ELAINE Trial Explores Lasofoxifene in ESR1+ Breast Cancer

Matthew P. Goetz, MD

Patients with estrogen receptor (ER)—positive, HER2-negative breast cancer can develop resistance to tamoxifen and aromatase inhibitors with the emergence of ESR1 mutations, leaving oncologists questioning the next steps in treatment for this patient population, explained Matthew P. Goetz, MD.

“In [ER-positive] patients who have been previously treated with an aromatase inhibitor or tamoxifen, and who have done well on those drugs for a period of time, resistance can emerge,” said Goetz. “One of the mechanisms for resistance that has emerged is ESR1, which is present in up to about 30% to 40% of patients who have been treated with hormonal therapy. This appears to be an acquired mechanism as opposed to a de novo mechanism of resistance. When these mutations are present, they have been known to confer a worse prognosis for patients with endocrine resistant breast cancer.”

The phase II ELAINE trial (NCT03781063) is examining lasofoxifene versus fulvestrant (Faslodex) in female patients with ER-positive, HER2-negative metastatic breast cancer who have ESR1 mutations, which will be detected by a circulating tumor DNA (ctDNA) assay.

Eligible patients have progressed on an aromatase inhibitor in combination with a CDK4/6 inhibitor, received 1 prior chemotherapy regimen in the neoadjuvant or adjuvant setting, and have an ECOG performance status of 0 or 1.

The primary endpoint of the study is progression-free survival (PFS). Secondary endpoints include clinical benefit rate, objective response rate, duration of response, time to response, overall survival, and safety. Additionally, an exploratory analysis will screen the presence of select mutations, including NF1, KRAS.

In an interview with OncLive^®, Goetz, a professor of oncology and pharmacology and consultant in the Department of Oncology at Mayo Clinic, discussed the current treatment landscape for patients with ER-positive, HER2-negative breast cancer who harbor ESR1 mutations, and provided an overview of the ELAINE trial.

OncLive: Could you discuss the current prognosis and available options for patients with ESR1-mutant breast cancer?

Goetz: [ESR1 mutations] are common, and we are just beginning to learn about new ways to potentially treat them. Right now, in the last 4 or 5 years, the major change in the therapy for patients with ER-positive breast cancer has been the introduction of CDK4/6 inhibitors. The very good news is that for women who have metastatic breast cancer with ESR1 mutations present, we know that CDK4/6 inhibitors improve the outcome.

The problem is that we don't necessarily know the best treatment after progression for patients with an ESR1 mutation who have been on a CDK4/6 inhibitor and have done well. This is clearly an unmet need. The other question for patients who have these ESR1 mutations is what the optimal hormonal drug is, and whether [said drug] should be combined with CDK4/6 inhibitors.

What is the patient profile for ER-positive, HER2-negative patients following progression on prior therapy?

This is something that we are just beginning to understand. In patients who progress on CDK4/6 inhibitors, we have not known the complete prognosis for these particular patients. There are emerging data that suggest patients who have progression on a CDK4/6 inhibitor have a potentially poor prognosis with standard endocrine therapy. This would be with a standard hormonal agent with a drug like tamoxifen or an aromatase inhibitor. We really need the data on whether we should continue CDK4/6 inhibitors past progression. We also need to understand the mechanisms of resistance that are driving the growth of the tumor in these women who have progressed on CDK4/6 inhibitors.

That is the most important area of research right now. As we go forward, clinical trials are going to be focused on these different subgroups. For example, we have data with alpelisib (Piqray); which is a drug that targets tumors with PIK3CA mutations. It has already shown efficacy in hormone-refractory groups of patients, and we are awaiting data on the efficacy of alpelisib in this group of patients that have progressed on CDK4/6 inhibitors. Very few patients have been treated thus far in SOLAR-1. We're awaiting data from the BYLieve trial, which will give us data on the optimal treatment for patients with PIK3CA mutations. In general, as women progress on CDK4/6 inhibitors or their tumors progress, we're going to need individualized strategies to address the different mechanisms that may develop.

How does degradation compare with the blockade approach?

The ER can be targeted a number of different ways. You can use an aromatase inhibitor, which simply reduces the ligand and is very effective. You can also use tamoxifen, which is a selective estrogen receptor modulator, meaning it binds to ER. There are a number of coactivator and corepressors that come in. There is tissue specificity in terms of whether the drug blocks ER or acts more like an agonist. There are selective estrogen receptor degraders (SERDs); the one that has been in clinic the longest is fulvestrant, which we know to be a very efficacious drug.

Over the past 5 to 10 years, there have been attempts to develop better SERDs. Fulvestrant, when used in the laboratory, is highly effective, but we're not able to achieve the concentrations that we would like in patients. Consequently, when we give fulvestrant, we don't see a lot of toxicities because it is well tolerated.

As researchers have developed better SERDs, one of the things that we're beginning to see is some of the toxicities that occur when you go into much higher concentrations of SERDs. This can include diarrhea, effects on the GI tract, and other toxicities that are still unknown. In general, when we think about drugs that target ER, they have been pretty well tolerated.

The other way to target ER is through selective estrogen receptor modulators (SERMs). The drug that is being studied in patients with ESR1 mutations is lasofoxifene. Lasofoxifene is also a SERM, and there are fair amounts of data with it in terms of safety, efficacy, and tolerability.

What are the adverse events (AEs) of aromatase inhibitors that distinguish them from other drugs?

Aromatase inhibitors are well studied, and the AEs are well known. AEs include arthralgias, which can be mild for some patients but absolutely intolerable for other patients. About one-third of patients get some joint aches and in about 10% to 15%, [the arthralgia] is intolerable to the point where patients need to switch to a different aromatase inhibitor or a different class of drugs.

Another AE that is associated with aromatase inhibitors is bone loss and bone fractures that result from osteoporosis. Most bone loss typically occurs in the first year that the drug is administered, and then it seems to level out over time. There are a number of drugs that can prevent bone loss from the aromatase inhibitors, including zoledronic acid or bisphosphonates. The bone AEs, while they are substantial, seem to be preventable.

The other AE associated with aromatase inhibitors is vaginal dryness. This can lead to urinary tract infections, dyspareunia, and other sexual AEs that can be very troublesome to patients and their partners. These AEs, as a whole, are different than [those of] SERMs and fulvestrant.

Could you discuss how the ELAINE trial is addressing this ESR1-mutant patient population?

The ELAINE trial specifically targets patients who have ESR1 mutations and evaluates the drug lasofoxifene. Lasofoxifene is a SERM that was developed by Pfizer many years ago in the 1990s. It's been studied extensively, especially in the setting of osteoporosis and vulva/vaginal health. [Lasofoxifene] demonstrated efficacy in terms of reducing fractures and a substantial decrease in the incidence of breast cancer.

For example, in the Young-PEARL trial, where there were over 8000 patients randomized to either lasofoxifene or placebo. In that trial, there was a greater than 80% reduction in breast cancer incidence. Lasofoxifene has been studied at higher concentrations. Additionally, in the laboratory within the last several years, it's been demonstrated that lasofoxifene can inhibit both ER transcription as well as the growth of breast cancer cells that exhibit ESR1 mutations. Furthermore, when compared with fulvestrant, this drug has been shown to reduce the incidence of metastases in models where ESR1 mutations are present.

Overall, with lasofoxifene, there was a wealth of prior data, and now there is renewed interest in studying this drug in this particular subtype of patients with ESR1 mutations. The ELAINE study is looking at women who have progressed on a CDK4/6 inhibitor who carry one of the ESR1 mutations. This can be detected either within the tumor or by ctDNA. Patients are randomized 1:1 to receive either fulvestrant or lasofoxifene, and patients are stratified based on the type of ESR1 mutation and/or the presence of visceral metastases.

Patients who are eligible for this study are women who have progressed on a CDK4/6 inhibitor and who would otherwise be treated with standard fulvestrant in this situation. Patients must not have received prior PI3K or mTOR inhibitors. There's a limit in terms of the number of chemotherapy regimens that they could have received in the metastatic setting.

How could the approval of lasofoxifene change standard of care for this patient population?

The very exciting of part of the lasofoxifene study and other studies is that this is truly a drug that is specifically focused on the ER that is mutated. [Lasofoxifene] fits within the binding pocket of the mutated receptor, thereby affecting and reducing ER transcription.

The in vivo data are very exciting and makes this an exciting, individualized drug. It's exciting because this is a high area of need. We need new therapies for women with this relatively common mechanism—these ESR1 mutations. If the ELAINE trial was proven to actually meet its endpoints, this would be a drug that would have the ability to move forward and change the practice for a group of patients that otherwise don't have good treatment options right now.

What other research is ongoing for this patient population?

In general, there is a lot of interest in studying the mechanisms by which women develop resistance to CDK4/6 inhibitors. We know that these ESR1 mutations confer resistance, but we also know that the mechanism of resistance to CDK4/6 inhibitors are diverse. This group of patients that will be coming onto the ELAINE study are those who had prior endocrine therapy and will have demonstrated some degree of endocrine sensitivity. They will be required to be on a CDK4/6 inhibitor for at least 1 year. This [patient population is] quite interesting because we're just beginning to learn the mechanisms that drive resistance for this patient population.