“The combination allows us to target the estrogen receptor with a next-generation oral SERD while maintaining CDK4/6 inhibition, potentially extending the benefit of endocrine-based therapy and delaying the need for chemotherapy,” Dr. Anastasia Martynova, breast cancer specialist and medical oncologist with USC Norris Comprehensive Cancer Center, tells SurvivorNet.

Inluriyo and Verzenio have been approved for patients with breast cancer that is classified as estrogen receptor-positive (ER+) and HER2-negative (HER2-), with something called an ESR1 mutation. This means the tumor is fueled by estrogen and doesn’t over-express the HER2 protein. An ESR1 mutation refers to a change in the estrogen receptor gene that often develops after prior hormone therapy. It can make the cancer resistant to older drugs like aromatase inhibitors.

“This FDA approval is truly a major and exciting milestone for advancing metastatic breast cancer care,” Dr. Nusayba A. Bagegni, a medical oncologist with Siteman Cancer Center at WashU Medicine, tells SurvivorNet.

What Do the Data Show?

During the EMBER-3 clinical trial, patients using the drug combination saw notably longer progression-free survival, around 9.4 months, compared to imlunestrant alone, making it a strong option for a second-line treatment, which is given after someone’s first hormone-based regimen. Usually, this happens after the first treatment — an aromatase inhibitor plus a CDK4/6 inhibitor like palbociclib, ribociclib, or abemaciclib — has stopped working.

The newly approved drug combo gives oncologists a way to keep using CDK4/6 inhibition, this time paired with a newer, more potent oral SERD (selective estrogen receptor degrader) designed specifically to overcome ESR1-driven resistance. It lets patients avoid switching to chemotherapy for longer.

Dr. Martynova says this approval reinforces the importance of assessing tumor biology with ctDNA testing.

“Identifying ESR1 mutations at progression can directly inform treatment selection and allow us to further personalize endocrine-based therapy,” Dr. Martynova adds.

Inluriyo (imlunestrant) is also approved as a monotherapy for adults with ER+, HER2-, ESR1-mutated advanced or metastatic breast cancer that has progressed after hormone therapy.

Dr. Bagegni stresses that the newly approved combination approach offers a distinct quality of life benefit.

“The result is better cancer control, which delays the need for chemotherapy and maintains quality of life. As a physician who personally cared for patients enrolled in the EMBER-3 trial at WashU Medicine and Siteman Cancer Center, I saw firsthand how valuable this combination therapy is for providing optimal and personalized care,” Dr. Bageni says.

Inluriyo + Verzenio: Potential Side Effects

Prescribing information for the drugs lists several side effects to be aware of. Both Inluriyo (imlunestrant) and Verzenio (abemaciclib) include warnings about embryo-fetal toxicity, meaning the drugs can harm a developing embryo or fetus.

Abemaciclib can also cause:

• Diarrhea
• Neutropenia (low white blood cells)
• Interstitial lung disease/pneumonitis
• Hepatotoxicity (liver injury)
• Venous thromboembolism (blood clots)

Understanding ESR1 Mutations

Some ER+ breast cancers can become resistant to common hormone therapies, such as aromatase inhibitors (anastrozole or letrozole). One key reason for this resistance is the emergence of ESR1 mutations, which change the estrogen receptor’s structure so it no longer responds to standard treatments. This can allow the cancer to keep growing despite therapy.

“ESR1 mutations lead to changes in the estrogen receptor and are a common cause of acquired resistance to endocrine therapy,” Dr. Eleonora Teplinsky, a breast and gynecologic medical oncologist at Valley Health System, tells SurvivorNet.

Detecting these mutations early is critical because it lets doctors switch treatments quicker, ideally before the tumor shows outward signs of progression.

Questions To Ask Your Doctor

• How will I be monitored for cancer progression on hormone therapy?
• Have I been/do I need to be tested for an ESR1 mutation?
• Am I a good candidate for Inluriyo plus Verzenio?
• How does this combination compare to other options for my subtype of cancer?

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