Oral SERDs Could Fulfill Unmet Need in ESR1-Mutant, ER-Positive Breast Cancer

Patients with estrogen receptor (ER)–positive breast cancer whose tumors harbor ESR1 mutations can develop resistance to aromatase inhibitors. Although patients may retain sensitivity to the selective estrogen receptor degrader (SERD) fulvestrant (Faslodex), novel oral SERDs could represent an improved treatment option for this patient population, according to Aditya Bardia, MD, MPH.

In addition to discussing the potential benefit of oral SERDs in patients with ER-positive breast cancer, Bardia highlighted how the use of circulating tumor DNA (ctDNA) could help drive treatment decisions for patients with ESR1-mutated disease before radiographic progression is detected during presentations at the 2022 International Congress on the Future of Breast Cancer West®.

“Oral SERDs would fill an unmet need because they still work when tumors are resistant to aromatase inhibitors due to ESR1 mutations, because the tumor is ER dependent. They can provide a non-chemotherapy option for patients in the endocrine-resistance setting,” Bardia said in an interview with OncLive®.

In the interview, Bardia, an associate professor of medicine at Harvard Medical School, and an attending physician in Medical Oncology at Massachusetts General Hospital, discussed recent and ongoing trials evaluating oral SERDs in ER-positive breast cancer, the effect of ESR1 mutations on treatment efficacy, and how the use of ctDNA continues to evolve across the breast cancer space.

OncLive^®: What unmet needs can oral SERDs address in the treatment of ER-positive breast cancer?

Bardia: Endocrine therapy is the mainstay in the management of [localized and metastatic] ER-positive breast cancer. Right now, the only SERD that is FDA approved is fulvestrant, but that’s given as an intramuscular shot. There is a need for better therapies, including oral SERDs, and there are various oral SERDs in development.

This is particularly relevant in the metastatic setting because we know a subset of [patients with] ER-positive breast cancer can develop a mutation in the estrogen receptor, called ESR1 mutations, and those tumors are resistant to aromatase inhibitors. Drugs that directly bind to ER, like fulvestrant, would work, although that’s given as [an intramuscular] shot.

Oral SERDs would fulfil an unmet need [for patients with ESR1-mutated, ER-positive breast cancer]. That’s why there’s a lot of excitement related to these oral SERDs. [These agents] would also work in ESR1 wild-type [ER-positive breast cancer] in the right context in localized breast cancer and other settings. [My presentation focused on] the biology of ESR1 mutations and the role of oral SERDs in ER-positive breast cancer.

What has the emergence of ESR1 mutations as drivers of resistance to endocrine therapies meant for the treatment of patients with ER-positive breast cancer?

ESR1 mutations are one of the most common mechanisms of resistance to aromatase inhibitors. If you think about their mechanism of action, aromatase inhibitors lower estrogen, but when there’s a mutation in the ER, the tumor becomes estrogen independent, [leading to resistance] to aromatase inhibitors. But a drug that can bind directly to the ER would work in that setting, and that’s why we routinely check for ESR1 mutations as part of comprehensive tumor genotyping via blood or tissue, because that could affect therapeutic decision making.

What efficacy have been seen with oral SERDS so far in clinical trials?

There have been a couple large, randomized, phase 2 and phase 3 trials, looking at oral SERDs vs single-agent endocrine therapy. The key is that those are trials that provide scientific proof of principle comparing a newer agent vs an existing agent. For example, the [phase 3] EMERALD trial [NCT03778931] looked at elacestrant vs standard-of-care endocrine therapy in the second- and third-line settings. [Elacestrant] demonstrated an improvement in progression-free survival [PFS] and a trend toward improvement in overall survival [OS]. But that’s in the endocrine-resistance setting.

Moving forward, there will be interest in looking at combination therapy in the endocrine-resistance setting. If a tumor has a PIK3CA mutation, [since] the [FDA] approval of alpelisib [Piqray], we tend to use fulvestrant and alpelisib. But if you have a better endocrine backbone, like elacestrant or other oral SERDs, [those agents are] likely going to do better with alpelisib. Wherever fulvestrant is being used, if you have a better endocrine agent that would likely work, be it single-agent or combination therapy, [that would be preferable].

Oral SERDs are also being investigated in the first-line setting. For example, the [phase 3] AMEERA-5 trial [NCT04478266] is examining amcenestrant [SAR439859] plus the CDK4/6 inhibitor [palbociclib (Ibrance)] vs standard endocrine therapy plus [palbociclib]. [The phase 3] persevERA trial [NCT04546009] is looking at giredestrant [(GDC-9545) plus palbociclib vs letrozole plus palbociclib] in the first-line, metastatic setting.

Finally, there are trials looking at oral SERDs in the adjuvant setting. For example, the [phase 3] lidERA trial [NCT04961996] is looking at adjuvant giredestrant vs [physician’s choice of] endocrine therapy for patients with localized ER-positive breast cancer. There are a lot of ongoing studies [generating] excitement related to [oral SERDs].

Why is it important to evaluate oral SERDs in different settings?

If you look at endocrine therapy, we have to carefully evaluate the setting. It’s not just about the drug, but also the study population. Especially in the second- or third-line setting, a subset of tumors is estrogen receptor independent. They are dependent on other pathways. In that setting, it’s unlikely we would see benefit with single-agent endocrine therapy. [Other than] results, the context and the study population matter. We have to look at the details before drawing strong conclusions.

In another presentation, you spoke on lessons from the phase 3 PADA-1 trial (NCT03079011) and phase 2 SAFIR02 trial (NCT02299999). What did the detection of an ESR1 mutation and the switch from an aromatase inhibitor to fulvestrant mean for patients with metastatic breast cancer?

ESR1 mutations confer resistance to aromatase inhibitors, and that’s something that can be detected by plasma-based genotyping or ctDNA analysis. The PADA-1 trial looked at patients who were getting first-line therapy with an aromatase inhibitor plus a CDK4/6 inhibitor. They were monitored for ESR1 mutations. When a patient had emergence of an ESR1 mutation before radiological progression, they continued the same therapy or switched from an aromatase inhibitor to fulvestrant. This showed that there was an improvement in PFS with this switch. This provides proof of principle that monitoring of ctDNA and [choosing] therapy based on that might have potential clinical utility.

But I would caution [switching therapies based on ctDNA] is not ready for primetime yet. The ongoing phase 3 SERENA-6 trial [NCT04964934] is asking that question, and we need results of large, phase 3 trials before changing practice. [It is also important to look] at OS. If you make an early switch [of treatment], does it affect OS? We need to see improvement in OS before we can incorporate a switch strategy into clinical practice.

The other trial that was very insightful was the SAFIR02 trial, also in metastatic breast cancer, that looked at genotype-directed matched [targeted] therapy. The bottom line there was that it’s not just about genotype-directed matched therapy, but the level of evidence. If patients have ESCAT I/II [genomic alterations], you’re likely going to see an improvement in survival, but [in patients with] ESCAT III/IV [genomic alterations], the investigators couldn’t see much improvement. The level of evidence also matters. It is not just about selecting matched [targeted] therapy.

What did the phase 2 c-TRAK-TN (NCT03145961) trial reveal about the use of ctDNA to drive treatment decisions in breast cancer?

The c-TRAK trial was an interesting trial because it looked at [patients with] triple-negative breast cancer who had residual disease after standard therapy or after surgery [and monitored] for ctDNA. If a patient had detectable ctDNA, they could receive immunotherapy. The trial was insightful for 2 reasons. The first is that in patients who had detectable ctDNA, a large number of them already had radiologically detectable metastatic disease. This highlights that if you have ctDNA that is positive, these are patients who are at very high risk, and many of them already have metastatic disease.

The second [reason] was in terms of the effect of immunotherapy. Because only a few patients received immunotherapy, it was difficult to analyze the effect of immunotherapy in this setting. But there are other ongoing studies looking at this question. If you detect ctDNA and you add a therapy, can you prevent metastatic disease? The key there is going to be the delta between detectable ctDNA and the emergence of radiologically detectable metastatic disease. The longer the delta is, the more time you have to intervene and make an impact. But if it’s a very short delta, intervention is unlikely to be helpful.

What still needs to be learned about the utilization of ctDNA to inform treatment in breast cancer?

ctDNA is routinely being used in metastatic breast cancer for therapy selection. The things that still need to be determined include the value of serial ctDNA, be it for monitoring or, at the time of disease progression, to have another switch in therapy.

The other unmet need related to ctDNA is in the adjuvant setting. In that setting, we need sensitive assays, and we need to see what the value of ctDNA is for therapy selection. If you find detectable ctDNA, what can be done about it in terms of matched [targeted] therapy? There are ongoing studies looking at this question, so we eagerly await the results of those studies.

What are the next steps for examining the use of ctDNA in future clinical trials?

The utilization of ctDNA is increasing and will continue to increase over the years. It started with its application in metastatic breast cancer for therapy selection. Now, there’s interest in monitoring and understanding resistance in the metastatic setting. In early breast cancer [we are examining] similar principles, [including] detection, monitoring, and therapy selection.

Finally, [we can look at] early detection. Can you utilize ctDNA to detect [breast] cancer before you can see it on the mammogram? Similarly, can you detect ctDNA before a patient develops colon cancer? The use of ctDNA and similar blood-based assays for early detection is also very exciting.