Oral SERDs, PROTACs Could Add to Expanding ER+ Advanced Breast Cancer Arsenal

Although treatment with CDK4/6 inhibitors have bolstered the treatment paradigm for estrogen receptor (ER)–positive metastatic breast cancer, novel classes of agents could add therapy options for patients who develop resistance and experience disease progression, according to Komal Jhaveri, MD, FACP.

Oral selective estrogen receptor degraders (SERDs) have already entered the space after elacestrant (Orserdu) was approved by the FDA in January 2023 for the treatment of postmenopausal women or adult men with ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy.¹

Another novel class of agents known as proteolysis targeting chimeras (PROTACs) could be the next to alter the treatment paradigm. Vepdegestrant (ARV-471) is currently under investigation in the phase 3 VERITAC-2 study (NCT05654623), which is evaluating the oral PROTAC as monotherapy vs fulvestrant (Faslodex) alone in patients with previously treatment ER-positive, HER2-negative advanced breast cancer.²

“We have to think about how we use agents that may be available, and more importantly, focus on mechanisms of resistance [of different classes of] agents and how to optimally sequence them with various combinations to further improve outcomes for our patients [with advanced ER-positive breast cancer],” Jhaveri explained in an interview with OncLive®. “A lot more still needs to be done, but these are exciting times. We are looking forward to more data to understand this better.”

In the interview, Jhaveri discussed the gamut of emerging treatment options and strategies in ER-positive metastatic breast cancer. She highlighted current limitations of frontline treatment; the development of oral SERDs and PROTACs, noting key differences between these 2 classes; and treatment approaches for patients without targetable mutations following disease progression on a CDK4/6 inhibitor.

Jhaveri serves as the section head of Endocrine Therapy Research Program, clinical director of the Early Drug Development Service, and the Patricia and James Cayne Chair for Junior Faculty at Memorial Sloan Kettering Cancer Center in New York, New York.

OncLive: What current limitations exist within the frontline treatment setting for patients with ER-positive metastatic breast cancer?

Jhaveri: First-line therapy has been an unprecedented game changer for our patients with the addition of CDK4/6 inhibitors to endocrine therapy, and [data for these agents] have now read out to [show an] overall survival [OS] benefit. In fact, with ribociclib [Kisqali], we saw a median OS more than 5 years [in the phase 3 MONALEESA-2 trial (NCT01958021) when combined with endocrine therapy], regardless of menopausal status.

[The addition of CDK4/6 inhibitors to endocrine therapy] has been revolutionizing in terms of how we treat our patients in the first line. Despite this [progress], there is a proportion of patients who either have primary endocrine resistance or develop acquired resistance to [CDK4/6 inhibitors], which is why the tumors continue to grow. 

We want to figure out how to treat these patients effectively once the tumors have progressed on first-line therapy, and that's been our big focus in terms of figuring out the optimal way of sequencing therapies following progression on CDK4/6 inhibitors.

What has been seen in the investigational landscape for patients who experience disease progression on CDK4/6 inhibitors? How do endocrine therapies fold into this equation?

A lot of research is either ongoing or has been conducted. The one thing that has become successful in the clinic is trying to understand the genomic landscape for patients. [This means] not only understanding if patients have any germline BRCA mutations, where we could utilize PARP inhibitors, but also understanding the [greater] tumor genomic landscape. How could that be contributing to tumor growth?

In that context, the oral SERD elacestrant [Orserdu] was approved [by the FDA] for those tumors that harbor ESR1 mutations. For patients with tumors that harbor either a PIK3CA, AKT1, or PTEN mutation, we recently had an approval for the AKT inhibitor capivasertib [Truqap] in combination with fulvestrant. We've also had approval of the PI3K inhibitor alpelisib [Piqray] in combination with fulvestrant for those patients with tumors that harbor PIK3CA mutations.

This is [what we] think about in clinic when a patient's tumor progresses. How do we assign the best next treatment option? We consider a few of these factors, including biomarker testing, to figure out the right way of approaching [treatment for] a patient in clinic.

How do you approach the treatment of patients with an absence of any of the actionable mutations with approved targeted therapies?

For patients who do not have an actionable mutation, we do have FDA approval for everolimus [Afinitor].That approval predates the data for CDK4/6 inhibitors. We have real-world data sets and some smaller data sets for CDK4/6 inhibitors [after progression on a prior CDK4/6 inhibitor]. We have data for everolimus in combination with exemestane—which led to an FDA approval—from the phase 3 BOLERO-2 trial [NCT00863655]. We also have some data with other endocrine agents, including fulvestrant and tamoxifen.

Clinical trials are relevant in this context because there are a lot of novel endocrine agents that are now being studied in combination with various targeted agents, including agents targeting the PI3K, AKT, and mTOR pathways, as well as CDK4/6 inhibitors. Later [in 2024], we also hope to see data from the phase 3 EMBER-3 trial [NCT04975308], which evaluated the oral SERD imlunestrant [LY3484356] compared with standard-of-care endocrine therapy; we will also evaluate data for imlunestrant in combination with abemaciclib [Verzenio] in the same trial. Therefore, we [will] have another dataset for a CDK4/6 inhibitor [after progression on a] CDK4/6 inhibitor, but these will be the first data [for a CDK4/6 inhibitor after progression] in combination with a novel endocrine agent—in this case, an oral SERD.

Talking about the role of CDK4/6 inhibitors beyond CDK4/6 inhibitors as a potential treatment strategy, we have data now from the phase 3 postMONARCH trial [NCT05169567] that was presented by Kevin Kalinsky, MD, MS, of Winship Cancer Institute of Emory University in Atlanta, Georgia, at the 2024 ASCO Annual Meeting. We saw modest improvement in median progression-free survival favoring the combination compared with fulvestrant alone. That difference in benefit seemed to be rather modest; however, the hazard ratio seemed like it was effective and statistically significant.

What was interesting in the subgroup analysis, which was also shown by Kalinsky, was that the combination was effective regardless of ESR1 or PIK3CA mutation status. For some patients, potentially, that strategy may also be considered, and it could be an attractive strategy for patients without those mutations. When we're thinking about patients without actionable mutations, we're thinking about the reintroduction of a CDK4/6 inhibitor with endocrine therapy and switching the endocrine backbone. In this case, it was fulvestrant.

In terms of elacestrant, where has that agent fallen short, and how could some of these novel combinations help fill that gap?

We have good monotherapy data that led to the approval [in patients with] tumors that harbor ESR1 mutations. There were some interesting analyses that were presented and published earlier [in 2024] in Clinical Cancer Research by Aditya Bardia, MD, MPH, FASCO, of the University of California, Los Angeles, and colleagues, where they focused on evaluating patients with tumors that harbored ESR1 mutations who had a durable benefit on a CDK4/6 inhibitor prior to receiving elacestrant. We learned that, potentially, in patients who had a durable benefit on a CDK4/6 inhibitor and harbored an ESR1 mutation, it may be appropriate for a single-agent oral SERD—in this case, elacestrant.

The ongoing phase 1b ELEVATE trial [NCT05563220] is evaluating various combinations of elacestrant with other targeted agents, including other CDK4/6 inhibitors and agents targeting the PI3K, AKT, and MTOR pathways. We also have [the phase 1b/2 ELECTRA trial (NCT05386108)] evaluating the role of elacestrant [in combination with abemaciclib] in patients with brain metastases, which is not as common early in the disease course for patients with ER-positive breast cancer, unlike patients with triple-negative breast cancer or HER2-positive breast cancer.

Those attempts of trying to understand elacestrant’s role in these patient populations are important and relevant. We are hoping to see additional data sets coming out for combinations, and then hopefully some larger studies will further establish the role of these elacestrant-based combinations.

Other oral SERDs are also in late-phase development. We have the phase 3 evERA trial [NCT05306340], which is evaluating giredestrant [GDC-9545] in combination with everolimus compared with endocrine therapy plus everolimus. That study is currently ongoing.

The phase 3 pionERA trial [NCT06065748] is evaluating giredestrant plus fulvestrant and a CDK4/6 inhibitor compared with a standard-of-care fulvestrant plus a CDK4/6 inhibitor.

[Oral SERDs such as elacestrant] are effective compared with standard-of-care endocrine therapy, especially in [patients with] ESR1-mutant tumors as monotherapy. Perhaps for a larger group of patients, combinations [with oral SERDs] are relevant, and these combinations might establish the role of novel endocrine agents as the backbone-preferred partner once we have some readouts from larger studies. [We are] looking forward to that and hoping that we can further impact the outcomes for our patients with these combinations.

How are PROTACs mechanistically different from SERDs?

[In the ER-positive breast cancer space], we have novel selective estrogen receptor modulators [SERMs], oral SERDs, PROTACs, and complete estrogen receptor antagonists [CERANs]. What we are trying to achieve with all these agents is one common, ultimate goal: identifying novel endocrine therapies that can overcome the toxicities that patients face with tamoxifen, aromatase inhibitors, and fulvestrant. For instance, oral SERDs can overcome the issue of ESR1 mutations that fulvestrant might not potentially be able to overcome. The efficacy with fulvestrant following CDK4/6 inhibitors has not been super promising. Oral SERDs [could represent an improvement] over endocrine therapy, and elacestrant has shown that.

Similarly, PROTACs are [being investigated in a similar fashion]. We're trying to see if these agents have an optimal therapeutic window, if they have optimal therapeutic efficacy, and how they differ in their toxicity profiles. The goal is to have down regulation of the ER and overcome any pharmacologic limitations and resistance mechanisms, such as ESR1 mutations. However, we must also establish the best therapeutic window, therapeutic efficacy, and safety profile.

PROTACs are slightly mechanistically different [from oral SERDs] in that they have a different way of achieving ER degradation and down regulation. Larger studies [with PROTACs] are already ongoing. This includes the first PROTAC vepdegestrant [ARV-471], and we're looking forward to trials such as the phase 3 VERITAC-2 study [NCT05654623], which is comparing vepdegestrant monotherapy vs fulvestrant monotherapy.

Additional phase 1 trials [are investigating vepdegestrant] in combination with other agents [with the goal of understanding] if, in clinic, that difference in mechanistically down regulating the ER will translate into a benefit and show that PROTACs may be a better way to approach [treatment]. However, we are never going to have head-to-head trials. We're not going to have a head-to-head trial comparing a PROTAC with an oral SERD. Will we be able to definitively address whether a PROTAC is better than any other agent? Maybe not; however, depending on the efficacy signal and safety profile, we may be able to learn something about this. 

References

1. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. January 27, 2023. Accessed September 11, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-elacestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast-cancer
2. A study to learn about a new medicine called ARV-471 (PF-07850327) in people who have advanced metastatic breast cancer (VERITAC-2). ClinicalTrials.gov. Updated August 2, 2024. Accessed September 11, 2024. https://clinicaltrials.gov/study/NCT05654623