SERDs, ESR1 Mutations Dominate Updates in ER-Positive Breast Cancer

Sara A. Hurvitz, MD, FACP

Emerging approaches for overcoming resistance to endocrine therapy in patients with estrogen receptor (ER)-positive breast cancer are showing promise, according to recent clinical trial findings. For example, the development of several novel selective estrogen receptor degraders (SERDs) have demonstrated an expanding role for this patient population in combination and as monotherapy. Unpacking the role of detection and early intervention against ESR1 mutations also has sparked progress in tailoring treatment regimens leveraging the genomic data.

In a recent OncLive The Talk^™ video program, Sara A. Hurvitz, MD, FACP, led a panel of breast cancer experts—Aditya Bardia, MD, MPH; Patrick Neven, MD, PhD; and Kevin Kalinsky, MD, MS—in a review of key data from the 2021 San Antonio Breast Cancer Symposium (SABCS). The program featured updates from several trials including the following:

• AMEERA-1 (NCT03284957): a phase 1/2 study of amcenestrant in postmenopausal patients with ER-positive advanced breast cancer¹;
• EMERALD (NCT03778931): a phase 3 study of elacestrant vs standard of care for patients with ER-positive, HER2-negative advanced breast cancer²;
• First-in-human study (NCT04072952): a phase 1/2 trial of ARV-471 alone and in combination with palbociclib (Ibrance) in patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer³; and
• PADA-1 (NCT03079011): a phase 3 clinical utility trial evaluating clinical benefit outcomes for patients who switch from treatment with an aromatase inhibitor plus palbociclib to fulvestrant plus palbociclib following detection of rising ESR1 mutations.⁴

For more information on the trials and the outcomes, see TABLES 1-4.^1-4

Updates from 2021 SABCS in ER-Positive Breast Cancer

Hurvitz: Some interesting data were presented [at 2021 SABCS] regarding SERDs, a new class of medications to treat ER-positive breast cancer. The first poster I want to go through relates to the updated data from AMEERA-1 looking at amcenestrant.

Kalinsky: [Investigators presented a] readout with updated data for amcenestrant, an oral SERD, in combination with the CDK4/6 inhibitor palbociclib. All patients in this particular study were endocrine resistant. Approximately[25%] of patients had prior chemotherapy in the advanced setting [and approximately] one-third were getting frontline therapy. The big picture [takeaway] is that amcenestrant was a well-tolerated agent. There were some [reports of] low-grade nausea and fatigue and some hot flashes that might have been attributed to the SERD.

The dose was 200 mg with the approved dose of palbociclib [125 mg once daily], and investigators saw an [objective] response rate of [34.2%] and clinical benefit rate of [73.5%] [TABLE 1¹].

The other thing that was notable in the abstract was a clearance of ESR1 mutations, which included Y537S, which is a mutation that [is] resistant to the only approved SERD, which is fulvestrant.

These are some interesting data that have implications including in their ongoing studies in the phase 3 setting, such as in AMEERA-5 [NCT04478266], which is a frontline study comparing an AI [aromatase inhibitor] plus a CDK4/6 inhibitor vs this oral SERD plus a CDK4/6 inhibitor, specifically the CDK4/6 inhibitor palbociclib. We’ll see what the activity is for that in the frontline setting.

We’re all eagerly awaiting randomized data from AMEERA-3 [NCT04059484], which was a study of amcenestrant in pretreated patients vs physician-choice hormonal therapy. [There is] more to come with this agent, including ongoing studies in the operable setting that are ongoing at this time.

Hurvitz: Very interesting data. What do you think of that objective response rate in this setting? A [rate of approximately one-third] is generous, but as you said, a fair number of the patients were [receiving amcenestrant] in the frontline setting. Do you think that the clinical benefit rate and objective response rate you saw were promising enough to support enrollment of these trials?

Kalinsky: Yes, I think so. Sometimes when you have such a heterogeneous group and you have patients including those who are getting a SERD in the second line or the third line, those response rates are not as robust and the degree of clinical benefit is not quite the same. [The data are] hard to interpret when it’s such a heterogeneous population, but amcenestrant is certainly a well-tolerated agent.

Seeing this clinical benefit rate really does make it seem promising in terms of the responses. I think this is why these randomized data are going to be so important—they’ll be in a specific setting. Looking at the combination of palbociclib with this drug in a frontline setting in a randomized study, that’s what’s really going to tell the story. It is certainly interesting and worthy of further evaluation.

Hurvitz: And speaking of randomized data, Dr Bardia, you presented some big data at SABCS on elacestrant from the EMERALD study. Can you please go through your data and share with us what that study ended up showing?

Bardia: Yes, absolutely. The EMERALD trial was a randomized phase 3 clinical trial looking at a novel oral SERD, elacestrant, vs endocrine therapy of physician’s choice as second- or third-line therapy for patients with ER-positive metastatic breast cancer. In the frontline setting we tend to use endocrine therapy plus a CDK4/6 inhibitor. The trial answered the question what to do after that in the second-line and third-line settings.

Patients were required to have disease progression following frontline treatment with a CDK4/6 inhibitor plus endocrine therapy. Investigators randomized [patients] to elacestrant vs endocrine therapy or physician’s choice therapy, which could either be an AI or fulvestrant. The study had coprimary end points of progression-free survival [PFS] in all patients and PFS in patients with ESR1 mutations, [which] confer resistance to AI, but not necessarily SERDs.

More than 450 patients were enrolled and randomized 1:1 to either standard of care or oral elacestrant. In terms of the results, the study met both its primary end points in all patients as well as patients with ESR1 mutations [TABLE 2²]. Among all patients there was a reduced risk of disease progression or death [with elacestrant], or in other words improvement in PFS [HR, 0.697] in the overall population. In patients with ESR1 mutations, the signal was stronger with a hazard ratio of 0.55.

Looking at the curves, there was an interesting trend that was seen, which was that there was a sharp decline early on in both arms. You could see a separation in the curves. The initial decline was likely due to endocrine resistance because the trial was looking at 2 different endocrine options as monotherapy. Patients who had endocrine-resistant disease just had disease progression. But then you could see a separation in the curve suggesting that in the endocrine-sensitive population, a better endocrine therapy is likely going to work better.

We looked at landmark analysis at 6 months and 12 months to really capture this point. And at 6 months the PFS rate was much higher with elacestrant than standard of care, and similarly at 12 months was much higher. At 12 months it was approximately 20% with elacestrant vs less than 10% with standard-of-care endocrine therapy.

In terms of adverse effects [AEs], the No. 1 AE was nausea. It’s an oral pill, so nausea was seen with this medication. But other than that, hot flashes, arthralgias were pretty much similar. Finally, in terms of overall survival [OS], at interim analysis there was a trend in favor of elacestrant vs standard-of-care endocrine therapy. But these data are not mature. In approximately a year or so we’ll have mature data to do final OS analysis.

Dr Neven is a coauthor on the abstract and upcoming manuscript as well [and] our take was that this study provides the first proof of principle, scientific proof of principle that elacestrant might be superior to standard endocrine therapies and is good news for the field in terms of additional development.

In the later-line setting, we probably still need combination therapy. Single-agent treatment is not enough to result in robust PFS outcomes. But if you are looking at single-agent endocrine therapy, the adjuvant setting would be the best setting to evaluate 2 endocrine monotherapy agents.

Hurvitz: Very important proof-of-principle, phase 3 data, the first phase 3 randomized data to support the use of one of these oral SERDs. At last count I think we have approximately 8 ER degraders and blockers that are in development. It’s great to finally have these data in spite of the fact that [they] really do underscore the poor prognosis associated with heavily pretreated disease. That PFS is quite short in both arms, but [it is] great to see that elacestrant was better.

I want to turn now to another novel agent that blocks or degrades the ER. Using PROTAC [proteolysis targeting chimera] technology, there was a study looking at ARV-471. Dr Neven, can you take us through that data and explain to us a little bit about how this agent works?

Neven: There was a poster [presented at 2021 SABCS] on this new compound, and for me it seems to be really an ER degrader, as you said. It’s a small molecule targeting the ER. It indeed belongs to the PROTACs or virtualizes targeting chimera. It’s a novel class of drugs containing 3 chemical elements—a target protein-binding ligand, the E3 ubiquitin ligase-binding ligand, and a conjugate linker.

When these 3 elements bind, they take the advantage of the endogenous ubiquitin proteasome system leading, in this case, to the degradation of the estrogen receptors. In these estrogen receptors, it not only inhibits the classically regulated ER target genes, but also self-proliferation in case of ESR1 mutations such as Y537S and D538G. There does not appear to be any agonistic activity in the uterus.

The poster was on a xenograft model where they have found more robust tumor growth inhibition and ER α degradation compared with fulvestrant. The combination of ARV-471 with palbociclib in the same model resulted in a significant tumor regression and overall superior antitumor activity when compared with fulvestrant and palbociclib.

Dr Hurvitz, you were the senior author, and the poster discussion was presented by Erica Hamilton, MD. [Results were from] a multicenter f irst-in-human, open-label, phase 1, 3 + 3 dose escalation study with dosing from 30 mg to 700 mg, assessing ARV-471 in 60 patients with metastatic ER-positive HER2-negative disease, 47 of whom had evaluable disease. Investigators included pre- and postmenopausal women [and] assessed safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity.

Patients who were heavily pretreated all had prior CDK4/6 inhibitors, 80% had prior fulvestrant, and 80% had prior chemotherapy. The compound does not seem to be related to highgrade toxicity. In terms of efficacy, investigators reported an impressive clinical benefit rate of 40% [TABLE 3³]. Among the 47 patients with evaluable disease, 2 patients had a partial response [lasting at least 24 weeks]. Responses were observed in patients pretreated with CDK4/6 inhibitors and fulvestrant.

ARV-471 is now being taken further in phase 2 studies and a phase 1b study with palbociclib.⁵ This reminds me of my first experience with CDK4/6 inhibitors in 2013, with abemaciclib [Verzenio] in MONARCH 1 [NCT02102490]. It’s impressive.

Hurvitz: Thank you so much for that great description, [and] I think it is notable in this heavily pretreated patient population.

The VERONICA study [NCT03584009] looking at venetoclax [Venclexta] with fulvestrant [in patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer who experienced disease recurrence or progression during or after a CDK4/6 inhibitor] only yielded a clinical benefit rate of approximately 14% [with fulvestrant and 11.8% with the combination].⁶ Although 40% [with ARV-471] doesn’t sound great, when you look at the post CDK4/6-inhibitor setting, it is sort of notable that this drug is associated with this early evidence of activity.

I want to move now to an earlier-line setting, because we know there are a number of mechanisms of resistance to disease to therapeutics developed for ER-positive metastatic breast cancer, one of these being the acquisition of ESR1 mutations. The PADA-1 study was designed to look at switching patients from AI with palbociclib to fulvestrant plus palbociclib if there was a detection in a rise in ESR1 ctDNA [circulating tumor DNA] without evidence of progression.⁴

A very interesting trial design. Dr Bardia, can you take us through this study design and the early data presented at SABCS regarding PADA-1?

Bardia: PADA-1 was an interesting trial. It is a hybrid first/second-line or 1.5-line [setting] because the trial essentially enrolled patients who were on first-line therapy with an AI plus CDK4/6 inhibitor. Investigators monitored ctDNA in these patients, and if a patient had a rise in ctDNA during the treatment with AI plus CDK4/6, they were randomized to continue the same treatment or make an early switch to a SERD or fulvestrant. Patients could continue palbociclib.

Essentially it was asking the question: If there’s a rise in ctDNA, which could be suggestive of eventually disease progression, would making an early switch to a different endocrine backbone result in better outcomes? It was an interesting proof-of-principle trial. The team enrolled more than 1000 patients—1017 to be exact.

Among the 1017 patients, 172 had a rise in ctDNA and were randomized to receive AI plus palbociclib vs fulvestrant plus palbociclib [TABLE 4^4,7]. You had to screen a large number of patients to identify this group. The group of patients who switched from the endocrine backbone to receive fulvestrant plus palbociclib had better outcomes. The median PFS was 11.9 months compared with 5.7 in patients who had continued the same regimen of AI plus palbociclib.

These data provided a scientific proof of principle that if you switch therapy based on ctDNA levels, that could result at least in improvement in PFS. The criticism of the study has been that we don’t know whether this early switch would eventually affect overall survival. Additional follow-up is needed. But scientifically, these data provide a nice concept where you can monitor ctDNA and act on it to make a change in therapy.

Hurvitz: Interesting as well that they required a rise in ESR1 mutations and not just the presence of detectable ESR1 mutation. I think a lot of investigators are taking note of these data as they design other studies looking at the use of SERDs in this type of setting.

Kalinsky: I thought that this was a really interesting investigator-initiated study. And I wanted to highlight that there’s an ongoing study, a randomized global study that’s looking at this question with SERENA-6 [NCT04964934] with an oral SERD [camizestrant; AZD9833] for patients who have received an AI and a CDK4/6 inhibitor, in this case palbociclib or abemaciclib. If ESR1 mutations are detected, patients are randomized to continue on that vs switching to camizestrant plus a CDK4/6 inhibitor. Investigators are including a second PFS population, as well, to look at the total duration [of response]. [This will let us] see how an oral SERD plays out in a larger study.

Hurvitz: That’s interesting [that] investigators are using detection of ESR1 mutations in that setting and not the rise in it. It may be easier to enroll actually because you’re not waiting for a rise.

Neven: I think we could take it a step further. If you have a patient with a very long disease-free interval, luminal-A–like metastatic disease, why not give single-agent endocrine treatment and look for ESR1 mutation and then add the CDK4/6 inhibitor?

Hurvitz: There are so many questions that are begged. Every time we see data [such as] these coming from an elegantly designed trial, they generate a number of new questions and new ways for us to design trials going forward. I love it.

References

1. Chandarlapaty S, Linden HM, Neven P, et al. Updated data from AMEERA-1: phase 1/2 study of amcenestrant (SAR439859), an oral selective estrogen receptor (ER) degrader (SERD), combined with palbociclib in postmenopausal women with ER+/HER2- advanced breast cancer. Cancer Res. 2022;82(suppl 4):P1-17-11. doi:10.1158/1538-7445.SABCS21-P1-17-11
2. Bardia A, Neven P, Streich G, et al. Elacestrant, an oral selective estrogen receptor degrader (SERD) vs investigator’s choice of endocrine monotherapy for ER+/HER2- advanced/metastatic breast cancer (mBC) following progression on prior endocrine and CDK4/6 inhibitor therapy: results of EMERALD phase III trial. Cancer Res. 2022;82(suppl 4):GS2-02. doi:10.1158/1538-7445.SABCS21-GS2-02
3. Hamilton E, Vahdat L, Han HS, et al. First-in-human safety and activity of ARV-471, a novel PROTAC estrogen receptor degrader, in ER+/HER2- locally advanced or metastatic breast cancer. Cancer Res. 2022;82(suppl 4):PD13-08. doi:10.1158/1538-7445.SABCS21PD13-08
4. Delaloge S, Hardy-Bessard AC, Bachelot T, et al. First line aromatase inhibitor (AI) + palbociclib with randomized switch to fulvestrant + palbociclib upon detection of circulating ESR1 mutation in HR+ HER2- metastatic breast cancer patients: global safety results of PADA-1, a UCBG-GINECO phase III trial. Cancer Res. 2022;82(suppl 4):P1-18-16. doi:10.1158/1538-7445.SABCS21-P1-18-16
5. Arvinas and Pfizer announce PROTAC protein degrader ARV-471 continues to demonstrate encouraging clinical benefit rate in patients with locally advanced or metastatic ER+/HER2- breast cancer. News release. Pfizer. December 10, 2021. Accessed March 6, 2022. bit.ly/3IZCdun
6. Lindeman GJ, Bowen R, Jerzak KJ, et al. Results from VERONICA: a randomized, phase II study of second-/third-line venetoclax (VEN) + fulvestrant (F) versus F alone in estrogen receptor (ER)-positive, HER2-negative, locally advanced, or metastatic breast cancer (LA/MBC). J Clin Oncol. 2021;39(suppl 15):1004. doi:10.1200/ JCO.2021.39.15_suppl.1004
7. Bidard FC, Hardy-Bessard AC, Bachelot T, et al. Fulvestrant-palbociclib vs continuing aromatase inhibitor-palbociclib upon detection of circulating ESR1 mutation in HR+ HER2- metastatic breast cancer patients: results of PADA-1, a UCBG-GINECO randomized phase 3 trial. Cancer Res. 2022;82(suppl 4):GS3-05. doi:10.1158/15387445.SABCS21-GS3-05