Highlights From the 2021 SABCS Symposium

Phase III EMERALD: Elacestrant vs Standard of Care in ER+/HER2- MBC

Joyce O’Shaughnessy, MD:
The first study we will review from SABCS 2021 focuses on elacestrant, an oral SERD. The EMERALD trial is the first phase III oral SERD data for patients with hormone receptor–positive, HER2‑negative MBC who received a CDK4/6 inhibitor in the metastatic setting.¹ Patients had to have progressed after 1 or 2 lines of therapy including a CDK4/6 inhibitor and ≤1 line of chemotherapy. Patients were randomized to receive either elacestrant (n = 239) or physician’s choice of an aromatase inhibitor (AI) or fulvestrant (n = 238). Coprimary endpoints were PFS in all patients and PFS in patients with an ESR1 mutation.

EMERALD: Baseline Characteristics

Joyce O’Shaughnessy, MD:
Focusing on baseline characteristics, everyone received a CDK4/6 inhibitor, and the majority of patients had not received prior chemotherapy. So, it was mainly an ET-pretreated population.

EMERALD: PFS by BICR (Primary Endpoints)

Joyce O’Shaughnessy, MD:
The EMERALD trial met both coprimary endpoints with statistically significant results. The median PFS of the overall population improved from 1.91 months with ET to 2.79 months with elacestrant (HR: 0.697; 95% CI: 0.552-0.880). The PFS for patients with an ESR1 mutation improved from 1.87 months to 3.78 months (HR: 0.546; 95% CI: 0.387-0.768).

I think the most interesting result is the tail on the curve, the percentage of patients who were progression free at 6 and 12 months. This is a noteworthy difference. Patients with ESR1 mutations are less sensitive to ET than those with wild-type ER. With elacestrant, the percentage of patients with ESR1 mutations who were progression free at 12 months tripled to 27% vs 8% with ET. To me, that is the real value and it is great to see elacestrant as a treatment option for these patients with a difficult-to-treat ESR1 mutation. This is a group where we rarely use a single‑agent endocrine treatment but elacestrant could be an option.

Sara Tolaney, MD, MPH:
In my opinion, these median PFS values are not impressive and suggest that the post-CDK4/6 control arm did not do well. A PFS of approximately 2 months is not good, and this is consistent with other studies. The VERONICA study also showed weak PFS results in the control arm for fulvestrant in a post-CDK4/6 setting; the data are consistent.²

EMERALD: Additional Survival Outcomes

Joyce O’Shaughnessy, MD:
These early results show an interesting trend emerging in OS. The HR for survival for all patients was 0.75 (95% CI: 0.542-1.038; P = .08) and was not statistically significant. However, for those with an ESR1 mutation, the HR was 0.59 (95% CI: 0.361-0.958; P = .03). This suggests that elacestrant may have a survival advantage for patients with an ESR1 mutation.

EMERALD: Safety

Joyce O’Shaughnessy, MD:
The safety data were excellent; the treatment arm was minimally different from the control arm. Only 3.4% of patients discontinued the elacestrant because of toxicity. There were slightly more incidents of nausea and vomiting with the elacestrant—a very minimal increase and largely at the grade 1/2 level. More fatigue was reported, but not appreciably different from the standard of care.

EMERALD: Conclusions

Joyce O’Shaughnessy, MD:
In summary, I think this is an excellent proof of concept. I believe this will be the first treatment available directed to the ESR1‑mutant population. The big issue is determining which patients with the ESR1 mutation are benefiting from this single‑agent approach, because there are several combination strategies for ET in the metastatic setting.

Sara Tolaney, MD, MPH:
Certainly, this was an interesting study. It suggests that we might be able to add to our armamentarium a single‑agent oral therapy that is tolerated well and does better than single‑agent ET. Currently, we have moved toward using combination therapy post-CDK4/6 therapy. The challenge is how to use a single‑agent SERD in a post-CDK4/6 setting where, even in the ESR1‑mutant population, the median PFS is under 4 months.

This study confirms that some patients in this population have a very prolonged PFS. Can we identify them? Most of us are using fulvestrant with alpelisib for patients with a PIK3CA mutation or fulvestrant plus everolimus in this setting. I would love to see data for elacestrant plus alpelisib or everolimus. But it is hard to determine who should receive monotherapy. For example, I would consider monotherapy for a patient with minimal visceral metastases and very endocrine‑sensitive disease who has had a long-duration response to CDK4/6. But those are just clinical characteristics and do not help us tease out a profile of patients who had prolonged benefit on elacestrant. I think we need to move toward treatment combinations in a post-CDK4/6 setting.

Joyce O’Shaughnessy, MD:
A majority of the patients in this study had fulvestrant as the control-arm agent, and it is nice to see that elacestrant had better results than fulvestrant. This gives us hope for the adjuvant setting too. I agree that we need to look at patients with ET‑sensitive disease, and we should consider trying an oral SERD to minimize the toxicity from combinations.

AMEERA-1: Amcenestrant Plus Palbociclib in ER+/HER2- Advanced Breast Cancer

Sara Tolaney, MD, MPH:
Other oral SERDs are also in development, and efficacy and safety data from the AMEERA-1 trial of amcenestrant plus palbociclib in ER-positive, HER2-negative breast cancer were updated at SABCS 2021.³ This open-label phase I/II study enrolled postmenopausal women with ER-positive, HER2-negative advanced breast cancer who relapsed or progressed on ET (n = 44). Patients received amcenestrant (200 mg or 400 mg QD) plus palbociclib (125 mg, Days 1-21 of 28-day cycle).

AMEERA-1: Baseline Characteristics

Sara Tolaney, MD, MPH:
The heterogeneity of the enrolled patients is shown in the baseline characteristics. Some patients were treatment-naive but others had received previous ET and chemotherapy. Two patients had previous CDK4/6 therapy. This heterogeneity made interpreting the data a challenge.

AMEERA-1: Efficacy

Sara Tolaney, MD, MPH:
Despite a small, heterogeneous sample, the PFS was promising with a median of almost 15 months and a 12-month PFS of approximately 60%. This suggests the combination could be effective.

AMEERA-1: Safety

Sara Tolaney, MD, MPH:
Earlier results for amcenestrant monotherapy demonstrated that it is well tolerated, with minimal toxicity,⁴ and the updated results here concur. The combination of SERD with CDK4/6 was tolerated well, with minimal toxicity (mostly grade 1/2) and no grade ≥3 toxicities.

AMEERA-1: Conclusions

Sara Tolaney, MD, MPH:
This study confirmed antitumor activity and safety with this combination. It is already in phase III development in combination with the CDK4/6 inhibitor palbociclib in the first‑line setting (AMEERA-5) (NCT04478266).AMEERA‑3 compares amcenestrant to ET of choice in a predominantly post-CDK4/6 setting (NCT04059484).It has completed enrollment, and we await those data. An oral SERD option is welcome as fulvestrant is a challenge for some patients.

There are now several SERDs in development. Dr. O’Shaughnessy, do you think there are any differentiating factors among them, and do you think they are ready to move into the adjuvant space?

Joyce O’Shaughnessy, MD:
I, too, was impressed by the median PFS in AMEERA-1. Most of the patients had already received chemotherapy, with 60% in the metastatic setting, and a small number had had a CDK4/6 inhibitor. It was not a first‑line population. Despite the small number of patients, the 14.7‑month median PFS was solid. The safety of these therapies is important because most will be used in combination in the curative setting. I think the safety and the ability to combine are critical. I think oral SERDs hold great promise.