Centering discussion on the EMERALD trial, Dr Hope Rugo, reflects on the safety and efficacy of elacestrant in patients with HR+/HER2- mBC.
Case: A 57-Year-Old Woman with HR+/HER2- Metastatic Breast Cancer
Physical exam, clinical workup, and imaging
Hope Rugo, MD, FASCO: It’s important to think about the patient population that was treated in the EMERALD trial because this wasn’t a second-line study. It was a second- or third-line study. That tells us something. When you get into the third-line setting, we see a lot more endocrine resistance. A lot of patients had visceral disease. Most patients had not received fulvestrant but may have received 2 lines of an aromatase inhibitor therapy. More than two-thirds of patients received fulvestrant as their endocrine partner. You couldn’t receive the same endocrine therapy that you just had progressive disease on. If you’d progressed on fulvestrant, you couldn’t get it again. That’s an important point to know about the EMERALD trial.
The other thing is that their group of patients had received CDK4/6 inhibitors. That was required. That’s really important because we’re seeing a bit of a difference in responses. Even anecdotally, with distribution of more visceral disease, [there’s a difference] after progression on CDK4/6 inhibitors. Having a patient population who were uniformly treated with CDK4/6 inhibitors is helpful in terms of understanding efficacy and defining the patient population most likely to benefit.
TheEMERALD trial was designed to look at the efficacy of elacestrant based on the ESR1 mutation. The trial was designed to look at how elacestrant works in ESR1 mutations, and it was a stratification factor to balance between the 2 arms. But there also was an assessment in the intent-to-treat population looking at the overall population and the population who had ESR1 mutations. The trial was powered to look at, “Does elacestrant work in patients with ESR1 mutations?” Although the results were positive in the intent-to-treat population, if you looked at the subset of patients who had wild-type for ESR1, the benefit was narrower. It seemed as if the contribution to intent-to-treat was from the ESR1-mutant population.
That’s a really interesting approach. Some of the phase 2 trials that we were disappointed with in 2022, regarding oral SERDs [selective estrogen receptor degraders], weren’t designed to look at patients who had ESR1 mutations. They looked at the intent-to-treat population. When they separated the patients with ESR1 mutations, it looked like there was a trend toward benefit in 1 trial more than another. We have to be able to power for that subgroup of patients who have more resistance to our known endocrine therapies now that we’re moving into the land of oral SERDs and other agents that affect the estrogen receptor and cause degradation.
One area that’s important to talk about is how we approach adverse event management. There are some warnings about dyslipidemia and embryo fetal toxicity. Embryo fetal toxicity [can occur] in patients who have metastatic disease and are on an endocrine therapy. They shouldn’t be getting pregnant because it’s not good for babies to have all these drugs. In general, we suppress the ovaries of premenopausal patients in any case. This is true for many of our drugs that have embryo fetal toxicity. The dyslipidemias are interesting. Patients who take aromatase inhibitors also tend to have elevation in cholesterol and triglycerides. If they’re already going to have them, that gets worse with menopause because we’re dropping the estrogen level even further. If a patient has normal cholesterol, we tend not to see that elevation. The elevation with elacestrant was in LDL [low-density lipoprotein] and total cholesterol, not triglycerides. That can be managed medically and is something to look for periodically. Obviously, we’re looking at the long-term effects of cholesterol, which are less of an issue in patients with metastatic disease, but we want to take good care of our patients.
The most common toxicity, nausea, we can manage well with antiemetics. What was striking in the EMERALD trial was how few patients got antiemetics. We want to be aware of this adverse effect of chronic low-level nausea, even though patients didn’t stop treatment on EMERALD due to nausea. We want to make the quality of life of our patients as good as possible. We definitely want to manage this with as-needed medications. We use olanzapine at bedtime at very low doses—2.5 or even 1.25 mg. It also helps patients sleep, which is a nice added benefit, and it helps with nausea. Patients take the usual suspects, like ondansetron, for managing nausea if they have that. It’s individual: some patients don’t have much nausea at all. We want to watch out for GI [gastrointestinal] toxicities, but we didn’t see other serious toxicities with the drug.
Transcript edited for clarity.