The Present and Future of Endocrine Therapy in Breast Cancer

Erika Hamilton, MD

Endocrine therapies for breast cancer are rapidly evolving, with several promising agents emerging. According to Erika Hamilton, MD, oral selective estrogen receptor degraders (SERDs) and proteolysis-targeting chimeras (PROTACs), in particular, are transforming the treatment landscape for breast cancer, especially in the post-CDK4/6 inhibitor setting.

Elacestrant (Orserdu) is an oral SERD that is FDA approved for patients with ESR1 mutations, and camizestrant, another SERD, has demonstrated superior efficacy compared with fulvestrant and may soon be available for broader use.^1,2 Additionally, PROTACs like vepdegestrant (ARV-471) offer a new mechanism for degrading the estrogen receptor (ER) and are currently being tested in combination with CDK4/6 inhibitors.³

Several ongoing clinical trials are also exploring novel strategies, including first-line therapies combined with CDK4/6 inhibitors and treatment in adjuvant settings with curative intent. The results of these studies could potentially shift the current treatment paradigms.

“With all these trials ongoing, we will certainly have a rich dataset to improve our endocrine therapies,” explained Hamilton, director of breast cancer research at the Sarah Cannon Research Institute, in an interview with Targeted Oncology^TM.

In the interview, Hamilton discussed how these therapies offer new hope for patients with breast cancer by improving progression-free survival and potentially delaying the need for more toxic treatments like chemotherapy.

3D rendered medically accurate illustration of breast cancer: © SciePro - stock.adobe.com

Targeted Oncology: What are some of the most promising emerging endocrine therapies in breast cancer?

Hamilton: There are quite a few emerging endocrine therapies. We have 1 FDA-approved oral SERD, elacestrant, that is restricted currently to patients with ESR1 mutations, but there are a lot more coming. The other to have randomized data was camizestrant. It essentially looked at 2 different doses of camizestrant, but it easily beat fulvestrant. I think we know we are going to see data in multiple settings with that drug coming.

One of the other classes that is getting talked about quite a lot are the PROTACs or proteolysis-targeting chimeras. It is a different way to degrade estrogen through proteasome and ubiquitination of the target the estrogen receptor. The one farthest along is ARV-471, and we have seen data from the phase 1 trial, as well as in combination with palbociclib [Ibrance], and that is also currently enrolling in registrational trials.

There are other newer agents coming, and then I like to call it the word salad of endocrine therapy. But we have CERANs, complete estrogen receptor antagonists; we have SERMs, newer selective estrogen receptor modulators; we have SERCAs, selective estrogen receptor covalent antagonists—a lot of different drugs coming to essentially work for patients.

How are novel endocrine therapies improving treatment for metastatic breast cancer?

What we are seeing is that CDK4/6 [inhibitors] are really the mainstay of our treatment. In the first line, they extended progression-free survival by almost a year, improving overall survival in many cases. However, post-CDK4/6 [inhibitor], drugs we used to [rely on], like fulvestrant, are not performing as well as they used to. Now, we have 2 randomized trials in that second-line, post-CDK4/6 [inhibitor] setting, where fulvestrant gives us a progression-free survival of less than 2 months, which is certainly not good enough for our patients.

I think the unmet clinical needs are for these patients whose tumors remain endocrine sensitive. We need better endocrine therapy so they can remain on endocrine therapies or endocrine combinations and delay having to move to other treatments with more toxicities, such as chemotherapy.

What upcoming developments in the space are you most excited about?

There are a lot of trials ongoing. First, there are multiple companies developing novel endocrine agents, and they are diversifying their approaches. The area that will likely be actionable first is the second-line, post-CDK [inhibitor] space. However, there are also ongoing trials in the first-line setting in combination with CDK4/6 inhibitors as a switch strategy for positive [circulating tumor DNA (ctDNA)], with results expected to read out relatively soon.

Additionally, there are adjuvant trials for curative breast cancer [treatment] that may replace our traditional endocrine backbones. These trials come in 2 varieties: comparing the new agents up front with aromatase inhibitors and using a switch strategy after 2 to 5 years on an aromatase inhibitor. With all these trials ongoing, we will certainly have a rich dataset to improve our endocrine therapies.

Can you describe the different classes of endocrine therapies and how they compare to one another?

Tamoxifen [Soltamox] is our oldest endocrine agent, and that is a SERM, a selective estrogen receptor modulator. We also have aromatase inhibitors. This is our mainstay of endocrine therapy, I would say. Then there is fulvestrant, which is an intramuscular injection form of a SERD. We now have new SERDs coming, and they are different because they are oral, not intramuscular, and have better activity. One of them is approved, elacestrant, for patients with ESR1 mutations, and there are many more oral SERDs on the way.

Additionally, we have PROTACs, which work by using an E3 ligase molecule to bind the target—in this case, the estrogen receptor. This leads to the ubiquitination of the estrogen receptor, marking it for degradation by the proteasome. I tell my patients it "chews up" the estrogen receptor and "spits it out.”

We also have a novel SERM called lasofoxifene [Fablyn], which is a tamoxifen-like drug. It offers some advantages in terms of adverse effects because it does not act as a full antiestrogen throughout the body—it acts as a proestrogen in some areas and an antiestrogen in others.

Finally, there are CERANs, SERCAs, and other new agents, all of which essentially work to block estrogen's interaction with cancer cells. They either lower estrogen levels so there is nothing to bind, get rid of estrogen receptors on the cell surface, or block estrogen receptors so that estrogen cannot bind to them.

How do you approach treatment after progression on first-line therapy in hormone receptor-positive breast cancer?

It is way more complicated than it used to be. There are a few actionable things. Does the patient have an ESR1 mutation? If so, they are eligible for elacestrant, our oral SERD. Do they have a PIK3CA or PTEN mutation? Then they are eligible for fulvestrant in combination with alpelisib [Piqray]. We also still have PARP inhibitors that are actionable for patients with BRCA alterations.

For those with what I call a "bland profile," where there are no actionable mutations, we are not very happy with what fulvestrant alone offers. So, we have the option of using fulvestrant with everolimus, an older combination, or we have more data from the MONARCH-E trial [NCT03155997] suggesting there may be a benefit to continuing CDK4/6 inhibitors in the second line. Specifically, in a switch strategy, if someone received palbociclib or ribociclib [Kisqali] in the first line, you might consider abemaciclib [Verzenio] in combination with fulvestrant in the second-line setting. What used to be pretty straightforward, where many patients got fulvestrant, has become much more complicated in recent years.

How important is it to continue targeting estrogen receptors after progression on endocrine therapy?

It is really important. There are many patients whose tumors continue to be sensitive to endocrine agents. One of the biggest unmet clinical needs right now is that we do not have a reliable way to predict which patients fall into this category. Some patients post-CDK4/6 [therapy] may not benefit from further endocrine therapies, even though their tumors are still ER positive. They may or may not have an ESR1 mutation, but we lack a strong assay to determine whose tumor remains endocrine sensitive and whose does not.

From my experience working with all these classes of agents through clinical trials at Sarah Cannon, I have seen patients stay on these novel agents for up to 2 years. It is hard to argue against trying additional endocrine therapies, with close follow-up, because some patients achieve meaningful disease control for a significant amount of time without having to move on to more toxic treatments like chemotherapy.

What are the treatment options for patients who progress on CDK4/6 inhibitors?

For patients we suspect are endocrine resistant—such as those who progressed on their CDK4/6 inhibitor within 6 months, when the average progression-free survival should have been closer to 24 months—this indicates that the cancer may no longer be responding to estrogen axis modulation. In these cases, we are likely moving on to antibody-drug conjugates [ADCs], which are new and have shown promise. We now have 2 ADCs approved for ER-positive breast cancer: fam-trastuzumab deruxtecan-nxki [Enhertu; T-DXd], a HER2-targeting ADC for those with low HER2 expression, and sacituzumab govitecan [Trodelvy], a TROP2-targeting ADC. It is definitely a rapidly evolving field.

What are the next steps for research in the field?

One of the takeaways is that genomic profiling patients' tumors is here. It used to be something we talked about being actionable in the future, and now, with ESR1, PI3K, BRCA, PTEN, this is actionable, and so we do need to think about after CDK4/6 [therapy] getting this mutation data, whether this is from either tissue or a blood-based assay, and thinking about which of the options our patient in front of us may qualify for.

REFERENCES:

1. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. News Release. FDA. January 27, 2023. Accessed October 23, 2024. https://bit.ly/3WHsEq8

2. Oliveira M, Pominchuk D, Nowecki Z, et al. Camizestrant, a next generation oral SERD vs fulvestrant in post-menopausal women with advanced ER-positive HER2-negative breast cancer: Results of the randomized, multi-dose Phase 2 SERENA-2 trial. 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, Texas; abstract GS3-02. Accessed December 8, 2022.

3. Arvinas and Pfizer’s vepdegestrant (ARV-471) receives FDA fast track designation for the treatment of patients with ER+/HER2- metastatic breast cancer. News release. Arvinas, Inc. February 5, 2024. Accessed October 23, 2024. http://tinyurl.com/4hp95z77