EMERALD: elacestrant superior to S.O.C. for patients with ER+ HER2- metastatic breast cancer

The EMERALD trial, presented by Aditya Bardia, MD, MPH, of Massachusetts General Hospital, in Boston, MA, was a hot topic of discussion at the San Antonio Breast Cancer Symposium (SABCS) 2021. The Phase III trial (NCT03778931) was a randomized, open-label, global study, involving 477 patients with estrogen receptor-positive (ER+) HER2-negative (HER2-) metastatic breast cancer, 228 of whom had an ESR1 mutation. Patients with an ESR1 mutation often develop resistance to aromatase inhibitors, which are used for estrogen deprivation therapy.

The trial investigated the use of elacestrant, a novel oral selective estrogen receptor degrader (SERD) in the second- or third-line setting, compared to standard of care (SOC) endocrine therapy, either fulvestrant or an aromatase inhibitor. This was the first randomized Phase III trial to investigate the use of an oral SERD to treat breast cancer. Currently, fulvestrant is the only SERD approved for use (in the USA and Europe) in patients with advanced HR+ breast cancer and was only approved as a first-line therapy recently, in 2017. 1   Unlike fulvestrant, elacestrant is an oral drug.

The co-primary endpoints of the study were progression-free survival (PFS) in the overall population and PFS in patients with mutant ESR1.

The reported results of the trial were promising, with a 30% reduction in risk of progression or death in the overall population, compared to SOC. In patients with an ESR1 mutation, this reduction in risk rose to 45%. 22.3% of patients in the elacestrant arm achieved 12-month PFS, compared to 9.4% of patients in the SOC arm. Again, patients with ESR1 mutations achieved even better results, with 26.8% achieving 12-month PFS on elacestrant, compared to 8.2% on SOC. Additionally, although final overall survival (OS) results have not yet been reported, there was a trend towards improved OS in patients who received elacestrant, compared to SOC.


The most commonly experienced adverse event was nausea, which was more severe in patients receiving elacestrant (25.3%) than those receiving SOC (8.7%). 7.2% of patients receiving elacestrant experienced adverse events that were grade 3 or higher, compared to 3.1% receiving SOC.

EMERALD tackles a current unmet clinical need for effective endocrine therapies for patients with ER+ HER2- metastatic breast cancer. The results of the study indicate that elacestrant achieves better PFS than SOC endocrine therapy of fulvestrant or aromatase inhibitors, especially in patients with ESR1-mutated breast cancer.

12-year follow-up of SOFT and TEXT trials


The randomised, Phase III SOFT (NCT00066690) and TEXT (NCT00066703) trials investigated the use of adjuvant endocrine therapy combined with ovarian function suppression (OFS) in pre-menopausal women with hormone receptor-positive (HR+) breast cancer. The results from the 12-year follow-up analysis of the two trials were presented at SABCS 2021 by Meredith M. Regan, ScD, of Harvard Medical School in Boston, MA.



Over 5700 women were enrolled across the two trials. In SOFT, patients were randomised to receive either tamoxifen alone, or tamoxifen/exemestane plus OFS. In TEXT, all patients received OFS (via triptorelin) and were randomised to also receive either tamoxifen or exemestane. Patients in both trials received treatment for 5 years.

The 12-year follow-up results show that those who underwent OFS in combination with either tamoxifen or exemestane achieved a persistent, long-term reduction in risk of distant recurrence (progression-free survival). This reduction was greatest in patients receiving exemestane. The use of OFS was also reported to reduce the risk of death in the long-term.

The long follow-up period of these trials has allowed more reassurance that the use of tamoxifen/exemestane plus OFS is an effective and safe treatment plan for young women with HR+ breast cancer.

KEYNOTE-522: EFS sensitivity & subgroup analyses


The randomized, Phase III, placebo-controlled KEYNOTE-522 trial (NCT03036488) investigated the use of neoadjuvant pembrolizumab in combination with chemotherapy, followed by adjuvant pembrolizumab, for patients with early-stage triple-negative breast cancer (TNBC). An update on event-free survival (EFS), along with subgroup analyses, was presented at SABCS 2021 by Peter Schmid, MD, PhD, FRCP, of Barts Cancer Institute in London, UK.

1174 patients with untreated stage II/III TNBC were randomized 2:1 to either chemotherapy plus pembrolizumab or chemotherapy plus placebo. The co-primary endpoints of the trial were pathological complete response and EFS.

After a median follow-up of 39 months, results from the trial have shown that the addition of pembrolizumab to chemotherapy significantly improves both primary endpoints. In terms of EFS, 16% of patients in the pembrolizumab arm experienced disease events, compared to 24% of patients in the placebo arm. The subgroup analyses presented at SABCS 2021 showed a consistent benefit of pembrolizumab across all subgroups.



This trial was the first randomized Phase III trial to investigate the use of immunotherapy for patients with early TNBC. Given the difficulty of successfully treating patients with TNBC in comparison to other types of breast cancer, these are promising results which encourage further research into the use of immunotherapy for these patients.

DEBBRAH: T-DXd in HER2+ or HER2-low advanced breast cancer with CNS involvement


First results from the international Phase II DEBBRAH trial (NCT04420598), were presented at SABCS 2021 by Marta Vaz Batista, MD, of Hospital Professor Doutor Fernando Fonseca in Amadora, Portugal.

The trial evaluated the use of trastuzumab deruxtecan (T-DXd) in patients with HER2-positive (HER2+) or HER2-low expressing advanced breast cancer plus central nervous system (CNS) involvement (brain metastases or leptomeningeal carcinomatosis). Last year, the DESTINY-Breast03 trial reported practice-changing progression-free survival (PFS) results when it compared the use of T-DXd to trastuzumab emtansine (T-DM1) for HER2+ metastatic breast cancer, which has led to a lot of excitement about the use of this antibody-drug conjugate. 2 The DEBBRAH trial is building on these results by looking into the use of T-DXd for patients with HER2+ breast cancer who have developed brain metastates, which is a great unmet clinical need.



Of the 5 cohorts enrolled in the study, findings from cohort 1 and 3 were presented at the meeting. Cohort 1 consisted of patients with HER2+ breast cancer who had no disease progression after local therapy, and cohort 3 consisted of patients with HER2+ breast cancer who had experienced disease progression after local therapy.

The primary endpoint for cohort 1 was reached, with 7 out of 8 patients achieving progression free survival (PFS) after 16 weeks. The primary endpoint for cohort 3 was central nervous system overall response rate (ORR), which was 44.4%.

The early results from this trial indicate that T-DXd has a tolerable safety profile in this patient population. The majority of grade 3 and 4 side effects were fatigue and neutropenia and only 1 patient experienced pneumonitis (a key concern of using T-DXd) which was successfully treated.

Despite the short follow-up period, the early results of the DEBBRAH trial indicate that T-DXd could become an effective treatment for pre-treated patients with advanced HER2+ breast cancer who have stable/progressing brain metastases.

Written by Helena Gibbon

Edited by Sol Yohannes


  1. Wang G. Fulvestrant as a reference antiestrogen and estrogen receptor (ER) degrader in preclinical studies: treatment dosage, efficacy, and implications on development of new ER-targeting agents. Translational Cancer Research. 2020 Aug;9(8):4464.
  2. Cortes J. DESTINY-Breast03: T-DXd is superior to T-DM1 in HER2+ metastatic breast cancer. VJOncology.com. 2021 [cited 27th January 2022]. Available from: https://www.vjoncology.com/video/5d8jlhi6iai-destiny-breast03-t-dxd-is-superior-to-t-dm1-in-her2-metastatic-breast-cancer/

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