Dr. Mersad Alimoradi 21 Feb 2023

Antiestrogen hormone (endocrine) therapy remains the first-line cancer treatment in patients with estrogen receptor (ER)-positive advanced breast cancer. 

The introduction of CDK4/6 inhibitors combined with endocrine therapy has transformed the management of hormone receptor-positive metastatic breast cancer.

However, although most (ER)-positive breast cancer patients initially benefit from first-line endocrine therapy, most become resistant to hormonal treatment because of ESR-1 mutations.

Recently, the FDA approved Orserdu (elacestrant), a new oral hormone therapy.

Continue reading to learn more about Orserdu, the latest endocrine therapy for estrogen receptor-positive metastatic breast cancer, and how it offers patients with ESR-1 mutations new hope.  

What Is Estrogen Receptor-Positive, HER2-Negative, ESR-1 Mutated Breast Cancer?

Breast cancer is caused when cells in the breast grow out of control, forming an abnormal lump or a mass of breast tissue.

Normal, non-cancerous breast cells and some breast cancer cells have estrogen hormone receptors. When estrogen attaches to these receptors, it stimulates the growth of breast cells. A breast cancer case with many estrogen receptors is classified as estrogen receptor (ER) positive. 

Doctors can treat ER-positive breast cancers with hormone therapy drugs that block estrogen receptors to stop the uncontrollable growth of breast tissue.

However, most metastatic, estrogen receptor-positive breast cancers become resistant to hormonal therapy after a while. Studies have shown that a mutation in the ESR-1 gene (responsible for making estrogen receptors) can cause breast cancer to become resistant to hormone therapy.

The human epidermal growth factor receptor 2 (HER2) is another receptor that sits on the surface of breast cells and helps control the growth of healthy breast tissue. Some breast cancers are HER2-positive. In such cases, the breast cells overproduce HER2, which causes the breast cells to multiply uncontrollably, subsequently leading to breast cancer.   

In estrogen receptor-positive, HER2-negative, ESR-1 mutated breast cancer, the cancerous breast cells overexpress the mutated version of the estrogen receptor but not HER2. These breast cancers can be more challenging to treat because doctors cannot use drugs targeting the HER2 protein or standard antiestrogen hormone therapy.    

What Is Orserdu?

Orserdu (elacestrant) is a once-daily oral (pill) hormonal therapy developed by the biopharmaceutical company Stemline Therapeutics.

Orserdu is a selective estrogen receptor downregulator or degrader (SERD) – it binds to the estrogen receptors on ER-positive breast cancer cells.

By doing so, Orserdu fills up the estrogen receptors and prevents estrogen from attaching to cancer cells and helping them grow.

In January 2023, the Food and Drug Administration (FDA) approved Orserdu (elacestrant) to treat metastatic, estrogen receptor-positive, HER2-negative breast cancer with an ESR1 mutation following at least one line of endocrine (hormone) therapy. 

Patients with advanced or metastatic ER-positive, HER2-negative, ESR-1 mutation breast cancer that has grown during treatment with hormonal therapy now have Orserdu as a new treatment option. 

Scientific Evidence Supporting Orserdu As A Treatment For Metastatic Breast Cancer

A randomized phase 3 trial investigated the efficacy of Orserdu (elacestrant) in pretreated ER-positive, HER2-negative advanced breast cancer. 

CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, are medicines that interrupt cancer cell growth by blocking cyclin-dependent kinases 4 and 6. When combined with hormone therapy, CDK4/6 inhibitors significantly increase progression-free survival (the duration before cancer grows and spreads).

All the patients in the study had previously undergone at least one hormonal therapy regimen, including CDK4/6 inhibitors, and none had received chemotherapy for metastatic breast cancer. About 50% of the participants in the study had an ESR-1 mutation.

Approximately  half of the patients (239 participants) randomly received Orserdu (elacestrant 400 mg) orally once daily. The other half (238 participants) received endocrine monotherapy of Faslodex or an aromatase inhibitor.  

The researchers assessed progression-free survival (how long the patient lives without cancer growing or worsening) and the hazard ratios (survival of patients given Orserdu compared to other treatments).

Results show that cancer patients with ESR-1 mutation who took Orserdu had a 45% lower risk of their cancer growing or dying from cancer than those who took the other treatments. 

Even breast cancer patients without the ESR-1 mutation had better chances of survival and living progression-free with Orserdu than with standard-of-care endocrine monotherapy.

These results show that Orserdu (elacestrant) can be an effective treatment for ER-positive, HER2-negative advanced breast cancer with ESR-1 mutation. 

What Are The Side Effects Of Orserdu?

Like any other cancer treatment, Orserdu can cause side effects or adverse events, some of which are severe.

The mentioned EMERALD study reported adverse events (AEs) in 92% of patients who received Orserdu therapy and 86% of those who received the other treatments.

The most common possible side effects of Orserdu were the following:

  • Nausea (35% of patients)
  • Fatigue (19% of patients)
  • Vomiting (19% of patients)
  • Loss of appetite (14.8%)
  • Joint pain (14.3%)

More severe possible side effects of Orserdu (elacestrant) included the following:

  • Severe nausea (2.5 % of patients)
  • Back pain (2.5 % of patients)
  • Elevated Alanine transaminase (ALT) liver enzyme (2.1% of patients)

However, the researchers reported that the Orserdu treatment only caused 63% of the mentioned symptoms.

How Does Orserdu Help Metastatic Breast Cancer Patients?

Orserdu (elacestrant) is the first oral SERD to produce better results than standard-of-care endocrine therapy in patients with advanced breast cancer.

It is also the first endocrine therapy approved for ER-positive metastatic breast cancer in over 20 years since the antiestrogen fulvestrant was approved in 2002.

Unlike other hormone therapies for cancer, Orserdu comes in pill form and is taken orally instead of intramuscular (or IM) injections or subcutaneous (SC or sub-Q) injections. That means less pain and discomfort when receiving treatment for breast cancer patients.

Breast cancer patients with ESR-1 mutation who took Orserdu had better chances of living without cancer growing or worsening. That is considered a significant breakthrough since those patients usually have limited treatment options due to ESR-1 mutations causing hormone therapy resistance. 

Therefore, if you have estrogen receptor-positive, HER2-negative, ESR-1 mutated breast cancer that no longer responds to standard hormone therapy, you can ask your doctor about Orserdu and whether it might be a helpful treatment in your situation. 

To search for the best Oncology healthcare providers in Germany, India, Malaysia, Singapore, Spain, Thailand, Turkey, the UAE, the UK and the USA, please use the Mya Care search engine.

To search for the best healthcare providers worldwide, please use the Mya Care search engine.

About the Author:
Dr. Mersad is a medical doctor, author, and editor based in Germany. He's managed to publish several research papers early in his career. He is passionate about spreading medical knowledge. Thus, he spends a big portion of his time writing educational articles for everyone to learn.