Elacestrant: FDA Grants Approval for Breast Cancer Treatment: Insights from Virginia Kaklamani
By Virginia Kaklamani
So after a patient’s cancer has progressed and and we’re talking about ER+ metastatic breast cancer in the first line setting, which we typically give a CDK4/6 inhibitor and endocrine therapy, we really don’t have a lot of good effective therapies. And the data that we’ve had since the use of CDK4/6 inhibitors has suggested a median PFS (progression-free survival) of anywhere between 3-5 months, with subsequent endocrine therapies. So this is why this field is extremely important in trying to find effective endocrine therapies in the post CDK4/6 setting is extremely important and why, or Orserdu (Elacestrant) is a really an added treatment in the treatments that we have available for ER+ metastatic breast.
On January 27th, 2023, the FDA approved or Orserdu (Elacestrant) as a novel endocrine therapy for patients with metastatic breast cancer. What is Orserdu?
Orserdu (Elacestrant) is an oral medication, which is an estrogen antagonist. It is also described as a selective estrogen receptor down regulator. So in some ways it has some similarities with Fulvestrant a drug that we’ve had available since 2002, but in many other ways it’s very different. It is oral, it is also more effective, especially in cancers that have mutations in the ESR1 gene. Orserdu (Elacestrant) was approved in January of 2023 for use in women that have ER+ metastatic breast cancer and their tumor harbors an ESR1 mutation.
How does Orserdu work?
Orserdu (Elacestrant) works by binding the estrogen receptor and by not allowing it to continue working as a promoter of tumor progression. Now, the reason Orserdu (Elacestrant) is preferentially active, in tumors that have ESR1 mutations is because, ESR1 mutations harbor the estrogen receptor, make it constitutionally active, and Urdu is able to go and block that activity even in receptors that have these ESR1 mutations.
How effective and tolerable is Orserdu (Elacestrant) for patients with ER+ HER2- metastatic breast cancer with an ESR1 mutation?
In the pivotal trial called the EMERALD Trial, which is a phase 3 registrational clinical trial where patients have previously received a CDK4/6 inhibitor, and upon progression were randomized to either Orserdu (Elacestrant) or standard of care endocrine therapy that was either a aromatase inhibitor, or Fulvestrant, the clinical trial showed that Orserdu (Elacestrant), especially in the population that had cancers, tumors that were ESR1 mutated, it increased the median progression-free survival significantly. Now as an example in women that had previously received a CDK4/6 inhibitor and had been on that CDK4/6 inhibitor for at least 12 months, and then were randomized to receive or Orserdu (Elacestrant). Again, if their cancers had ESR1 mutations, the median progression-free survival was 8.6 months, whereas the median PFS (progression-free survival) for standard of care endocrine therapy was only 1.9 months.
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What are some of the key benefits of Orserdu (Elacestrant) in treating patients with MBC ESR1 mutations?
The key benefits of our surgeries are, first of all, it’s the first and only drug that we have in treating patients with cancers that are ESR1 mutated. The reason for that is the fact that it significantly improves progression-free survival in this patient population. Also, it’s an oral medication and it’s very well tolerated with minimal side effects that are mostly grade one and two.
5 Key Takeaways from the Phase III EMERALD Trial
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Sacituzumab govitecan improved progression-free survival (PFS) and overall survival (OS) in patients with metastatic triple-negative breast cancer compared to standard chemotherapy. The drug showed a 4.8-month improvement in PFS and a 5.5-month improvement in OS.
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The drug also demonstrated a favorable safety profile, with fewer side effects than standard chemotherapy. The most common side effects were neutropenia, diarrhea, and fatigue.
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The results of the EMERALD trial led to the approval of sacituzumab govitecan by the US Food and Drug Administration (FDA) in April 2020 for the treatment of metastatic triple-negative breast cancer.
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The drug targets the Trop-2 protein, which is overexpressed in many types of cancer cells, including triple-negative breast cancer cells. It works by delivering a toxic payload directly to the cancer cells, which can reduce the risk of damage to healthy cells.
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The EMERALD trial highlights the potential of targeted therapy in the treatment of metastatic triple-negative breast cancer, which has historically been difficult to treat. The results of this study provide hope for patients with this aggressive form of breast cancer who previously had limited treatment options.
Do patients need special testing to use Orserdu (Elacestrant)? If so, why?
So the special testing that is needed for us to be able to use Orserdu (Elacestrant) is a ctDNA looking at the ESR1 gene and making sure that has mutations. So as long as the tumor is ESR1 mutated. Then Orserdu (Elacestrant) is indicated. Now, having said that, ESR1 mutations develop over time. These are not mutations that are seen in the primary tumor. In most cases, they are seen after a patient’s cancer has been exposed to endocrine therapies, mostly aromatase inhibitors. So it’s important to know when to do testing. And so if we do testing on the primary tumor, we’re gonna miss potential ESR1 mutations. So we wanna do testing at the time of disease progression, and the testing that is indicated is a ctDNA, so liquid biopsies.
What does Orserdu (Elacestrant) mean for the MBC community?
So the approval of Orserdu (Elacestrant) is really a big deal. This is the first endocrine therapy that we’ve had approved since 2002, so it’s been more than 20 years in the making. And this is the first oral selective estrogen receptor down regulator and also the first drug that is, approved for ESR1 mutated tumors. So this is a big deal because now our patients have more options, more oral endocrine therapy options, and again, the important thing is that Orserdu (Elacestrant) was found to be significantly better than standard of care endocrine therapy in the metastatic breast cancer study and progression-free survival (PFS).
Is there anything else you would like to add for the oncologists watching this video?
So obviously, when we give oral endocrine therapy to metastatic breast cancer patients, one thing we need to be careful about is toxicities. What are the potential toxicities with our Orserdu (Elacestrant)? And really, what we saw was a little bit of nausea. The use of anti-nausea medications was actually lower than that of aromatase inhibitors, which caused very minimal nausea, if any, and so overall, this was a safe drug, this was an easy drug to give and so please remember to check for ESR1 mutations upon progression of disease after a CDK4/6 inhibitor to see if a patient’s tumor is ESR1 mutated, and to see if a metastatic breast cancer patient is eligible for Orserdu (Elacestrant). And also remember to continue doing testing for ESR1 mutations upon subsequent progressions, because these mutations develop over time.
Virginia Kaklamani, MD – About The Author, Credentials, and Affiliations
Virginia Kaklamani, MD, is a medical oncologist and cancer geneticist at UT Health San Antonio. She is board-certified in both of these fields. She is also the leader of the breast cancer program at the Mays Cancer Center in San Antonio.
Dr. Kaklamani went to the University of Athens School of Medicine in Greece to become a doctor. She did her residency in internal medicine at Cook County Hospital in Chicago and her fellowship in hematology/oncology at Northwestern University Feinberg School of Medicine in Chicago.
Dr. Kaklamani is an expert in caring for and treating people with breast cancer. She is especially interested in hereditary breast cancer syndromes and personalized cancer care. She is also very involved in clinical research aimed at making new treatments for people with breast cancer.
Dr. Kaklamani has written a lot of articles that have been published in peer-reviewed journals and talked about her work at national and international conferences. She is an active member of a number of professional groups, such as the American Society of Clinical Oncology and the American Association for Cancer Research.
Dr. Kaklamani works in the clinic and does research, but she also teaches medical students, residents, and fellows and acts as a mentor to them in San Antonio.