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Safety Concerns Associated With Oral SERDs


Dr Vidula reviews the safety concerns associated with oral selective estrogen receptor degraders (SERDs) in comparison to other therapies for ER+/HER2– metastatic breast cancer.

Ryan Haumschild, PharmD, MS, MBA: As I think about what you spoke about, there are so many benefits from clinical end points. But another thing you called out that I think about a lot in my practice are the safety profiles of these new medications. Throughout all of breast cancer treatment, whether it’s going to be a PIK [phosphoinositide kinase] inhibitor, I’m worried about hyperglycemia or worried about diarrhea with a CDK [cyclin-dependent kinases] 4/6 or LFTs [liver function tests], I think I’m always looking at the adverse effect profile with my patients. I want to be proactive with them. If I have a chance in clinic, I want to sit down and really counsel them: You might see these adverse effects; here’s how we’re going to get ahead of them; you need to have early intervention; if we need a dose reduction, that might be a normal course of your therapy. A lot of patients, I think, engage really well because they’re concerned about their quality of life as much as they are about their overall survival. With the safety considerations in play here, Dr Vidula, I’d love for you to review some of the safety concerns that come with oral SERDs [selective estrogen receptor degraders] compared with some of the therapies that we utilize in the current state for ER [estrogen receptor]-positive, HER2 [human epidermal growth factor receptor 2]-negative metastatic breast cancer.

Neelima Vidula, MD: That’s a great point. When we’re thinking about taking care of patients who have advanced breast cancer, we always want to manage the quality of life with benefit to the patient. In general, endocrine therapies have less irreversible toxicity than chemotherapy. That being said, unfortunately, there can be adverse effects affiliated with all of the different endocrine therapies that we have available. SERDs as a class are tending to show us more evidence of gastrointestinal [GI] toxicity. We’re often seeing in some of the studies that have been presented with various SERDs that patients are experiencing nausea, vomiting, and diarrhea. With elacestrant, which is now approved, you can also see fatigue and arthralgias as common adverse effects. Camizestrant has also been associated with bradycardia. So that’s something to be mindful of if that agent enters our clinical practice in the coming years and also vision changes. But in general, the common class effect that we’re seeing tends to be GI toxicity. In comparison, fulvestrant—which is also a SERD, but an older SERD—tends to have adverse effects such as pain at the injection site because those are injections that patients are receiving sometimes can be painful to patients. In addition, sometimes patients have some arthritis, and some hot flashes similar to endocrine therapies. Aromatase inhibitors, which we’ve been using for a very long time for the treatment of advanced hormone receptor– positive/HER2-negative breast cancer are associated with hot flashes, arthritis, sometimes some fatigue, sometimes some vaginal dryness as well, are things to be mindful of. CDK4/6 inhibitors, which are generally our first-line therapy for patients with advanced hormone receptor–positive/HER2-negative breast cancer, have been associated with cytopenias. Often, uncomplicated neutropenia is something that we have to look out for, so patients need to come in for blood draws to make sure that their blood counts are holding up. Additionally, with abemaciclib, folks sometimes experience diarrhea, so that’s something to be mindful of as well. With ribociclib, there can be QTc [heart rate–corrected interval] prolongation, so it’s important to monitor EKGs, and sometimes patients may also experience elevations in their liver enzymes. So it’s important to monitor those. In terms of the PIK3CA [phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic subunit alpha] inhibitor that we have approved, alpelisib, with that we often see hyperglycemia, and this can be pretty severe in patients. Patients who don’t have diabetes may end up with very high blood sugar. So, in general, we should be monitoring hemoglobin A1C prior to starting. And then checking on that every couple of months or so while they’re on treatment and have a very low threshold to initiate oral hypoglycemic agents such as metformin to help manage that. There can also be a rash, but that can be mitigated by using an antihistamine. So those are some of the key adverse effects to be mindful of with these various endocrine therapies.

Ryan Haumschild, PharmD, MS, MBA: That was a great review of the landscape. When you’re having the conversation with your patients about oral SERDs, obviously these patients might be treatment-experienced or might have some underlying toxicities—how does that conversation happen? What are the key things you’re trying to remind them of at the start of therapy so they can be prepared for any type of dose reduction or any type of adverse effects throughout the course of treatment?

Neelima Vidula, MD: That’s a great question. So, the oral SERD that we currently have approved is elacestrant so when I’m talking to patients about that agent, I think one of the great selling points is that it’s an oral agent. Patients are happy to hear that it’s a pill that they can take at home and they don’t need to come into clinic for an infusion or so forth. Typically, the adverse effects we’re counseling patients about with that drug are nausea, vomiting, fatigue, arthralgias, and so forth. Those are just important things to bear in mind and to talk to patients about. The other SERDs are still in clinical development, so generally, when I’m talking to patients about those, I’m talking to them about participating in a clinical trial. Depending on which agent we’re discussing, I’ll tell them what has been observed in prior earlier phase studies of that agent, but it does vary. But in general, as I was saying before, that class effect tends to be GI toxicity.

Transcript edited for clarity.

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