Treatment Failure and Resistance Before Oral SERDs


Drs Lu and Vidula discuss treatment failure with other agents that are used before oral selective estrogen receptor degraders (SERDs) and treatment resistance in patients with ER+/HER2- metastatic breast cancer.

Ryan Haumschild, PharmD, MS, MBA: When we talk about this treatment—not in the combination setting, but oral SERDs [selective estrogen receptor degraders] alone—we know that a lot of patients will be treated with prior agents. It could be CDK4/6 inhibitors, or it could be endocrine therapy. Dr Lu, when you think about a patient who has failed therapy, how do you define treatment failure with other agents that are used before oral SERDs?

Janice Lu, MD: Treatment failure is a standard way to define regardless of oral SERDs, CDK, or others. Basically, it’s the clinical findings. We see metastatic patients regularly. I tend to see them every 3 or 4 weeks and make sure their blood counts are good. Thank God, oral SERDs don’t have the neutropenia issue like CDK4/6 inhibitors. I also check their tumor markers, clinical findings, and imaging. I routinely do imaging every 3 to 4 cycles, about 3 months or so. And if there’s any progression based on the imaging, the clinical findings, and tumor markers in 1 of the markers for that indicator, that’s when we’ll define treatment failure. That’s the time to switch the line of therapy.

Ryan Haumschild, PharmD, MS, MBA: [That’s an] excellent overview. When we look at treatment failures, within oncology as a whole, treatment resistance is something that exists, even in hematologic malignancies. When we’re treating patients with multiple myeloma, we might have to change the protease inhibitor or the IMiD [immunomodulatory imide drug] because we’re having treatment resistance. In the context of breast cancer, Dr Vidula, how do you define treatment resistance in patients who are ER [estrogen receptor]–positive and HER2 [human epidermal growth factor receptor 2]–negative? Do oral SERDs play a role in patients who’ve experienced treatment resistance?

Neelima Vidula, MD: One thing that will occur regardless of what treatment we give patients with ER+/HER2- advanced breast cancer is the development of treatment resistance. Because with time, the tumor will acquire mutations and change in its biology. As a result, the current treatment won’t be effective in managing its growth. The pure way that we’ve been defining treatment resistance has been by using radiographic imaging. You know a patient has developed resistance to a therapy when there’s clear evidence of the progression of disease on imaging scans or on their clinical exam. For example, if a patient has skin and chest wall metastases, if you’re seeing overt growth of those metastases. That’s why it’s important to track a patient’s clinical exam and to get periodic imaging scans.

That being said, there may also be an opportunity to overcome treatment resistance. That’s where cell-free DNA testing can be quite helpful. In a portion of patients—20% to 40% of patients treated with a prior aromatase inhibitor [AI]—they will go on to develop an ESR1 mutation, and that can be detected using a cell-free DNA assay or tumor tissue genotyping. The benefit of the cell-free DNA assay is that it’s easier for the patient to have that done because it’s a blood draw as opposed to another biopsy. In that setting, where an ESR1 mutation is detected using 1 of these genotyping assays, there’s an opportunity to intervene and give a patient an oral SERD. Right now, we have the approval of elacestrant in that specific situation, but a number of other agents are being looked at in clinical trials.

There are also emerging data to look at biomarkers and how that might catch earlier treatment resistance. But there are a lot of unanswered questions because we don’t know the best timing when to check cell-free DNA. I’ll also add the caveat that you never want to burn through your therapies too quickly because there’s a finite number of therapies a patient can receive. If you’re changing treatment very early on based on biomarker evidence of progression, you might end up using up all your therapies sooner. We also need more research in this area [to determine] whether there’s a role for rotating therapies. For example, if you make a switch and then 10 months later come back to a therapy, there could be an opportunity there. But this is an area where we need more research.

Ryan Haumschild, PharmD, MS, MBA: We’ll definitely be watching for the allotted data throughout the rest of this research and development in clinical trials. When I think about sitting in a breast clinic with a patient, talking to them about a therapeutic, 1 thing I’m always considering is whether there’s anything that I should let this patient know or screen this patient for, whether that’s drug-drug interactions or contraindications. When we think about different therapies, we know that some patients might have pre-exposure to certain toxicities, so they wouldn’t be good candidates. Another thing I think about is the P-glycoprotein or cytochrome P450, in terms of drug interactions, whether they’re inducers or inhibitors of the mechanism of action. That’s important as we consider different treatment options for these patients. Dr Lu, what are some of the contraindications providers should be thinking about when they’re prescribing or selecting oral SERDs for treatment?

Janice Lu, MD: That’s a good question. In my clinics, I won’t use the word contraindications. I don’t think oral SERDs have contraindications. However, for individual patients, we need to rely on the patient’s prior history and performance status, the treatments she got in the past, and the duration of therapy. If it’s endocrine resistant or endocrine sensitive, we come up with other treatment options. Otherwise, [we look at] adverse effects: nausea, vomiting, GI [gastrointestinal] symptoms, fatigue, muscle aches and pains, and those kinds of symptoms. You need to consider that. But the good thing is, neutropenia is very limited.

There are no contraindications, but hyperlipidemia is something to pay attention to for oral SERDs with elacestrant. The packages basically say that we need to check the baseline for hyperlipidemia issues vs periodically during therapy. This is something I routinely do, but for grades 3 and 4, toxicity is very limited. It’s less than 2%. For the patients I treat, it’s not a major issue. Overall, it’s well tolerated, and quality of life is not affected. There’s no adverse effect on quality of life at this time compared with other standard-of-care with AI or fulvestrant.

Transcript edited for clarity.

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