Unlocking the Potential of SERDs in Advanced ER+ Breast Cancer

The selective estrogen receptor degrader (SERD) amcenestrant (SAR439859) has demonstrated antitumor activity with acceptable safety in patients with estrogen receptor (ER)–positive breast cancer, according to Adam M. Brufsky, MD, PhD, who added that ongoing efforts are examining its benefit alone or in combination with other agents and to determine its role in the first-line setting.

Results of the phase 1/2 AMEERA-1 trial (NCT03284957), which were presented during the 2020 San Antonio Breast Cancer Symposium (SABCS), demonstrated that patients with advanced or metastatic, ER-positive disease experienced an objective response rate (ORR) of 8.5% after being treated with amcenestrant.¹ Additionally, patients experienced a clinical benefit rate (CBR) of 33.9%.

Although AMEERA-1 has showcased the promise of amcenestrant, efforts such as the phase 2 AMEERA-3 trial (NCT04059484) and the phase 3 AMEERA-5 trial (NCT04478266) are seeking to build on the success reported thus far with this approach, Brufsky said.

“The exciting trial that I would like to see [data from] is AMEERA-5, [which is examining] first-line amcenestrant and palbociclib [Ibrance] vs letrozole and palbociclib,” Brufsky said. “It is a study with a primary end point of progression-free survival [PFS]. This is a pivotal trial that will likely establish whether amcenestrant and oral SERDs have a role in first-line therapy. It is one of several other trials that are currently [examining] oral SERDs.”

In an interview with OncLive^®, Brufsky, a professor of medicine, associate chief in the Division of Hematology/Oncology, co-director of the Comprehensive Breast Cancer, and associate director of clinical investigation at the University of Pittsburgh, detailed the safety profile of amcenestrant and spotlighted the promise of other oral SERDs such as enobosarm (MK-2866).

OncLive^®: What is the mechanism of action of amcenestrant? How might this agent overcome resistance to aromatase inhibitors (AIs)?

Brufsky: Amcenestrant is [part of] a class of drugs referred to as SERDs. They bind to the ER and prevent its dimerization in the cytoplasm. Given that it is degraded by various cellular processes and pathways that are responsible for degradation of misfolded and misaligned cellular proteins, [the agent] is basically like fulvestrant [Faslodex], which is the classic [SERD] agent. Amcenestrant is an oral version of these [older] agents.

[The agent] could overcome resistance in a number of ways, but one of the interesting ways is that it has activity in certain mutations of the ER that make agents such as AIs and/or fulvestrant resistant.

What were the results of the AMMERA-1 trial examining amcenestrant?

[Data from] the phase 1/2 AMMERA-1 trial were presented during the 2020 SABCS. The [study evaluated] amcenestrant monotherapy in heavily pretreated women [who had received] multiple agents and had advanced metastatic, ER-positive breast cancer. It is not surprising that [among] the 59 evaulable patients, [there was] a modest ORR of about 8.5%, as well as a CBR, which is more important in this setting, of [approximately] 34%. Interestingly enough, you could [also look at] subsets. Among patients who have had 3 or fewer lines of therapy, the ORR was about 15% and the CBR was about 42%. In patients who did not receive prior CDK4/6 inhibitors, mTOR inhibitors, or fulvestrant, the ORR was about 21% and the CBR was about 65%.

It is interesting [because] there is now going to be some expansion of this. [Investigators] had a dose-escalation phase, [where the agent was evaluated at doses of] 20 mg to 600 mg, and the recommended dose as monotherapy was felt to be 400 mg per day, which is substantial. The safety profile [of the agent] was not too bad. The hot flashes [occurred in] 16.1% [of patients], constipation in 9.7%, arthralgias in 9.7%, decreased appetite in 8.1%, diarrhea in 8.1%, nausea in 8.1%, and fatigue in 6.5%.

The interesting [aspect of] amcenestrant is that it has adverse effects [AEs] at all. Fulvestrant really has very few toxicities. It is generic, but it is administered via intramuscular injection, and people do not like [to receive] 2 large intramuscular injections in their buttocks monthly; that is a lot. [Amcenestrant] does have other AEs that make it a little different than other SERDs, such as fulvestrant. [The agent] avoids a surprising AE that we see with other members of this class, which is bradycardia; this does not commonly occur and it is grade 2 in many cases. However, the interesting thing about the bradycardia is the mechanism. Some people feel there are ERs on the heart and others believe there are ERs in the brainstem that control heart rhythm. It is really fascinating for us to try to figure out what those receptors may be.

What other research efforts are being made with amcenestrant?

AMEERA-3 [NCT04059484] will evaluate the monotherapy with a broad variety of agents [that will be] compared with amcenestrant. It is basically a randomized phase 2 trial [examining the agent] against physician’s choice with a primary end point of PFS.

Several SERDs from a variety of different companies are really differentiated at this point by their AE profile. These drugs are not as benign as fulvestrant, probably not as benign as AIs, but they have the opportunity to help us out. At the end of the day, if these drugs do show activity and superiority to the standard AIs, then there is going to be a large push to use them in the early setting. We are really going to see whether [these agents] prevent recurrence at higher levels than AIs, which are the current standard of care in postmenopausal women in the adjuvant setting. Several trials are at least being considered. Many of us want to wait to see what the data show in the first-line metastatic setting before [these agents] really take off, but there is a lot more excitement in the space than there was a few years ago.

Another SERD under exploration is enobosarm. What is the potential of this agent?

Some fascinating preclinical data were published in Nature Medicine about 2 months ago; it was a very sophisticated experiment that was done in ER-positive cancer cell lines. If those cell lines were androgen receptor [AR] positive, it turns out AR acts like a tumor suppressor. It would displace when androgen is bound to it such as testosterone, [or] in this case, enobosarm, [which is] a synthetic androgen agonist. When it bound to that, the AR would displace the ER from all these sites on the chromosome where there were AR response elements. ERs drive gene transcription. [Enobosarm demonstrated antitumor activity] in ER-targeted endocrine therapy resistant and CDK4/6 inhibitor resistant metastatic human breast cancer models. It was really interesting stuff.

That really suggests that we have maybe been thinking about this a little bit wrong. We thought that we should be using enzalutamide [Xtandi] or flutamide. These AR antagonists are very popular in prostate cancer, and many of us have tried for many years [to use them in breast cancer]. However, I recall [from older] data that 1 of the therapies that was very useful up until probably the 70s, or maybe even the 80s, was fluoxymesterone or testosterone. In a certain fraction of women, testosterone was used and would work. Now, we [see] all sorts of AEs, but on the other hand, I believe that this Nature Medicine study may actually provide some of the preclinical basis to use drugs, such as enobosarm.

We may now have another tool that we did not really consider, and even a biomarker. It is a whole other area of manipulation of the hormone axis that allows us to prolong the ability of women with ER-positive metastatic disease to live without having to [receive] chemotherapy—especially intravenous chemotherapy. If you can have a woman go 3 to 6 years without actually having to receive intravenous chemotherapy, that is a real benefit.

What is being done to overcome resistance to CDK4/6 inhibitors?

CDK4/6 resistance is really interesting. CDK2 inhibitors or pan-CDK inhibitors that will not only inhibit CDK4, but CDK2, are in development; that is one of the first rational [efforts] that we are trying to [make]. It turns out that when you examine circulating tumor DNA in people who have been on fulvestrant and palbociclib, you find a lot of FGFR amplification. People have tried FGFR inhibitors as another [way] to overcome resistance, but it turns out they are kind of toxic. We are now on the third or fourth generation of these [agents], and we’re trying to find one that really does not have [that] toxicity and allows us to test this hypothesis once and for all. We will get there. I am intrigued by the CDK2 inhibitors; we are going to be [learning more about this] later on.

Reference

1. Linden HM, Campone M, Bardia A, et al. A phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2–) metastatic breast cancer (mBC): AMEERA-1. Presented at: 2020 San Antonio Breast Cancer Symposium; December 8-11, 2020; Virtual. Abstract PD8-08.