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Clinical Impact of Oral SERDs


Dr Lu and Dr Vidula review the clinical impact of oral selective estrogen receptor degraders (SERDs) on disease progression and response rates in patients with ER+/HER2- metastatic breast cancer and discuss if oral SERDs can be used in combination with other therapies in patients.

Ryan Haumschild, PharmD, MS, MBA: You gave us a great overview of progression-free survival, but I want to talk about the clinical impact. Dr Lu, what is the clinical impact of oral SERDs [selective estrogen receptor degraders] on disease progression in patients with ER [estrogen receptor]–positive, HER2 [human epidermal growth factor receptor 2]–negative metastatic breast cancer? What’s the clinical impact on the response rates with these patients as well?

Janice Lu, MD: That’s a great question. Back to oral SERDs, of the 5 on the market being developed, only elacestrant is FDA approved. The data show a 45% reduction in the risk of progression of death with elacestrant compared with standard-of-care, including fulvestrant AI [aromatase inhibitor], in the EMERALD study for patients with ESR1 mutation. In part, these are the data that led to FDA approval.

Ryan Haumschild, PharmD, MS, MBA: How do oral SERDs affect the rate of recurrence in these patients?

Janice Lu, MD: Comparing oral SERDs vs fulvestrant in EMERALD, a significantly higher percentage of patients stay on oral SERDs compared with fulvestrant AI. This gives the patients the benefit of a longer duration of therapy on oral SERDs vs the other standard therapy. That’s 1 point that will keep physicians and patients going. They treat the patients, and they get benefit with quite tolerable adverse effects.

Ryan Haumschild, PharmD, MS, MBA: Excellent, thank you. A lot of times throughout the treatment course of therapy, we’re seeing combination therapy. We see combination therapy with CDK4/6. We see combination therapy in a lot of areas with radiation and surgery. Dr Vidula, as we start to think about this therapeutic category, can oral SERDs be used in combination with surgery, radiation, chemotherapy, or other therapies in patients with ER+/HER2- disease?

Neelima Vidula, MD: You’ve asked a great question, but we don’t have a lot of data to guide that decision-making. There are clinical trials that are ongoing in earlier-stage settings, like in early stage breast cancer in the neoadjuvant and adjuvant setting. That might help answer some of the questions regarding the timing of surgery. But I can speak broadly to the considerations that I’d think about based on the data we have.

In general, we’re not typically taking patients to the operating room who have ER+/HER2- metastatic breast cancer. That’s because we don’t have great data to support that there’s a survival benefit in that setting. However, there are some situations where a patient, unfortunately, is experiencing cord compression or a fracture that needs to be intervened on. In that setting, I’d probably say, “These therapies aren’t causing cytopenia. We don’t have evidence that they impact wound healing.” It would probably be OK to take the patient to the operating room. If you wanted to be a little more on the safe side, maybe you could hold the drug for 2 weeks or so. But sometimes you don’t have the luxury of time.

In terms of radiation, we have data combining hormone therapy with radiation such as aromatase inhibitors. I’d probably feel comfortable combining an oral SERD with radiation if a patient needed radiation for palliation of a metastasis. If you wanted to be ultracautious, you could probably hold the drug for 2 weeks or so and give the patient a little washout before proceeding. But because the adverse effect profile of these agents doesn’t include cytopenias, I’d be comfortable with that.

We haven’t seen a lot of data combining chemotherapy with these oral SERDs. In general, when we manage ER+/HER2- advanced breast cancer, we tend not to combine chemotherapy with hormone therapy because chemotherapy usually has a strong effect and may have more adverse effects, so we aren’t combining the 2. We’re using endocrine therapy alone with targeted therapy or transitioning to chemotherapy. That situation doesn’t come up a whole lot.

But there are ongoing clinical trials looking at combinations of newer targeted therapies with oral SERDs. Notably, combinations are being explored with CDK4/6 inhibitors and oral SERDs. That’s a very appealing and potentially promising direction because we have CDK4/6 inhibitors approved with fulvestrant. If you’re able to demonstrate efficacy with an oral SERD, then a patient is able to take 2 oral therapies. That might be very appealing from a quality-of-life standpoint.

Janice Lu, MD: That’s a great answer. I want to add 1 more point. The ELEVATE trial is a study that’s being conducted to evaluate this question that Dr Vidula mentioned in combination with CDK4/6 inhibitors and with alpelisib for patients with PIK3CA mutations. We’re looking forward to data for the combination, hopefully with higher progression-free survival and leading to better overall survival.

Ryan Haumschild, PharmD, MS, MBA: It’s exciting when you think about synergistic mechanisms of action and the deeper responses you can get in some of these earlier therapies. I like how you walked us through the potential with CDK4/6 and also those with different PIKexpressions within the treatment algorithm. It’s going to be watch and wait. But as we see the data, I’m hopeful that we’ll see really good responses in these patients and a lot of therapeutic benefit. At the same time, for some patients who might not be fit or might have underlying toxicities, you’ll do a cost-benefit analysis with that patient through a shared decision-making framework to decide if they’ll be able to sustain therapy. We want to make sure they can sustain therapy and not abandon it due to some related toxicity.

Transcript edited for clarity.

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