Elacestrant, a product of Menarini Group received Priority Review designation from FDA and acceptance of Marketing Authorization Application for ER+/HER2- advanced or metastatic breast cancer all in the same August month. Elacestrant, if approved, would be the first oral selective estrogen receptor degrader (SERD) available for advanced or metastatic 2L and 3L ER + / HER2- breast cancer patients.
U.S. FDA has assigned a Prescription Drug User Fee Act (PDUFA) date of February 17, 2023
ELACESTRANT COULD POTENTIALLY OVERCOME THE ENDOCRINE RESISTANCE
Endocrine therapy, with either aromatase inhibitors (AI) or fulvestrant, plus a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor is the recommended first-line standard of care (SOC) for locally advanced or metastatic ER+/HER2- breast cancer. Subsequent progression is associated with endocrine resistance, which includes development of acquired mutations in a variety of genes.
Current treatment guidelines recommend sequential endocrine therapy in the absence of visceral crisis or until all endocrine therapy options have been exhausted; tamoxifen with or without everolimus is another option as later-line therapy. However, the clinical activity of endocrine monotherapy in patients who have received prior CDK4/6 or mammalian target of rapamycin inhibition is limited, with a median progression-free survival (PFS) of approximately 2 months, highlighting a major unmet clinical need in the field.
The MAA is based on pivotal Phase 3 EMERALD study (NCT03778931), which demonstrated a 30% reduction in the risk of disease progression following treatment with the SERD (n = 239) compared with standard of care (SOC; n = 238). The study statistically significant efficacy over current standard-of-care (SOC) medications for ER+/HER2- metastatic breast cancer and patients whose tumors harbor an ESR1 mutation
KEY ADVANTAGES OF ELACESTRANT
Elacestrant is the first in class of new agents, oral SERDs, which are agents that target the ER. The aim of elacestrant is to increase the effect of endocrine therapy over classic, older compounds such as aromatase inhibitors and fulvestrant [Faslodex], which was the first SERD, but was administered intramuscularly.
Elacestrant has the advantage of oral administration. It is given at a dose of 400 mg once a day, and daily intake is much easier for patients. The EMERALD trial determined whether elacestrant could prove more effective than SOC endocrine therapy for ER+/HER2- metastatic breast cancer patients after progressing on prior CDK4/6 inhibitors.
Elacestrant is better than current endocrine agents, which is good news for all the oral SERDs that are being developed. It also shows that it is possible for a new agent to be superior to older agents. Additionally, the PFS achieved in EMERALD is limited; it is short in the general population. Other methods should also be explored to stratify patients and understand which patients could be safely treated with single-agent elacestrant.
NEXT STEPS FOR ELACESTRANT
The next step for elacestrant as a compound is to be combined with other agents such as CDK4/6 inhibitors, PIK3CA inhibitors, and mTOR inhibitors. These compounds are key in the current management of ER+/HER2- metastatic breast cancer patients. Elacestrant as a single agent is superior to single-agent endocrine therapy, but we know that combinations are even better. Menarini would also try to develop elacestrant for the early stages of nonmetastatic breast cancer.
CURRENT CLINICAL LANDSCAPE FOR ELACESTRANT
|NCTid||Experimental Arm||Comparator Arm||Patient Segment||Phase||Primary endpoint|
|ELONA (to be initiated by Q4 2022)||ONA-XR + Elacestrant||NA||ER+/HER2- Advanced Breast Cancer after CDK4/6i therapy||Ib/2||NA|
|NCT04791384||Abemaciclib + Elacestrant||NA||Brain Metastasis Due to HR+/HER2- Breast Cancer||I/II||Safety & Efficacy|
|ELIPSE||Elacestrant||NA||Preoperative early HR+/HER2- Breast Cancer||Early I||Complete Cell Cycle Arrest|
|ELECTRA||Abemaciclib + Elacestrant||Elacestrant||Brain Metastasis Due to HR+/HER2- Breast Cancer||I/II||Safety & Efficacy|
|EMERALD||Elacestrant||SoC||ER+/HER2- Advanced Breast Cancer after CDK4/6i therapy||III||PFS in the ESR1-mut pts.|
|NCT05512364||Elacestrant||Standard endocrine treatment||ER+/HER2- Breast Cancer Patients With ctDNA Relapse||III||Distant metastasis free survival (DMFS)|
COMPETITORS TO ELACESTRANT IN ER+/HER2-BREAST CANCER
The market for SERD drugs is seen by analysts as a multi-billion-dollar opportunity. Other drugs in this space include Roche’s giredestrant, AstraZeneca’s camizestrant, Sanofi’s amcenestrant and others.
|Product Name||Company Name||Highest Stage of Development|
|Elacestrant||Radius/Menarini /Eisai||FDA NDA|
|Enobosarm||Veru Healthcare||Phase 3|
|Imlunestrant||Eli Lilly||Phase 3|
|Datopotamab deruxtecan||AstraZeneca||Phase 3|
|Lerociclib||G1 /EQRx/Genor Biopharma||Phase 3|
|Sacituzumab govitecan||Gilead||Phase 3|