The treatment of advanced/metastatic HR+/HER2- breast cancer has been evolving at a rapid pace. As seen at the 2024 ASCO Annual Meeting, researchers continue the work of discovering additional options for patients with advanced/metastatic HR+/HER2- breast cancer who progress on standard therapies.

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.

Approximately two-thirds of all cases of newly diagnosed breast cancer are HR+, and a fraction of these patients go on to develop recurrent metastatic disease. Currently, for those with HR+ disease who develop recurrence, or for those with de novo metastatic HR+/HER2- breast cancer, the standard of care is endocrine therapy, usually with a CDK4/6 inhibitor in the first-line setting. For patients who are postmenopausal, the endocrine component is usually an aromatase inhibitor, whereas patients who are not postmenopausal receive either ovarian suppression therapy or oophorectomy and, once postmenopausal, an endocrine agent. In the last 10 years, endocrine therapy has been partnered with CDK4/6 inhibitor therapy, and this has produced a longer progression-free survival (PFS) compared with endocrine therapy alone. Overall survival advantages have also been observed in some of these trials.

A fraction of patients with ER+/HER2- metastatic disease who receive a CDK4/6 inhibitor along with endocrine therapy have a shorter PFS, likely due to the development of resistance. Clinically, the progression-free duration helps inform us of the behavior and biology of the tumor. When recurrence occurs while a patient is still on adjuvant therapy, that is a tumor that may be de novo resistant. Disease that recurs 5 years after the patient completed adjuvant endocrine therapy is also concerning but is considered a different category of tumor compared with the previous example. To some extent, the approach to the management of metastatic disease reflects the nature of the earlier adjuvant therapy, which currently also includes a CDK4/6 inhibitor in some high-risk patients.

What should be done for the patient who develops progressive disease after being on a CDK4/6 inhibitor in the metastatic disease setting? Next-generation sequencing is usually done at first recurrence to determine if there are any actionable mutations. PIK3CA mutations are often truncal mutations that are present at the time of the original diagnosis (approximately 40%). In contrast, ESR1 mutations tend to emerge over time and with the pressure of sequential endocrine treatments. Elacestrant is US Food and Drug Administration (FDA) approved for patients with ESR1 mutations, and we now have alpelisib and capivasertib for PI3K/AKT pathway abnormalities, the majority of which are actually PI3K abnormalities. All these drugs may be possibilities when reviewing the treatment options post progression on a CDK4/6 inhibitor, although the duration of benefit post CDK4/6 inhibitor can be more modest.

And for those without mutations? If the patient is still a candidate for endocrine therapy, one might consider giving the combination of fulvestrant and an mTOR inhibitor such as everolimus, or simply giving endocrine monotherapy.

In patients with metastatic ER+ breast cancer, sequencing endocrine therapy over time has generally been preferred, but there are patients who may need to go straight to chemotherapy due to the tempo of the disease or having threatening visceral disease. This scenario is where the DESTINY-Breast06 presentation at ASCO 2024 comes in (abstract LBA1000). There are HR+ patients with metastatic disease, post CDK4/6 inhibitor therapy, in whom pivoting to chemotherapy may be appropriate. Eligible patients were those with ER+/HER2-low expression (including ultra-low, which was defined as >0 but <10%) with metastatic disease who had not received chemotherapy for advanced disease but did receive at least 2 lines of prior endocrine-based therapy in the metastatic disease setting or 1 line of prior endocrine therapy if progression occurred on adjuvant endocrine therapy within 24 months or if progression occurred on a CDK4/6 inhibitor within 6 months in the advanced disease setting. Patients were randomized to trastuzumab deruxtecan (T-DXd) or to chemotherapy with capecitabine, paclitaxel, or nab-paclitaxel. Data presented from the primary analysis showed that T-DXd significantly improved PFS by 5 months compared with chemotherapy (8.1 months to 13.2 months). This effect was observed in the overall population and in the subset defined as HER2 ultra-low. Overall survival is immature at this time.

T-DXd is currently approved by the FDA for the treatment of adult patients with unresectable or metastatic HER2+ (IHC 3+ or ISH+) breast cancer who have received a prior anti-HER2–based regimen either in the metastatic setting or in the neoadjuvant or adjuvant setting and have developed disease recurrence during or within 6 months of completing therapy. FDA approval was based on data from the phase 3 DESTINY-Breast04 trial (NCT03734029), which enrolled patients irrespective of hormone receptor status.