Continued Development of Oral SERDs Could Help Reshape ER+/HER2- Breast Cancer Treatment

Virginia G. Kaklamani, MD

As the oral selective estrogen receptor degrader (SERD) elacestrant approaches potential FDA approval for the treatment of patients with estrogen receptor (ER)­–positive/HER2-negative advanced or metastatic breast cancer, the agent represents how the class of agents could shift this treatment paradigm, according to Virginia G. Kaklamani, MD.

"[I hope we] start looking at combination therapies. Are oral SERDs more beneficial if we combine them with CDK4/6 inhibitors? Should we move SERDs into the adjuvant setting? There are ongoing trials that could reshape the field of ER-positive breast cancer,” Kaklamani said.

In an interview with OncLive^®, Kaklamani discussed the ongoing investigation of novel oral SERDs in patients with ER-positive/HER2-negative breast cancer, the remaining unmet needs for this patient population, and ongoing trials aiming to further understand the optimal use of oral SERDs. Kaklamani is a professor of medicine in the Division of Hematology/Oncology at the University of Texas (UT) Health San Antonio, and leader of the Breast Cancer Program at UT Health San Antonio MD Anderson Cancer Center, in Houston, Texas.

OncLive^®: What is the unmet clinical need in heavily pretreated ER-positive/HER2-negative breast cancer?

Kaklamani: We know that patients who have ER-positive metastatic breast cancer typically receive a CDK4/6 inhibitor in the first-line setting. However, we then struggle a bit with what our second- and third-line options will be. We have single-agent endocrine therapy, combination endocrine therapy, and chemotherapy.

However, we need to figure out whether a tumor is endocrine sensitive. At this point, we don’t have a good understanding of any biological tools to help us [understand endocrine sensitivity]. We use clinical tools, such as [the duration of] CDK4/6 inhibition, but this is also imperfect.

The unmet need is to understand what patients would benefit from single-agent endocrine therapy, such as elacestrant if it is approved, other endocrine therapies, or whether we should proceed with more toxic regimens, such as an AKT inhibitor. [Data from the phase 3 CAPItello-291 trial (NCT04305496)] presented at the 2022 San Antonio Breast Cancer Symposium [SABCS] suggested a benefit of capivasertib [plus fulvestrant (Faslodex)] compared with single-agent endocrine therapy in that setting.

In the case of endocrine-sensitive disease, how could oral SERDs address this need?

Oral SERDs are an evolving field that we are all excited about. Novel SERDs are exciting because they are oral, and most of them have good, tolerable safety profiles. Additionally, there are drugs that have shown sensitivity in patients with ESR1 mutations, and we currently do not have any other tool to address that.

Because patients who are eligible for the trials evaluating oral SERDs are typically heavily pretreated, how closely are investigators examining the safety profiles of these therapies?

When we look at single-agent endocrine therapy, one of the advantages is tolerability. We need to make sure that agent is well tolerated for patients.

Some of the SERDs that were developed had issues with sinus bradycardia, some had ocular toxicities, and some had gastrointestinal toxicities. The [oral SERDs] that are now in phase 3 trials are the ones that won the battle of toxicity. The hope is that when we have 1 or 2 oral SERDs approved, we will be able to have a good, tolerable agent that we can offer patients.

If elacestrant is approved, do you see it changing the standard of care for all comers, or just specific subsets of patients?

If elacestrant is approved, it will change the standard of care for all comers, mostly for [but not limited to] patients with ESR1 mutations. We have a single-agent medication that has efficacy, especially if used in the setting of endocrine sensitivity.

What other novel SERDs have generated intrigue in this space?

We have several other SERDS that are currently in clinical trials. For example, we have camizestrant [AZD9833], which is now being examined in phase 3 trials. We also have imlunestrant [LY3484356]. Those are the 2 SERDs that are likely the closest to [having] data from phase 3 clinical trials.

What other updates from the 2022 SABCS in ER-positive/HER2-negative breast cancer caught your eye?

The other major presentation looked at capivasertib, which is an AKT inhibitor. This drug was looked at in the CAPItello-291 trial, which was a phase 3, randomized trial of capivasertib plus fulvestrant compared with fulvestrant [plus placebo].

Capivasertib showed superiority. There is a question about tolerability, as [the combination regimen] caused diarrhea and other adverse effects. We will see in practice how tolerable the combination is. However, the efficacy results were impressive.

There were also [data from the phase 2 RIGHT Choice trial (NCT03839823)] looking at first-line CDK4/6 inhibition compared with chemotherapy in patients with fast-growing tumors. This trial showed that the combination of a CDK4/6 inhibitor and endocrine therapy was superior to combination chemotherapy. That is impressive for this class of agents.

What else should be emphasized about SERDs in this patient population?

In metastatic ER-positive setting, a lot of the work being done [is focused on] biomarkers. The [phase 3] EMERALD trial [NCT03778931] will be just one of the studies looking at biomarkers to see if we can tease out the patients that who benefit from oral SERDs vs other medications. It was interesting in the CAPItello-291 trial that all patients benefited from capivasertib, not just the patients with an ATK pathway alterations.

Funding supported by Stemline Therapeutics. Content independently developed by OncLive