Aditya Bardia, MD, MPH: On this topic on switching, how about switching endocrine therapy? Virginia, could you comment on the newer endocrine agents being developed, particularly in the second- and third-line settings? You were involved with the development of elacestrant and we’ve seen results from the EMERALD trial, so let’s review that.

Virginia Kaklamani, MD: This was probably the highlight from San Antonio [Breast Cancer Symposium]: second- and third-line endocrine therapies and novel endocrine therapies. We saw data with nicotine inhibitors. We saw data with PROTAC [proteolysis-targeting chimera] inhibitors. The data I want to go over are the SERD [selective estrogen receptor degrader] data. We’ve been using fulvestrant for a long time. It’s an intramuscular [IM] injection. One of the limitations is that we can’t give a very high dose because it’s an IM injection, but oral medications can achieve higher levels in the blood.

The initial data suggest that these oral SERDs are more active than other endocrine therapies, especially in the ESR1-mutated patient population. The data we presented with EMERALD—a phase 3 trial comparing elacestrant with standard-of-care endocrine therapy, either fulvestrant or an AI [aromatase inhibitor]—showed an improvement in progression-free survival [PFS] favoring elacestrant that was statistically significant. More important, the data showed in San Antonio looked at who we should be giving elacestrant to.

The initial data with PFS improved significantly with elacestrant, but both arms didn’t perform extremely well. But if you look at the patients who had been on a CDK4/6 inhibitor for at least 12 months, they had a median PFS of 8.6 months with elacestrant compared with 1.9 months with standard-of-care endocrine therapy. You’re starting to see a difference that’s clinically meaningful for those patients. These are patients with ESR1 mutations. I know the FDA is reviewing elacestrant and may be approving it in the next few weeks. We may have a nice option, but this highlights that we need to do ESR1 testing for these patients.

A second trial, SERENA-2, looked at camizestrant, which is another oral SERD. This was a phase 2 clinical trial that looked at 2 different doses of camizestrant, 75 and 150 mg. Overall, it looked like the 150-mg dose may have done better in the ESR1-mutated patient population compared with the 75-mg dose, with a median PFS of 6.3 months with 75 mg compared with 9.2 months compared with 2.2 with fulvestrant. We’re starting to see yet another SERD emerging that has some interesting data. For both, the toxicity profile is very favorable, and this is another thing we need to take into account for our patients with ER [estrogen receptor]–positive breast cancer. We’ll be using the oral SERD quite a bit in the future.

Aditya Bardia, MD, MPH: It’s great news for the field to have these newer agents available and have oral options as opposed to fulvestrant. Heather, are there other agents you’re excited about related to ER-targeting therapies? If you have multiple options available, how would we use 1 vs another?

Heather McArthur, MD: It’s worth highlighting the presentation by Sara Hurvitz and her colleagues, the ARV-471 ER degrader. The idea is that it would be superior in ER degradation than drugs like fulvestrant and further inhibit tumor growth. They presented a phase 2 study design focusing on the phase 2 cohort expansion group. In this group, the drug was administered at 2 dosages, 200 mg daily and 500 mg daily.… The clinical benefit rate was very similar for the 2 doses: 37.1% and 38.9% for the 200- and 500-mg cohorts, respectively. There was also an impressive clinical benefit rate in the ESR1-mutation subgroup, 47.4% and 54.5% in the 2 cohorts in a heavily pretreated population with 4 median prior regimens, all previously treated with CDK46. This reflects real-world experience. Those were exciting data. Even more exciting was the favorable toxicity profile. There didn’t seem to be any significant adverse effects with this agent, but I’m interested to hear what Sara’s firsthand experience has been with this drug.

Aditya Bardia, MD, MPH: Sara, what are your thoughts on these endocrine agents, including ARV-471? You’ll have the final word on this topic.

Sara A. Hurvitz, MD: It’s an exciting time. We all came out of ESMO [European Society for Medical Oncology Congress] a little disappointed and feeling down in the dumps about the prospects of SERDs. We had 1 positive ER study, EMERALD, and then some bad news regarding amcenestrant and other agents with negative trials. It was a highlight of San Antonio to see some positive data. The EMERALD data that Virginia presented were fascinating. They’re helping us home in on how to utilize single-agent oral SERDs—at least elacestrant—using response to prior therapy and ESR1 mutation to guide our decision-making. It gives us some hope that we’re going to become smarter about personalizing therapy for our patients.

The ARV-471 PROTAC technology is fascinating because fulvestrant indirectly recruits the proteasomal system to downregulate or degrade ER, and it does so by its confirmational changes of ER. Whereas this PROTAC technology binds directly to the ubiquitous ligase, and ER brings them together and tags them for proteasomal degradation. The degradation we saw in this study was quite impressive. It’s not a randomized study against fulvestrant, but the mean ER degradation over 70% in the biomarker analysis that was conducted speaks to the fact that it’s doing the work it should be doing. When you compare it with other biomarker data from fulvestrant, it compares favorably. The toxicity profile is favorable. I’ve seen patients who are heavily pretreated have responses, not just with stabilization of disease. It’s been promising. I’m looking forward to seeing a randomized trial with this agent.

Aditya Bardia, MD, MPH: That’s exciting.

Transcript edited for clarity.