Novel therapies for treating HR+/HER2– metastatic breast cancer: PROTAC and beyond

By Lisa Marie Basile | Fact-checked by MDLinx staff

Published March 8, 2025

Key Takeaways

Conference Buzz

“There is a high response rate with this antibody drug conjugate [datopotamab deruxtecan]. It’s very impactful data with durable responses, which is very encouraging.” — Heather McArthur, MD, MPH, Professor of Internal Medicine and Clinical Director of the Breast Cancer Program at UT Southwestern Medical Center
“ARV-471 treatment yielded substantially greater ER degradation and tumor growth inhibition than fulvestrant in breast cancer xenograft models." — William J. Gradishar, MD, FACP, Director of the Maggie Daley Center for Women’s Cancer Care at Robert H. Lurie Comprehensive Cancer Center

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This article is part of our Miami Breast Cancer Conference 2025 coverage. Explore more.

On day 2 of the Miami Breast Cancer Conference, attendees enjoyed an evening session—featuring dinner and wine—discussing innovations in HR+/HER2– metastatic breast cancer (MBC).

For HR+ and HER2– breast cancer to grow, it needs estrogen, but “resistance to endocrine therapy is very common in HR+/HER2– MBC,” Kevin Kalinsky, MD, MS, told the room of physicians and other healthcare professionals.

There are a few strategies to combat resistance to endocrine therapy: blocking estrogen synthesis, modulation or degradation of the estrogen receptor (ER), and targeted therapies that block the downstream signaling pathways, Dr. Kalinsky explained.

“There are various strategies one would think about to overcome estrogen resistance–whether we’re degrading the receptor or blocking estrogen synthesis,” he said. These methods include selective estrogen receptor modulators (SERMs), selective estrogen receptor degraders (SERDs), complete estrogen receptor antagonists (CERANs), selective estrogen receptor covalent antagonists (SERCAs), and Proteolysis Targeting Chimeras (PROTACs).

PROTAC

These are a new class of therapeutic agents, said Dr. Kalinsky, noting that PROTAC therapy shows great promise in MBC treatment. The drugs are protein degraders that act by attaching to ERs and flagging them for disposal.

According to authors writing in European Journal of Pharmaceutical Sciences, PROTAC therapy has “exciting potential to reshape the pharmaceutical industry landscape by leveraging the ubiquitin-proteasome system for targeted protein degradation.”^[]

Speaker William J. Gradishar, MD, FACP, discussed vepdegestrant (ARV-471), an oral PROTAC ER degrader. The drug targets wild-type and ESR1 mutations directly. Dr. Gradishar noted promising results of trials like VERITAC, which demonstrated doses are “well-tolerated whether at 200 or 500 mg.”

In contrast, SERDs “indirectly recruit the ubiquitin-proteasome system, secondary to conformational changes and/or immobilization of ER2.”

For example, the SERD fulvestrant only degrades 40%–50% of the ER protein at optimal dose. “ARV-471 treatment yielded substantially greater ER degradation and tumor growth inhibition than fulvestrant in breast cancer xenograft models,” Dr. Gradishar says. He explains that researchers are currently looking at combining vepdegestrant with other therapies—and that monotherapy isn’t always the preferred option.

Antibody-Drug Conjugates (ADCs)

Although multiple ADCs for HR+/HER2- have been available since 2022 (Enhertu, a HER2 directed ADC, was approved in August 2022, and Trodelvy, targeting Trop-2, was approved in February 2023), innovation in the space continued. A third option, Datopotamab Deruxtecan (Datroway), was recently approved in January of 2025 for the treatment of adult patients with unresectable or metastatic HR-positive, HER2-negative (IHC 0, IHC 1+ or IHC 2+/ISH-) breast cancer who have received prior endocrine-based therapy and chemotherapy for unresectable or metastatic disease.

In a different session, Heather McArthur, MD, MPH, Professor of Internal Medicine and Clinical Director of the Breast Cancer Program at UT Southwestern Medical Center, discussed TROP 2—a protein that ADCs like Datroway target, and how it is significantly overexpressed in triple-negative BC.

TROP-2/EGP-1 is a pan-epithelial cancer antigen. It is overexpressed in all breast cancer subtypes, with less expression on normal tissues—and it’s an excellent target for ADCs. It is a marker of poor prognosis (ie, larger tumor size, higher risk of recurrence), and high TROP-2 levels are associated with aggressive tumor resistance to chemotherapy.

Dr. McArthur says all ADCs have different antibodies, linkers, and payloads. She discussed Datroway, pointing to the TROPION trial.

"There is a high response rate with this antibody drug conjugate [datopotamab deruxtecan]. It’s very impactful data with durable responses, which is very encouraging."

— Heather McArthur, MD, MPH

"The earlier we apply effective drugs, the earlier the benefits," she says.

Elacestrant

Oral SERDS, like elacestrant (which was approved in 2023 and is the first oral ER antagonist to receive FDA approval for patients with ESR1 mutations^[]) are also making an impact, says Komal Jhaveri, MD, FACP, breast oncologist and Early Drug Development Specialist at Memorial Sloan Kettering. ESR1 mutations are linked to endocrine therapy resistance.

Dr. Jhaveri showed findings from the EMERALD phase III trial:“Elacestrant significantly prolonged progression-free survival (PFS) with manageable safety versus standard-of-care (SOC) endocrine therapy (ET) in patients with estrogen receptor-positive (ER+), HER2- metastatic breast cancer and tumors harboring estrogen receptor 1 (ESR1) mutation following ET plus a cyclin-dependent kinase 4/6 inhibitor (ET+CDK4/6i). In patients with ESR1-mutated tumors, we evaluated the efficacy and safety of elacestrant versus SOC based on prior ET+CDK4/6i duration and in clinical subgroups with prior ET+CDK4/6i ≥12 months.”

“Elacestrant is a well-tolerated drug,” Dr. Jhaveri says, noting limited side effects. “But you have to monitor the lipid profile. You can also dose reduce. In practice, I haven’t had to dose reduce for toxicity reasons, but if you have someone with intolerable fatigue or cholesterol… certainly that is something we can do for patients,” Dr. Jhaveri said.

Lasofoxifene

Dr. Gradishar also touched on the SERM lasofoxifene—originally studied in osteoporosis and vulvar-vaginal atrophy. Oddly, the drug largely went ignored for years.

"It sat on the shelf for two decades, but [we’ve] now seen a renewed interest in this drug."

— William J. Gradishar, MD, FACP

Lasofoxifene antagonizes the ER in malignant and premalignant breast cancer cells. Researchers found that lasofoxifene may advance an “unmet need for patients with metastatic ER+/HER2− breast cancer and an ESR1 mutation to offer a potential option for durable objective responses.”^[]