Video
Differences Between SERDs and Other Therapies
Dr Vidula and Dr Lu describe how selective estrogen receptor degraders (SERDs) differ in their mechanism of action from other therapies for ER+/HER2– metastatic breast cancer and how newer SERDs differ from first-generation SERDs like fulvestrant.
Ryan Haumschild, PharmD, MS, MBA: Hello, and welcome to this AJMC Peer Exchange program titled “Oral SERD Therapy in ER+/HER2– Metastatic Breast Cancer.” I am Dr Ryan Haumschild, director of Pharmacy Services at Emory Healthcare in the Winship Cancer Institute in Atlanta, Georgia. Joining me today in this discussion are my colleagues, Dr Lucy Langer, national medical director, of oncology and genomics at United Healthcare [in Portland, Oregon]; Dr Neelima Vidula, assistant professor of medicine at Harvard Medical School, attending physician and medical oncologist at Massachusetts General Hospital [in Boston, Massachusetts]; and Dr Janice Lu, clinical professor of medicine, division of Oncology at the USC [University of Southern California] Norris Comprehensive Cancer Center [in Los Angeles, California]. Today, our panel of experts will explore a novel class of medications for patients with metastatic breast cancer, the oral selective estrogen receptor degraders, otherwise known as SERDs. Thank you, and let’s begin.
As we start our discussion today, it’s really important we give more of an introduction and background on ER [estrogen receptor]-positive, HER2 [human epidermal growth factor receptor 2]-negative metastatic breast cancer, and the place in therapy for oral SERDs [selective estrogen receptor degraders]. Dr Vidula, could you please explain to our viewing audience how SERDs differ in their mechanism of action from other therapies such as endocrine-based therapies or CDK [cyclin-dependent kinases] 4/6’s for ER-positive, HER2-negative metastatic patients?
Neelima Vidula, MD: Endocrine therapies in general serve to deplete estrogen’s availability to bind the ER or target the ER or degrade the estrogen receptor. That’s the broad different classifications by which they exert their efficacy. SERDs are ER antagonists. They serve to form a complex with the ER and prevent it from translocating to the cell’s nucleus. So it can’t allow for the transcription of the ER genes. It’s also able to undergo proteasomal degradation. That’s the broad mechanism of action of these SERDs in contrast to other endocrine therapies such as aromatase inhibitors [AI], which block the conversion of androgens to estrogen and effectively decrease estrogen levels in postmenopausal women. Selective estrogen receptor modulators [SERMs], bind competitively to the ER. And a good example of that is tamoxifen, and that triggers an anti-estrogen effect. CDK4/6 inhibitors are also incorporated into our clinical care of patients with hormone receptor–positive, HER2-negative breast cancer impact cell cycle progression. So that’s the lay of the land of the various endocrine therapies that we’re looking at nowadays. Of course, there are a number of other targeted therapies such as PIK3C inhibitors that have also entered into our clinical practice, and PIK3C inhibitors target the PIK3CA [phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha] pathway of activation in cells.
Ryan Haumschild, PharmD, MS, MBA: Thank you, Dr Vidula, for that great overview. I think it’s so important for us to know that in the current state, yes, CDK4/6s and endocrine therapy are such a standard of care. But as we look forward, I’m excited about SERDs and SERMs and how they’re going to add additional agents to this patient population. I think one of the important things for us to know, and for our viewing audience to know, is that it’s not like we’ve never used SERDs before, because we’ve had fulvestrant. It is a therapy of choice with many providers, but I think the important thing is to start delineating how SERDs like fulvestrant differ from some of the newer SERDs that we’re seeing within the pipeline. Dr Lu, maybe I can pivot to you if you could give us a little bit of context: What are the differences between the first-generation SERDs like fulvestrant and some of the newer ones, and why was the development of new SERDs necessary for clinical practice?
Janice Lu, MD: We are very excited that we have first-line therapy using CDK4/6 inhibitors, as you mentioned, in combination with endocrine therapy. However, after a patient progresses on CDK therapy, about 20 months or so, or 2 years, what do we do next?We have quite a few different options now, including oral and injection SERD, which is fulvestrant. However, the efficacy of fulvestrant is limited. You have 2 or 3 months of duration response. And then you have to move on to the next line. Therefore, I think newer endocrine therapy with oral SERDs is essential to develop. Right now…we have 5 oral SERDs being developed at this point. [The] oral SERD elacestrant is one of those and the only one that has FDA approval. And in terms of mechanisms of action, the important thing is to get resistance to be converted into endocrine sensitivity. Again, using an oral SERD with elacestrant and treating a patient with ESR1 [estrogen receptor 1] mutation causes resistance to endocrine therapy with CDK4/6 inhibitors with AI [aromatase inhibitor] or fulvestrant. So this is the important part. We want to develop oral SERDs and newer oral SERDs for patients that can [offer] better response, duration, and quality of life.
Ryan Haumschild, PharmD, MS, MBA: I think you hit right on it. Better durability and duration of treatment. And I think ultimately quality of life is going to be one of the things that we’re really looking for in this patient. We want to make sure they have high survival, but also a quality of life while they’re living that out.
Transcript edited for clarity.
