpoint of the trial was progression-free survival in all patients. There was another primary endpoint which was progression-free survival in patients with ESR1 mutant hormone receptor positive metastatic breast cancer. As a reminder, this trial required patients to have received prior CDK4/6 inhibitor so it was in the post-CDK4/6 setting, second/third line setting. At SABCS 2021 we saw the first results from the EMERALD trial, which demonstrated that Elacestrant was superior to standard of care endocrine therapy. At SABCS 2022 we saw updated results from the EMERALD trial stratified by the duration of prior CDK4/6 inhibitor. The key findings were that the duration of prior CDK4/6 inhibitor was associated with benefit from Elacestrant because if we look at the curves from the EMERALD trial, we see an initial drop and then separation of the curves in favor of Elacestrant. The question was can we identify the endocrine sensitive population because the initial drop is likely endocrine resistant, and then the separation is the endocrine sensitive population. It looks like the duration of prior CDK4/6 inhibitor can help identify the endocrine sensitive population. For example, in all comers, the median progression-free survival in patients who had a prior CDK4/6 duration of at least 12 months, with Elacestrant the median PFS was close to six months versus about two months with standard endocrine therapy. This was even more pronounced in patients who had ESR1 mutant cancer, where the median PFS was more than eight months with Elacestrant versus about three months with standard endocrine therapy. So in summary, Elacestrant was superior to standard endocrine therapy in the second/third line setting for patients with hormone receptor positive metastatic breast cancer. Prior duration of CDK4/6 inhibitor was associated with benefit with Elacestrant with a median PFS of more than eight months in patients with mutant ESR1 breast cancer. The drug was, in general, well tolerated. It's an oral drug. Majority of patients were able to continue Elacestrant without discontinuing because of side effects so it provides us an oral option for patients with metastatic hormone receptor positive breast cancer in the second/third line setting. EMERALD looked at single agent Elacestrant versus standard endocrine therapy. There's a clinical trial called ELEVATE, which would look at Elacestrant in combination with other targeted therapies such as PI3 kinase inhibitor, mTOR inhibitor, CDK4/6 inhibitor. The ELEVATE trial would look at Elacestrant based combinations for patients with hormone receptor positive metastatic breast cancer.