Elacestrant Highlights Promise of Oral SERDs in HR+/HER2– Metastatic Breast Cancer

Antoinette R. Tan, MD, MHS

The FDA approval of the oral selective estrogen receptor degrader (SERD) elacestrant (Orserdu)underscores the potential for other oral SERDs currently under development, such as camizestrant (AZD9833) and imlunestrant (LY3484356) to become treatment options in this space, according to Antoinette R. Tan, MD, MHSc.

In January 2023, the FDA approved elacestrant for the treatment of postmenopausal women or adult men with estrogen receptor (ER)–positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy.1 The approval was supported by findings from the phase 3 EMERALD trial (NCT03778931), which showed that patients with ER-positive, HER2-negative, ESR1-mutated breast cancer who received the oral SERD experienced a median progression-free survival (PFS) of 3.8 months (95% CI, 2.2-7.3) vs 1.9 months (95% CI, 1.9-2.1) for those given fulvestrant (Faslodex) or an aromatase inhibitor (HR, 0.55; 95% CI, 0.39-0.77; P = .0005).

“This was an important study because it also showed activity of this class of compounds in patients who have received prior CDK4/6 inhibitor treatment. These promising results lay the groundwork for other oral SERDs that are currently undergoing clinical investigation,” Tan said following an OncLive® State of the Science Summit™ on breast cancer, which she chaired.

In an interview with OncLive, Tan discussed the promise of oral SERDs as they continue to be developed for the treatment of patients with ER-positive, HER2-negative breast cancer, factors that inform treatment decisions following disease progression on a CDK4/6 inhibitor, and the growing role of antibody-drug conjugates (ADCs) across the breast cancer spectrum. Tan is the chief of Breast Medical Oncology, codirector of the Phase I Program at Levine Cancer Institute, Carolinas Medical Center-Pineville, and a clinical professor in the Department of Medicine at the University of North Carolina in Chapel Hill.

OncLive: How have treatment options in the second-line setting for patients with hormone receptor (HR)–positive, HER2-negative breast cancer evolved with recent data and studies?

Tan: There has recently been an expansion in terms of the drugs that we can use to treat [patients with] HR-positive, HER2-negative metastatic breast cancer [in] the second line and beyond. Before these [additional therapies] were available, we were limited with using, for example, the steroidal aromatase inhibitor exemestane with an mTOR inhibitor, fulvestrant, and traditional chemotherapy.

It is an exciting time now to have availability of such agents that are more like targeted treatments. For example, it is exciting to see [the availability of] PARP inhibitors, such as olaparib [Lynparza] and talazoparib [Talzenna]. To treat patients with these [PARP inhibitors], one would have to know the germline BRCA[mutational] status.

Another example of drugs that are available now are PI3K inhibitors, specifically in the form of alpelisib [Piqray] in combination with fulvestrant. Oral SERDs are another new kid on the block, and the one that was recently approved is elacestrant. This is for patients who have tumors that harbor ESR1 mutations. Collectively, these drugs have made their way to changing the standard of care.

Another game changer is the availability of ADCs, specifically fam-trastuzumab deruxtecan-nxki [Enhertu] and sacituzumab govitecan-hziy [Trodelvy]. [Trastuzumab deruxtecan] has been available for patients with metastatic HER2-positive breast cancer, and sacituzumab govitecan [has been approved] for those with metastatic triple-negative breast cancer. I’m pleased to [now] be able to offer these 2 types of treatments to patients with metastatic HR-positive, HER2-negative [or HER2-low] breast cancer. Both of those ADCs have shown clinical benefit over treatment of physician’s choice for patients with HR-positive, HER2-negative [or HER2-low] metastatic breast cancer that has received prior endocrine therapy and prior chemotherapy.

What factors contribute to sequencing decisions for treatments following disease progression on a CDK4/6 inhibitor?

I do take in several factors when I have a patient who has progressed on a CDK4/6 inhibitor with endocrine therapy. Some of those include the patient’s functional status, what they received as prior adjuvant endocrine treatment, and what they received as first-line therapy. However, what’s becoming clearer and more important is tumor biology. Because we have biomarker-directed treatments, it’s very critical to test a patient’s tumor for any biomarkers that are altered.

For example, if a patient’s tumor is sampled or blood is obtained, and an alteration in ESR1 is detected, then a patient would be eligible to receive the oral SERD elacestrant. Therefore, the tumor biology comes into play when considering treatment options for patients post-CDK4/6 inhibitor therapy.

What does the approval of elacestrant mean for ongoing and future investigations of other oral SERDs, such as camizestrant and imlunestrant?

Elacestrant was the first oral SERD approved for [patients with] metastatic HR-positive, HER2-negative,ESR1-mutated breast cancer, who have received prior endocrine therapy. The EMERALD data are important for paving the way for oral SERDs as monotherapy for patients with metastatic disease. However, there are a lot of ongoing trials with other oral SERDs where they are being studied in combination with other targeted treatments, such as CDK4/6 inhibitors. Often, when we see beneficial results for patients with a new compound, the next step is to move it to the early-stage, adjuvant setting. The field is already seeing clinical development of oral SERDs for the adjuvant setting, so there is more to come with results and advancements in that area.

What is the importance of biomarker testing to inform treatment decisions for patients with HR-positive, HER2-negative breast cancer?

CDK4/6 inhibitors with endocrine therapy have been established as a standard-of-care treatment option as first-line therapy for [patients with] HR-positive, HER2-negative metastatic breast cancer. The options post–CDK4/6 inhibitor treatment have greatly expanded. Because of the expansion of available drugs that are biomarker-driven, it’s important that clinicians remember to sample either blood or tissue to test for the presence or absence of that biomarker, [which could] expand treatment choices for patients.

Arielle Heeke, MD, of Atrium Health Levine Cancer Institute, also discussed the use of CDK4/6 inhibitors for the treatment of patients with HR-positive, HER2-negative breast cancer. What role could these agents play in the adjuvant setting for this patient population?

The use of CDK4/6 inhibitors combined with endocrine [therapy] for [patients with] HR-positive, HER2-negative breast cancer has been one of the major breakthroughs in breast oncology in the past 2 decades. When you take all the data that have been evaluated with these drugs in the metastatic setting, [we have] seen improvements in terms of PFS and OS, as well as manageable toxicity profiles.

What is compelling to me is how [abemaciclib (Verzenio)] has moved into the adjuvant setting. The updated results of the [phase 3] monarchE trial [NCT03155997] showed continued benefit of using adjuvant abemaciclib with endocrine therapy after surgery for [patients with] early-stage HR-positive, HER2-negative breast cancer with a high risk of recurrence.

It is great to see that we can take what we learned in the metastatic setting and be able to apply it in the early-stage adjuvant setting to benefit our patients and help them live longer.

Neelam Desai, MD, of Atrium Health Levine Cancer Institute, discussed the role of trastuzumab deruxtecan. Could you expand on what this treatment has displayed for patients with HER2-positive or HER2-low metastatic breast cancer?

Trastuzumab deruxtecan is an ADC that targets HER2. ADCs are a novel way to deliver cytotoxic chemotherapy in a more directed fashion. We’ve seen compelling data with trastuzumab deruxtecan in all the DESTINY-Breast trials.

In [the phase 3] DESTINY-Breast02 trial [NCT03523585], treatment with trastuzumab deruxtecan over treatment of physician’s choice in patients who had received prior ado-trastuzumab emtansine [T-DM1; Kadcyla] improved progression-free survival [PFS] and overall survival [OS]. In the [phase 3] DESTINY-Breast03 trial [NCT03529110], the results [indicated that] trastuzumab deruxtecan again showed improvement in PFS and OS compared with treatment with T-DM1. The results [of DESTINY-Breast03] paved the way for our use of trastuzumab deruxtecan as second-line therapy for [patients with] metastatic HER2-positive breast cancer.

There is a new entity called HER2-low disease, which is identified in patients if they have a tumor with immunohistochemistry [IHC] 1+ or IHC 2+ not amplified by fluorescence in situ hybridization. In [the phase 3] DESTINY-Breast04 trial [NCT03734029], [we] saw similar results in that trastuzumab deruxtecan showed improvement in PFS and OS compared with treatment of physician’s choice in patients who had HER2-low metastatic breast cancer.

Are there any ongoing or upcoming trials at Atrium Health Levine Cancer Institute that you would like to highlight?

There is a very interesting [phase 1b] trial [NCT05508906] that I’m excited about that we’ll be opening at our institution with the novel agent called OP-1250. This is a complete ER antagonist. It acts similarly to an oral SERD in that it degrades the ER, but it also acts as an ER antagonist.

A phase 1 study [NCT04505826] was already conducted with this agent as monotherapy, and there were some early signals of [activity] in [patients with] breast cancer. The next step in the development of the drug is to study it in combination with FDA-approved agents. This phase 1b study will be evaluating OP-1250 in combination with ribociclib [Kisqali] and in combination with alpelisib to assess whether combining OP-1250 with these FDA-approved agents is safe and tolerable, as well as to [evaluate for] an early signal of efficacy. [OP-1250] was also given fast track designation by the FDA [in July 2022 for the treatment of patients with ER-positive, HER2-negative metastatic breast cancer], given the promising results [of the phase 1 monotherapy study].²

If all goes well, and [OP-1250] continues to advance in clinical development to phase 2/3 testing, it could be another drug added to our armamentarium to treat patients with metastatic HR-positive, HER2-negative breast cancer.

References

• FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. News release. FDA. January 27, 2023. Accessed May 17, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/
• Olema Oncology receives FDA fast track designation for OP-1250 for the treatment of ER+ / HER2- metastatic breast cancer. News release. Olema Pharmaceuticals, Inc. July 21, 2022. Accessed May 17, 2023. https://ir.olema.com/news-releases/news-release-details/