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 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.”

Zhenjie W, Siyao C, Zhiqiang Y. PROTAC: Novel degradable approach for different targets to treat breast cancer. Eur. J. Pharm. Sci.July 1, 2024.

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 immobilisation 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. 

Elacestrant

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.

Lasofoxifene antagonises 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.”

Nili Gal-Yam E, Levanon K. Lasofoxifene Monotherapy Induces Durable Complete Remission in a Patient with Estrogen Receptor-Positive, Metastatic Breast Cancer with an ESR1 Mutation. JCO Precis. Oncol. November 2, 2023.