The application of molecular profiling and personalization of therapy is as relevant in the management of metastatic breast cancer (mBC) as it is in most other aspects of daily oncology practice, a trio of phase 3 trials suggest.

Two of the trials shone a spotlight on 2 new agents — elacestrant and pyrotinib — with convincing benefits over commercially available competitors.

Data from the third trial — an investigation of trastuzumab deruxtecan (T-DXd) — will dictate a significant change in the treatment paradigm for patients with HER2-positive mBC. The “algorithmic shift” will have downstream effects on the use of other therapies.

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All 3 trials — EMERALD, PHOEBE, and DESTINY-Breast03 — were presented at the 2021 San Antonio Breast Cancer Symposium (SABCS).1-3

EMERALD Study: Elacestrant

EMERALD ( Identifier: NCT03778931) is an international phase 3 trial of elacestrant, an oral selective estrogen receptor degrader (SERD). EMERALD enrolled men and postmenopausal women with hormone receptor-positive (HR+), HER2-negative mBC. The patients must have received 1-2 prior lines of endocrine therapy (1 with a CDK4/6 inhibitor) and 1 or fewer lines of chemotherapy for advanced disease.

The patients were randomized to receive elacestrant at 400 mg orally daily (n=239) or standard endocrine therapy (n=238). Patients in the standard of care (SOC) arm could receive either an oral aromatase inhibitor or intramuscular fulvestrant, per physician choice. About 70% of SOC patients received fulvestrant. Patients were stratified for ESR1 mutation (mESR1) status, visceral metastases, and prior fulvestrant exposure.

The study’s results were presented at SABCS 2021 by Aditya Bardia, MD, of Mass General Cancer Center in Boston.1 Dr Bardia reported a 30% reduction in the risk of progression or death with elacestrant in all patients (hazard ratio [HR], 0.697; 95% CI, 0.552-0.88; P =.0018) and a 45% reduction in patients with mESR1 (HR, 0.546; 95% CI, 0.387-0.768; P =.0005).

For the entire cohort, the progression-free survival (PFS) rate at 12 months was 22.3% with elacestrant and 9.4% with SOC. In the mESR1 subgroup, PFS at 12 months was 26.8% with elacestrant and 8.2% for SOC.

Results in key prespecified subgroups, including patients with visceral metastases, number of prior lines of therapy, pretreatment with fulvestrant, and geographical region, were consistent with the overall outcome.

The prespecified interim overall survival (OS) analysis showed a trend in favor of elacestrant. The final OS analysis is expected this year.

Treatment-emergent adverse events (AEs) occurring in at least 10% of patients (with elacestrant and SOC, respectively) included nausea (35% vs 18.8%), vomiting (19% vs 8.3%), and fatigue (19% vs 18.8%). Most of these events were grade 1-2. There were no treatment-related deaths.

The investigators concluded that, with an acceptable toxicity profile, elacestrant demonstrated a clinically meaningful improvement in PFS over second- or third-line SOC endocrine therapy. Elacestrant particularly benefited patients whose tumors harbored mESR1 after progression on endocrine therapy plus a CDK 4/6 inhibitor.

Implications and Future Directions

As a potent oral SERD, elacestrant could be the first of a significant new class of drugs for patients whose tumors are HER2- and HR+. The oral SERDs would offer convenience and access for patients with practical challenges (geographic, socioeconomic, etc.) that make it difficult to attend frequent office visits for parenteral treatment.

Elacestrant produced a statistically and clinically meaningful increase in PFS for all HR+ patients with prior exposure to endocrine therapy plus CDK 4/6 inhibitors for mBC. The benefit of elacestrant extended to patients with prior fulvestrant treatment and those with mESR1.

In the EMERALD trial, premenopausal patients were excluded. Future studies in premenopausal women will define whether they too can benefit from oral SERDs.

Additional research will ascertain the magnitude of impact of oral SERDs in patients who lack mESR1. It is likely to be lower than noted in the mESR1 subgroup in the EMERALD study.