Advances are rapidly being made in the way that we treat HR+/HER2- breast cancer. Clinical trial data on emerging treatment regimens with potential practice-changing implications were presented at the recent 2024 ASCO Annual Meeting.

Following these proceedings, featured expert Sara M. Tolaney, MD, MPH, was interviewed by Conference Reporter Associate Editor-in-Chief Christopher Ontiveros, PhD. Dr Tolaney’s clinical perspectives on these findings are presented here.

I think that we are really moving away from using endocrine therapy as monotherapy. The estrogen receptor antagonist elacestrant is currently approved by the US Food and Drug Administration (FDA) for ER+/HER2-, ESR1-mutated, advanced/metastatic breast cancer. At ASCO 2024, we saw some preliminary data from the ELEVATE trial looking at elacestrant in combination with various targeted agents, including the mTOR inhibitor everolimus; CDK4/6 inhibitors ribociclib, palbociclib, and abemaciclib; and the PI3K inhibitor alpelisib (abstract 1069). This study showed us that it is safe to use these combination strategies. In the future, I think that we will have larger data sets from the ELEVATE trial that will really show us the efficacy of these combinations.

We have been fortunate over the last several years with the introduction of CDK4/6 inhibitors for the treatment of HR+ metastatic breast cancer. I think that these agents really represent the standard of care for such patients who are starting treatment. We have seen across trials that adding a CDK4/6 inhibitor to endocrine drugs improves progression-free survival (PFS) and overall survival. That has been transformational for our patient outcomes.

CDK4/6 inhibitors have also been investigated as potential treatments for patients with early-stage breast cancer. For example, data presented at ASCO 2024 from the NATALEE trial looking at adjuvant endocrine therapy with or without ribociclib for 3 years in patients with early-stage HR+/HER2- breast cancer were quite interesting (abstract 512). The results suggested that adjuvant ribociclib had a trend toward improved invasive disease-free survival in a subset of node-negative patients, for a 3% absolute improvement. The confidence intervals surrounding improvement are wide because it was a small subset of patients, but the findings make me think that CDK4/6 inhibition may have a role in the treatment of patients with node-negative, high-risk disease. We anticipate that FDA approval could come soon for adjuvant ribociclib. However, despite it not being FDA approved, we have already seen updates in ASCO treatment guidelines that include adjuvant ribociclib for patients with stage II or III HR+/HER2- early breast cancer with a high risk of recurrence.

An unmet need is how to address patients whose disease recurs after receiving an adjuvant CDK4/6 inhibitor. One promising strategy that we are seeing move up earlier in the treatment lines for HR+ metastatic disease is the use of ADCs. We saw some really impressive data at ASCO 2024 from the DESTINY-Breast06 study (abstract LBA1000). This study looked at the ADC trastuzumab deruxtecan (T-DXd) in patients with HR+/HER2-low or ultra-low metastatic breast cancer after disease progression on endocrine therapy and no prior chemotherapy. These are patients who were taking, for example, an upfront CDK4/6 inhibitor with endocrine therapy who then may go on to another line of endocrine treatment; traditionally, we would give these patients chemotherapy. In the DESTINY-Breast06 trial, however, patients who would have traditionally received chemotherapy were randomized to T-DXd or chemotherapy (ie, capecitabine or a taxane). Treatment with T-DXd resulted in a significant improvement in median PFS, from 8.1 months with chemotherapy to 13.2 months with T-DXd. I think that this was very clinically meaningful and that the guidelines are going to have to change regarding where we place T-DXd in terms of line of therapy.

Another study presented at ASCO 2024 with practice-influencing data was the olaparib expansion study (ie, the TBCRC 048 study), which was led by Nadine M. Tung, MD (abstract 1021). Her group had previously shown efficacy not only in patients with germline BRCA mutations but also in those with somatic BRCA and germline PALB2 mutations. The data that she initially showed in 2020 were from a very small subset of patients, so she went on to conduct a validation study to determine the efficacy of olaparib in additional patients with somatic BRCA and germline PALB2 mutations. At ASCO 2024, she presented data showing an objective response rate of 75% and a median PFS of 9.6 months with olaparib in 24 patients with germline PALB2 mutations. In 30 patients with somatic BRCA1/2 mutations, her group reported an objective response rate of 36.7% and a median PFS of 5.6 months. In my mind, these data confirm that olaparib can be a standard-of-care choice for patients with germline PALB2 mutations and for those with germline or somatic BRCA mutations.

I think that we are so fortunate because, over the last 5 years or so, the pace of FDA approvals for breast cancer treatments has been so different from what it used to be. We are seeing newer drugs emerge that are really having an impact on patient outcomes. It is incredible because it just goes to show how well we are doing in trying to improve outcomes for our breast cancer patients.