Vepdegestrant: The First PROTAC ER Degrader

A drug called vepdegestrant is the first PROteolysis Targeting Chimera (PROTAC) to be tested in phase 3 clinical trials. Like a selective estrogen receptor degrader (SERD), vepdegestrant gets rid of the estrogen receptor from breast cancer cells. Results from the phase 3 VERITAC-2 trial showed that vepdegestrant delayed ESR1 mutant metastatic breast cancer progression by 2.9 months compared to the SERD fulvestrant.¹ Unlike fulvestrant which requires injections, vepdegestrant is a pill that can be taken by mouth.

Imlunestrant: A new oral SERD

Results from the phase 3 EMBER-3 trial showed that a new oral SERD called imlunestrant reduced the risk of cancer progression by 38% compared to standard hormone therapy in ESR1 mutant hormone receptor-positive metastatic breast cancer.²  Importantly, researchers also showed that participants in the trial receiving imlunestrant had an improved quality of life and physical function compared to those taking standard hormone therapy.³

RLY-2608: Targeting breast cancer mutations

About 40% of hormone receptor-positive breast cancers have mutations in the PIK3CA gene. The mutated protein that arises from PIK3CA mutations promotes growth of the cancer cells. RLY-2608 is a new drug that specifically blocks the mutant protein from driving cancer growth. By blocking only the mutant protein and not the normal protein, it’s possible that this drug may have fewer unwanted side effects. Early results showed that RLY-2608 combined with fulvestrant led to a median of 10.3 months before participants’ metastatic breast cancer progressed. A phase 3 trial testing RLY-2608 in combination with fulvestrant is set to begin in 2025.⁴

New and improved technologies may be able to increase the speed and accuracy of detecting, diagnosing or monitoring breast cancer for progression and response to treatment.  

Circulating tumor DNA (ctDNA) to predict risk of recurrence

ctDNA is DNA from cancer cells that’s found in the bloodstream. ctDNA can be measured and analyzed through a blood sample, known as a liquid biopsy. Researchers are working to understand if ctDNA can be used to guide breast cancer treatment. Results from the PREDICT-DNA (TBCRC 040) trial showed that participants with detectable ctDNA after completing neoadjuvant chemotherapy were more likely to experience breast cancer recurrence than those without detectable ctDNA.⁵ While more studies are needed, this information may be used to identify patients that may need more aggressive treatment to reduce the risk of recurrence.

Artificial Intelligence (AI)-based risk assessment tool

Predicting one’s risk for developing breast cancer currently relies on several different factors including a person’s gender, age, ethnicity, health history and family health history. A new AI-based risk-assessment technology was recently granted authorization from the FDA. While the FDA has previously approved AI tools to assist in breast cancer detection and risk management, this is the first to receive authorization specifically for predicting five-year risk directly from a screening mammogram.⁶

With knowledge gained from clinical trials, researchers are seeking new ways to improve patient outcomes while using existing drugs. Some new breast cancer treatment breakthroughs are the result of combining certain drugs, finding which patients can skip certain elements of treatment or changing the order of their treatments to maximize effectiveness or to minimize side effects.

New drug to combat hot flashes from breast cancer treatment

Hormone therapy for breast cancer can result in menopausal-like symptoms such as hot flashes. There are currently no options for combatting side effects that have been specifically tested in breast cancer. Results from a phase 3 clinical trial showed that a new drug called elinzanetant was able to significantly decrease the number of hot flashes compared to a placebo.⁷ Importantly, this trial was conducted specifically in women taking hormone therapy for breast cancer. This is a good first step in improving quality of life for women taking hormone therapy – a treatment that lasts 5-10 years.

Antibody drug conjugates (ADCs) as the first line against metastatic breast cancer

Results from the phase 3 ASCENT-04 study showed that the ADC sacituzumab govitecan combined with pembrolizumab, an immunotherapy, significantly delayed cancer progression for participants with metastatic triple negative breast cancer by 3.4 months compared to chemotherapy plus pembrolizumab.⁸ Given this improvement and limited options for metastatic triple negative breast cancer, this will likely become a new standard of care.

Results from the phase 3 DESTINY-Breast09 trial showed that the ADC trastuzumab deruxtecan combined with pertuzumab significantly delayed cancer progression for participants with metastatic HER2-positive breast cancer by 13.8 months compared to current standard of care. Given the side effects of trastuzumab deruxtecan, researchers need more information about who is most likely to benefit from this treatment up-front before incorporating it into standard of care.