Novel PROTACs Broaden the HR+ Breast Cancer Investigational Landscape

The development of proteolysis targeting chimeras (PROTACs) is gaining traction in concert with an increased understanding of acquired resistance mechanisms in patients with hormone receptor (HR)­–positive breast cancer, according to Seth Wander, MD, PhD.

The phase 1/2 VERITAC trial (NCT04072952) evaluated the efficacy and safety of the PROTAC vepdegestrant (ARV-471) in patients with estrogen receptor (ER)–positive, HER2-negative breast cancer who had received a median of 4 prior lines of therapy, including mandatory CDK4/6 inhibitors. In evaluable patients (n = 71), the clinical benefit rate (CBR) was 38%, and the median progression-free survival (PFS) was 3.7 months.¹

The ongoing phase 3 VERITAC-2 trial (NCT05654623) is investigating vepdegestrant vs fulvestrant (Faslodex) in patients with ER-positive, HER2-negative advanced breast cancer who have received 1 line of a CDK4/6 inhibitor and up to 1 additional line of endocrine therapy, with PFS as the primary end point.²

“The PROTAC data will fit into the mix of the enlarging landscape of next-generation hormonal agents,” Wander said.

In an interview with OncLive^®, Wander discussed evidence to support the investigation of PROTACs in patients with HR-positive breast cancer; preliminary efficacy and safety findings with vepdegestrant; and potential strategies for targeting acquired ESR1 resistance mutations.

Wander is a medical oncologist at Massachusetts General Hospital and an instructor in medicine at Harvard Medical School in Boston.

OncLive: What is the rationale for investigating PROTACs in patients with breast cancer, and how do they compare with the oral selective estrogen receptor degraders (SERDs) in this landscape?

Wander: This is an exciting area. HR-positive breast cancer is the most common type of breast cancer, and for many years, anti-estrogen therapy and hormonal therapies have been the backbone of treatment, both in the early and advanced or metastatic disease stages. We’ve learned over the past several years, from clinical experience and translational research efforts, about many of the different mechanisms that can drive resistance to these drugs and provoke either relapse or progression in this large patient population.

One of the big imperatives in the field is to develop novel, tolerable next-generation estrogen-targeting agents that can overcome many of these resistance mechanisms. PROTACs are an exciting type of agent moving forward in the clinic. These [agents] target the estrogen receptor for degradation by the ubiquitin proteasome pathway.

Other available agents, for example, aromatase inhibitors [AIs], lower the total amount of estrogen produced in the body. SERDs were the first class of drugs designed to promote the breakdown or degradation of the estrogen receptor. SERDs act through several different mechanisms. They destabilize the estrogen receptor complex. They prevent translocation of that complex into the nucleus, where estrogen promotes transcription of many different target genes. Based on that conformational instability and the lack of movement, the complex becomes unstable and can indirectly be degraded at a higher rate.

PROTACs may be better at, for example, directly targeting the estrogen receptor for degradation. We’ve also started to learn about how different resistance mechanisms and mutations might be better targeted by some newer agents, such as novel, next-generation SERDs or PROTACs.

What is the unique mechanism of action of the investigational PROTAC vepdegestrant?

Vepdegestrant is an interesting PROTAC moving forward in the clinic. It’s been a pleasure to work with that team. We’re helping drive this agent forward in several different clinical trials. This agent targets the estrogen receptor via ubiquitination for degradation within the cell. In preclinical and early-phase clinical trials, this agent was generally well tolerated and has signs of preliminary efficacy, even in heavily pretreated patient populations.

This drug allows the ubiquitin proteasome system to target the estrogen receptor, resulting in effective breakdown. That’s true both for mutant forms of the receptor, for example, in patients who develop ESR1 mutations, and for the wild-type form. For example, the VERITAC expansion cohort had a group of patients who were heavily pretreated, most of whom had received many different prior anti-estrogen therapies, all of whom had received CDK4/6 inhibitors, and many of whom had received prior cytotoxic chemotherapy. This agent had an important CBR of approximately 38%. In the subgroup of patients with the ESR1 mutation, which traditionally have been harder to treat in clinical practice, the CBR was higher, at 51.2%. This agent is moving forward in several related phase 3 trials, both alone and in combination with other agents.

What was the safety profile of single-agent vepdegestrant in VERITAC?

There are many different expected toxicities based on the mechanism of action. We have decades of experience with agents that either reduce hormone levels or block estrogen activity. Not surprisingly, we see several low-grade toxicities, including fatigue, hot flashes, and nausea. Occasionally, we see transaminase elevation. However, overall, this agent was generally well tolerated, with no high rates of bradycardia, cardiac abnormalities, or visual disturbances, which are some adverse effects we’ve seen with some of the other newer agents that have been developed over the years.

What investigational treatment strategies may overcome acquired ESR1 resistance mutations in patients with ER-positive breast cancer?

Our expanding arsenal of knowledge about ESR1 is a great example of the power of both precision oncology and translational research. In sequencing efforts exploring the genetic makeup of tumors, particularly in the primary or untreated setting, only rarely was ESR1, the gene that targets the estrogen receptor, mutated. It wasn’t until we started sequencing, for example, metastatic biopsies or biopsies from patients who had relapsed after therapy with hormonal agents that we started to see increasing rates of mutation in the gene that encodes the estrogen receptor.

These mutations typically occur in the ligand binding domain and allow the estrogen receptor to be constitutively active even in the absence of the estrogen ligand. Drugs such as AIs that work by dropping the level of estrogen or dropping the level of the ligand are not effective against a mutant form of the receptor that’s constantly active. That’s where we see these mutations develop. Under selective pressure, particularly with AIs, we see increased rates of ESR1 mutations, particularly in the metastatic setting, as high as 25%, 35%, or 45%, depending on how heavily pretreated the population is and who you’re testing.

This underscores the importance of considering next-generation sequencing in the resistance setting. If you have a sequencing result from a primary tumor or an untreated metastatic sample, it’s important to potentially look after the patient progresses on first-line therapy, because you miss that ESR1 mutation earlier on.

This is becoming increasingly important because now we have an FDA approval for elacestrant [(Orserdu) in patients with] ESR1 mutations based on findings from the [phase 3] EMERALD trial [NCT03778931]. In that trial, in the entire patient population, which included both ESR1-mutant and ESR1-wild-type patients, all of whom had progressed on prior CDK4/6 inhibitor–based therapy, elacestrant was beneficial. It was particularly beneficial in the group of patients with ESR1 mutations, and even more in the group of patients with longer durations of therapy on prior CDK4/6 inhibitors, suggesting that there’s likely a population of patients who retain increased sensitivity to targeting estrogen-based signaling. You can identify those patients based on a variety of factors, including the mutational data, [such as the] presence or absence of a mutation like ESR1, as well as the clinical behavior of the tumor in patients who get longer durations of benefit on hormone-based or targeted therapy in the first- or second-line setting.

We still have more questions than answers. We’ve learned much about ESR1 and how these mutations arise, where they occur in the protein, and which drugs provoke their development. We’ve learned how [drugs] can provoke resistance, and in some cases, sensitivity, to some of the traditional and novel agents.

Moving forward, we need to understand more about how these mutations interact with other mutations in the cell. We need to understand which of these novel anti-estrogen agents, whether the PROTACs or the novel, next-generation SERDs, can target these ESR1 mutations. Are there differences between the mutations? Not all ESR1 mutations are likely to be equal regarding their ability to provoke resistance to these agents or their ability to upregulate downstream effects in the ER pathway. These are still early days. We’re asking the right questions and starting to develop some of the tools, both analytical research tools and clinical treatment tools, to move forward to deal with this common challenge in the clinic.

What are the rationale and design for the VERITAC-2 trial, and what patient population is being enrolled in this trial?

This is 1 of the most active areas of research for clinicians who focus on breast cancer. Understanding what to do in the second-line setting after patients progress on standard hormonal therapy, typically with a CDK4/6 inhibitor in the first-line setting, is the largest unmet need in HR-positive metastatic breast cancer.

VERITAC-2 is an important study in patients who have received a prior CDK4/6 inhibitor, none of whom are allowed to have received, for example, fulvestrant, the currently available intramuscular SERD, or prior chemotherapy in the metastatic setting. This is designed to be a population of patients who received, for example, an AI and a CDK4/6 inhibitor and have progressed. The target number of patients is 560. Patients will be randomly assigned to receive either fulvestrant or the novel PROTAC vepdegestrant.

Fulvestrant monotherapy is still in many ways the widely appreciated standard of care [SOC] after progression on an AI and a CDK4/6 inhibitor. If the patient has a PIK3CA mutation, which occur in approximately 40% of patients, then the SOC would be fulvestrant with a PI3K inhibitor such as alpelisib [Piqray]. However, for patients who are PIK3CA wild-type, the current SOC would be fulvestrant monotherapy, although there is a sense, particularly in patients who have developed resistance to CDK4/6 inhibitors, that fulvestrant monotherapy will likely not be the best option moving forward.

There’s an important unmet clinical need to develop better hormonal agents such as PROTACs to prove, for example, in the ESR1-mutant population, and in patients with other mutations that might drive resistance to hormonal agents, that there may be better options moving forward. VERITAC-2 will give us a sense of how these PROTACs work in comparison with the current SOC, which is still fulvestrant.

How might vepdegestrant be used in combination with other agents, and what ongoing investigations are seeking to determine the role of this drug in combination regimens?

In the first-line setting, using a combination of a targeted agent like a CDK4/6 inhibitor with a hormonal agent like an AI has produced substantial PFS and overall survival benefits. We’re learning much about how these agents work as monotherapies, for example, in EMERALD and VERITAC-2.

We’re also starting to think about the best combinations in the second-line setting. For example, in patients with PIK3CA-mutant disease, we would consider a combination of a PI3K inhibitor with an anti-estrogen agent.

The big question moving forward is: Where will these drugs fit in the second- and third-line settings? Will there be substantial signals for monotherapy efficacy, or will we move into a place where we’re seeking the right partner? Studies are investigating both [approaches].

In EMERALD, there was some single-agent activity of elacestrant. [We should try to] identify the patients who might get the best monotherapy efficacy from elacestrant. We think those are the patients with ESR1 mutations with prolonged durations of treatment on prior hormonal and CDK4/6 inhibitor therapy. However, as a community, we’re interested to see how these drugs perform in combination with, for example, CDK4/6 inhibitors, PI3K inhibitors, and other targeted agents such as AKT inhibitors. What are the toxicity profiles of these combinations? Will we see increased efficacy after progression on first-line hormonal therapy and CDK4/6 inhibitor therapy?

Based on work by our group and other groups, both in the clinic and the laboratory, the landscape of genomic and molecular resistance to CDK4/6 inhibitors is diverse. Several different pathways can provoke resistance. It will be important to determine whether specific drugs might work across some of those mechanisms, for example, or whether we will need a more precision-driven, patient-focused approach where, based on the molecular profile of the tumor, [patients will have] different options, for example, PI3K inhibitors, AKT inhibitors, or next-generation CDK4/6 inhibitors in combination with a novel SERD or PROTAC. This will depend on whether there’s an ESR1 mutation or another mutation in the PI3K, AKT, or MAPK pathway.

This will become increasingly complex as we layer those different options together. To decipher that, we need to understand the single-agent activity of these drugs, and we need to understand the toxicity profiles and activity of the drugs in combinations.

What does the future look like for PROTACs in patients with HR-positive breast cancer?

We’re excited about the compound. We’re excited about the class of drugs. We have many interesting new options coming. One of the most surprising developments in the field over the past year or 2 has been the different signals we’re seeing from the next-generation oral SERDs. It’ll be interesting to compare the signals we’re seeing with drugs such as elacestrant, amcenestrant [SAR439859], and imlunestrant [LY3484356] with, for example, PROTACs.

We will need to decipher why some of those differences may be arising. Do they have to do with the drug itself? Do they have to do with the design of the study and, for example, the prior therapies those patients had, or their mutational profiles or rate of ESR1 mutations? We will try to dissect these aspects.

Cross-trial comparisons are perilous. However, we need to do those sometimes to try to make sense of some of the different signals we’re seeing across these phase 2 and phase 3 studies. That’s another important unanswered question.

References

1. Arvinas announces ARV-471 achieves a clinical benefit rate of 38% in evaluable patients and continues to show a favorable tolerability profile in its phase 2 expansion trial (VERITAC). Arvinas. News Release. November 22, 2022. Accessed August 9, 2023. https://ir.arvinas.com/news-releases/news-release-details/arvinas-announces-arv-471-achieves-clinical-benefit-rate-38
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 July 24, 2023. Accessed August 9, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05654623