Endocrine therapy is the backbone of treatment for HR+/HER2- breast cancer; however, patients inevitably develop endocrine resistance. Several researchers at the 2024 ASCO Annual Meeting presented emerging data from clinical trials evaluating treatments for endocrine-resistant HR+/HER2- breast cancer.

Following these proceedings, featured expert William J. Gradishar, MD, FACP, was interviewed by Conference Reporter Associate Editor-in-Chief Christopher Ontiveros, PhD. Dr Gradishar’s clinical perspectives on these findings are presented here.

The endocrine therapies that we currently have do not cure patients with metastatic ER+ breast cancer, either alone or in combination with targeted therapy; these individuals ultimately die from their disease. There are some patients who have metastatic ER+ disease for a decade or even longer, but I wish that there were a lot more of them. Inevitably, the disease becomes more endocrine refractory, at which point you have to transition to systemic therapies other than endocrine therapy. The choice of therapy may be dictated by the volume and pace of the disease. You do not always have a lot of time if the disease explodes and the patient is clinically symptomatic, so you may make the transition to chemotherapy.

You could also consider the postMONARCH trial approach, which was presented at ASCO 2024, and you could consider revisiting the same or a different CDK4/6 inhibitor that will buy you more time (abstract LBA1001). I think that the postMONARCH trial was a highlight in the endocrine space at the meeting, with many people talking about how they would use it. The trial enrolled patients with HR+/HER2- advanced breast cancer who had previously received a CDK4/6 inhibitor and went on to receive abemaciclib plus fulvestrant or fulvestrant alone at disease progression. There was a suggestion that you can gain something by the sequential use of CDK4/6 inhibitors, and, although the magnitude of that benefit is modest in terms of progression-free survival, it is something that could be considered.

Older drugs such as the SERD fulvestrant and the mTOR inhibitor everolimus could also be considered. A variety of SERDs are under development and are also being evaluated in combination with targeted therapies, as discussed at ASCO 2024 (abstracts TPS1126 and TPS1135). One of the obvious strategies is combining a SERD with a CDK4/6 or PI3K inhibitor.

Preliminary data from a small number of patients from the ELEVATE and the ELECTRA trials were presented at ASCO 2024 (abstracts 1069 and 1064, respectively). The phase 1b/2 ELEVATE trial is evaluating elacestrant, an oral SERD with activity in patients with ESR1 mutations, in combination with everolimus, alpelisib, ribociclib, palbociclib, or abemaciclib (abstract 1069). The phase 1b ELECTRA trial is evaluating the recommended phase 2 dose of elacestrant with abemaciclib (abstract 1064). These preliminary data basically told us that you can use these combinations without prohibitive toxicity. No particular combination is ready to be approved by the US Food and Drug Administration (FDA); the bottom line is that these presentations were early results.

Finally, the oral SERM lasofoxifene has activity, particularly in patients who had ESR1 mutations. Now it, too, is being combined with other drugs in clinical trials, and the design for the phase 3 ELAINE 3 study was presented at ASCO 2024 (abstract TPS1127).

My hope is that with the insights and knowledge we gain about the molecular abnormalities that can develop in tumors, new drugs will come along that can address those abnormalities as they arise.