FDA Approves Oral SERD Elacestrant for ESR1-Mutant ER+, HER2– Metastatic Breast Cancer

The FDA has granted an accelerated approval to elacestrant (Orserdu) for the treatment of patients with estrogen receptor–positive, HER2-negative advanced or metastatic breast cancer following at least 1 prior lines of endocrine therapy. The approval is supported by data from the phase 3 EMERALD study (NCT03778931).¹

The investigational oral selective estrogen receptor degrader (SERD) was evaluated among patients with ESR1-mutant disease (n = 115) vs standard-of-care (SOC) endocrine therapy (n = 113) of either fulvestrant or an aromatase inhibitor. The median progression-free survival was 3.8 months (95% CI, 2.2-7.3) vs 1.9 months (95% CI, 1.9-2.1) with the SERD and SOC, respectively (HR, 0.55; 95% CI, 0.39-0.77; P = .0005).² The overall survival outcomes were not statically significant (HR, 0.90; 95% CI, 0.63-1.30).²

An exploratory analysis of patients without ESR1-mutant disease reported a 14% reduction in the risk of disease progression of death with elacestrant, indicating that improvements in the overall population were attributed to the ESR1-mutant population on study.^1,2

The label comes with a warning for dyslipidemia and embryo-fetal toxicity and patients should be advised to avoid breast feeding when taking elacestrant. Additionally, those with severe hepatic impairment of Child-Pugh C should avoid the SERD, whereas those with Child-Pugh B disease should receive a reduced dose.

The most common reported all-grade adverse events (AEs) with elacestrant included musculoskeletal pain (41%), nausea (35%), fatigue (26%), vomiting (19%), decreased appetite (15%), diarrhea (13%), headache (12%), abdominal pain (11%), and hot flush (11%). In terms of all-grade laboratory abnormalities, cholesterol increase (30%), aspartate aminotransferase increase (29%), triglycerides increase (27%), and hemoglobin decrease (26%) were the most common. The most common grade 3 event was musculoskeletal pain (7%).

The agent is administered as a once daily 345 mg tablet, taken whole not chewed, crushed, or split prior to swallowing with food, and should be administered at approximately the same time each day.²

Fatal AEs occurred in 1.7% of patients and included cardiac arrest, septic shock, and diverticulitis occurring in 1 patient each. An additional patient died of unknown cause. A total of 6% of patients discontinued elacestrant due to and AE with most attributed to musculoskeletal pain (1.7%) and nausea (1.3%). Dose interruptions were reported in 15% of patients, the most common causes being nausea (3.4%), musculoskeletal pain (1.7%), and increased alanine transaminase (1.3%).

Results presented during the 2022 SABCS showed that the duration of prior CDK4/6 inhibition played a role for patients who received elacestrant. Among those with ESR1-mutant disease who received at least 12 months of CDK4/6 inhibition (n = 78), the median PFS was 8.61 months vs 1.91 months with SOC (n = 81; HR, 0.410; 95% CI, 0.262-0.634). The 6-, 12-, and 18-month PFS rates were 55.81%, 35.81%, and 28.49% with elacestrant vs 22.66%, 8.39%, and 0% with SOC.³

For those who received at least 6 months of CDK4/6 inhibition, the median PFS with elacestrant (n = 103) was 4.14 months vs 1.87 months with SOC (n = 102; HR, 0.517; 95% CI, 0.361-0.738). The 6-, 12-, and 18-month PFS rates were 42.43% vs 19.15%, 26.02% vs 6.45%, and 20.70% vs 0%, respectively.³

In addition to the accelerated approval, the FDA also approved the Guardant360 CDx assay as a companion diagnostic device to identify patients with ESR1-mutantbreast cancer for treatment with elacestrant.¹

References

1. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. January 27, 2023. Accessed January 27, 2023. bit.ly/3Hbxxln
2. Orserdu. Prescribing information. Stemline Therapeutics Inc; 2023. Accessed January 27, 2023. bit.ly/40kf8Ma
3. Bardia A, Bidard FC, Neven P, et al. EMERALD phase 3 trial of elacestrant versus standard of care endocrine therapy in patients with ER+/HER2- metastatic breast cancer: updated results by duration of prior CDK4/6i in metastatic setting. Presented at 2022 San Antonio Breast Cancer Symposium; December 6-10, 2022; San Antonio, TX.