Breast tissue responds to fluctuations in estrogen and progesterone throughout a woman’s menstrual cycle. Unfortunately, when breast cancer cells have receptors for estrogen or progesterone — as they do in hormone positive breast cancer — the natural presence of these hormones can promote tumor growth.

To fight back, oncologists often use endocrine therapies to lower the level of hormones in the body or stop them from reaching the tumor. But many patients develop resistance to these drugs over time.

“There's a lot of work to be done because, especially in advanced disease, patients will continue to ultimately become refractory to their therapies and progress, and when you have metastatic disease — disease that's outside of the breast and has moved to other parts of the body — it's not curable,” said Julia Perkins Smith, the former Oncology Global Clinical Lead at Pfizer, who is now at Eli Lilly and Company.

Perkins Smith focuses on hormone positive breast cancers that express normal or low levels of the human epidermal growth factor receptor 2 (HER2) protein, which encourages cancer cells to grow quickly. At the recent San Antonio Breast Cancer Symposium in December 2024, her team presented over 30 abstracts about their new research in this space, including an update on the first proteolysis targeting chimera (PROTAC) degrader in clinical trials to treat breast cancer. The compound, vepdegestrant, is a PROTAC estrogen receptor degrader developed by the biotech company Arvinas, who Pfizer entered into a partnership with in 2021.

Perkins Smith said that she and her colleagues are ultimately trying to help patients live longer and better. “A big part of that has to do with thinking about what are the causes of the progression on current therapies, and so how do we attack the tumor differently?”

Why are new treatments needed for hormone positive breast cancers?

As patients progress through their early endocrine therapy, in particular when taking drugs to reduce estrogen, they can develop what's called an estrogen receptor 1 (ESR1) mutation (1). An ESR1 mutation signals that the tumor is still somewhat dependent on the endocrine pathway, and those tumors tend to be fairly refractory to the commonly prescribed endocrine therapies like aromatase inhibitors and, depending on the type of mutation, the estrogen receptor antagonist drug fulvestrant.

The largest subset of breast cancers is known as estrogen receptor- (ER) positive HER2-negative, and then within that group, 40 percent or so of patients develop an ESR1 mutation. That means that a large portion of patients could benefit from targeting the endocrine pathway in a new way.

How does the PROTAC degrader vepdegestrant work to target ER-positive HER2-negative breast cancer?

The PROTAC brings the ER in proximity with the E3 ligase, which is an enzyme that attaches ubiquitin to the receptor to mark it for proteasome degradation in the body. So, it’s using the body's disposal systems to break down the ER. For ER-positive tumors, that helps cut off one of the pathways that feeds the tumor and causes it to grow.

What are the most recent results with vepdegestrant that you reported at the San Antonio Breast Cancer Symposium in December?

We presented our Phase 1b trial investigating vepdegestrant in combination with abemaciclib, which is a kinase inhibitor approved to treat advanced breast cancer. Clinicians usually give endocrine therapies with another targeted therapy. This really speaks to the fact that the new drugs we’re developing are not, hopefully, just more effective by themselves, but also will be a backbone to other therapies.

We studied patients who already received an endocrine therapy and a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor, which blocks the CDK4 and CDK6 proteins involved in regulating the cell cycle. We found minimal impact on the exposure of either drug when they're dosed together, and their safety profile looks pretty similar to what we would expect of the individual drugs. We saw that the clinical benefit rate — which looks at the percentage of patients who show a complete or partial response to the drug or patients who attain stable disease beyond six months after taking the drug — was 62.5 percent.

What other novel therapies did your team present results for?

We presented new results on a next-generation highly selective CDK4 inhibitor called atirmociclib. It targets the cell cycle inhibition pathway of cancer growth. We looked at patients who had no prior treatment, and we paired atirmociclib with letrozole, which is a very commonly given aromatase inhibitor. This work showed a good safety profile and some promising anti-tumor activity as well.

We also presented updated results on a histone lysine acetyltransferase (KAT) inhibitor for KAT6. KAT6A and KAT6B are epigenetic regulatory enzymes, so the KAT6 inhibitor disrupts the cancer growth by targeting the cell’s gene expression machinery. Based on non-clinical work, it may have the potential to overcome resistance to cell cycle inhibitors as well as endocrine therapy, which is important for these patients. This drug continues to show a good safety profile, a respectable response rate and clinical benefit rate, and progression-free survival. We're anticipating starting a Phase 3 trial in patients who have already taken CDK4/6 inhibitors, which is a high unmet need area in 2025.

These are early studies, but we're encouraged by what we're seeing and excited about further exploration and clinical trials for all three of these therapies.

What do you hope to see in the future with these compounds?

I hope that we will see that our enthusiasm was well placed and that these drugs really can offer something to patients who are facing this diagnosis. That would be really exciting.

This interview has been condensed and edited for clarity.

Reference

1. Dustin, D., Gu, G., & Fuqua, S.A.W. ESR1 mutations in breast cancer. Cancer  125, 3714–3728 (2019).