Amcenestrant’s Potential Role in ER+/HER2- Metastatic Breast Cancer
Sarat Chandarlapaty, MD, offers his opinion on the potential roles amcenestrant could have in the treatment of ER+/HER2- metastatic breast cancer.
Sarat Chandarlapaty, MD: The potential roles for amcenestrant could be a replacement of every place we use antiestrogen therapy in breast cancer. There’s potential for replacement of aromatase inhibitors, in the neoadjuvant stage, in the adjuvant setting. There’s potential for replacement of other forms of hormone therapy, whether it’s fulvestrant, tamoxifen, or aromatase inhibitors in the metastatic setting as a single agent or as combinations with targeted agents. It has all the hallmarks of a hormone therapy that could inhibit ER [estrogen receptor] and is well tolerated enough to combine with other agents. All those are being tested. In terms of newer potential areas where the drug could synergize, there’s growing interest in looking at HER2 [human epidermal growth factor receptor]–positive breast cancer where roughly 50% of patients also have estrogen receptor expression. When patients in that setting are going into a maintenance phase, they’re often given endocrine therapy together with HER2 therapy. That’s another setting in which the combination would be interesting to look at.
One of the questions that we’re faced with in the metastatic setting is, “How do we treat patients whose genomic profile comes back with an estrogen receptor mutation?” This tells us about a cancer that has a mutation that causes estrogen receptor to be constitutively active. This tells us that drugs like aromatase inhibitors won’t work, that drugs that sort of lower estrogen levels won’t work with a constitutively active estrogen receptor.
What we need are drugs that actually engage the mutant estrogen receptor. Amcenestrant and other oral SERDs [selective estrogen receptor degrader] have the potential to potently occupy the estrogen receptor when it’s mutated. Whether that’s as a single agent or in combination with CDK4 inhibitors or PI3 kinase inhibitors, when an estrogen receptor mutation is present on the genomic profiling, it favors the notion that you would treat with a SERD or a direct estrogen receptor antagonist like amcenestrant. In the AMEERA trials, we did observe that there was activity for amcenestrant regardless of whether the estrogen receptor was wild type or mutant. This is an increasingly prevalent phenomenon, where we’re profiling patients to see if they have, for instance, a PI3 kinase mutation to allow them to be treated with alpelisib. If we also find that patient has an estrogen receptor mutation, that becomes an important consideration in the endocrine therapy partner that’s chosen.
Transcript edited for clarity.
