For patients whose breast cancer progresses on either an aromatase inhibitor or tamoxifen in the adjuvant setting, the first thing that we typically do is perform a biopsy. If a patient is progressing because of loss of the estrogen receptor (ER), we would obviously want to transition them to a nonhormonal therapeutic approach. Currently, the majority of patients who are progressing on hormonal therapy are candidates for CDK4/6 inhibitor therapy. The standard approach is to utilize a CDK4/6 inhibitor such as ribociclib or abemaciclib along with fulvestrant, as these drugs have consistently led to a survival advantage in the metastatic setting.

Additionally, there is a lot of interest and momentum right now in developing new or novel hormonal therapies. For those tumors that continue to express the ER, one of the most common mechanisms of resistance is the development of activating mutations in the ESR1 gene; this mutation confers resistance to aromatase inhibitors. We have a new drug, elacestrant, that was recently approved for patients with ER-positive (ER+)/human epidermal growth factor receptor 2–negative (HER2-), ESR1-mutated breast cancer that progressed following CDK4/6 inhibitor–based therapy. Results of the phase 3 EMERALD trial showed a modest improvement in progression-free survival (PFS) with elacestrant monotherapy compared with standard care of fulvestrant or aromatase inhibitor monotherapy in patients with ER+/HER2- breast cancer and progression on a CDK4/6 inhibitor. Other selective estrogen receptor degraders, including camizestrant, imlunestrant, giredestrant, and vepdegestrant, are also in development and have already shown encouraging antitumor activity.

Further, new selective estrogen receptor modulators (SERMs) are under investigation for patients who have progressed after aromatase inhibitor and CDK4/6 inhibitor therapies. The SERM lasofoxifene has demonstrated activity either as monotherapy (ELAINE-1) or as combination therapy with the CDK4/6 inhibitor abemaciclib (ELAINE-2) in patients with ER+/HER2- metastatic breast cancer and an ESR1 mutation and progression after previous CDK4/6 inhibitor therapies. The upcoming ELAINE-3 US Food and Drug Administration registration clinical trial will compare fulvestrant plus abemaciclib vs lasofoxifene plus abemaciclib in patients with an activating ESR1 mutation and progression on either palbociclib or ribociclib.  

Additional therapeutic targets are being evaluated for patients who have progressed on CDK4/6 inhibitor therapies. Inhibitors of other cyclin-dependent kinases, such as CDK2 and CDK7, and degraders of CDK4 and CDK6 are in development. Another strategy that is currently being evaluated is the use of the Aurora A kinase inhibitor alisertib. A recently published phase 2 study found that treatment with alisertib was associated with some exciting antitumor activity, with an objective response rate of approximately 20% and a median PFS that approached 6 months in patients with endocrine-resistant HER2- metastatic breast cancer. 

We must not forget about the importance of the PI3K/AKT/mTOR pathway. We have evidence from the phase 2 BYLieve trial demonstrating that alpelisib clearly has antitumor activity for patients with hormone receptor–positive (HR+)/HER2-, PIK3CA-mutated breast cancer who progressed on aromatase inhibitor–plus–CDK4/6 inhibitor therapies, again with PFS rates around that 6-month mark. We also have recent data from the phase 3 CAPItello-291 trial demonstrating the antitumor activity of capivasertib in patients with aromatase inhibitor–resistant HR+/HER2- who had progression on a CDK4/6 inhibitor and who had an alteration in the PI3K/AKT pathway. I think that, in the future, capivasertib will become a go-to drug, especially for patients whose tumors progress on CDK4/6 inhibitor therapy and exhibit mutations in that PI3K/AKT pathway.