Oral SERD Therapy: Elacestrant's Impact on Metastatic Breast Cancer

Introduction

October is the Breast Cancer Awareness Month of 2024. Breast cancer remains a significant global health challenge, with over 2.3 million new cases diagnosed worldwide in 2022, according to the IARC. The disease burden is disproportionately higher in countries with medium or low levels of the Human Development Index (HDI), where access to information and healthcare is limited. This article delves into the recent FDA approval of elacestrant, a novel oral selective estrogen receptor degrader (SERD), for the treatment of ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer in post-menopausal women and adult men.

The Challenge of ESR1 Mutations

Estrogen receptor-positive (ER+) breast cancer accounts for approximately 70% of all breast cancer cases. Traditional endocrine therapies, while effective, often face the challenge of resistance, particularly in the presence of ESR1 mutations. These mutations are associated with a decrease in progression-free survival (PFS) and an increase in disease progression.

Elacestrant: A Promising New Oral SERD

Elacestrant, approved by the FDA on January 27, 2023, offers a new oral alternative to traditional SERDs like fulvestrant, which requires monthly intramuscular injections. This oral SERD has demonstrated significant improvements in PFS, a key metric for evaluating the effectiveness of cancer treatments.

Modified from Qureshi, Z. et al. Elacestrant in the treatment landscape of ER-positive, HER2-negative, ESR1-mutated advanced breast cancer: a contemporary narrative review. Annals of Medicine & Surgery 86, 4624–4633 (2024).

The EMERALD Trial: A Pivotal Study

The phase III EMERALD trial (NCT03778931) was a defining moment for elacestrant. It showed a statistically significant extension in PFS compared to standard endocrine therapy in patients with advanced/metastatic ER+/HER2- breast cancer, particularly in those with ESR1 mutations. The trial involved 477 individuals, providing robust evidence for elacestrant's efficacy and tolerability.

Efficacy and Safety Profile

Elacestrant's safety profile is favorable, with most adverse events being of grade 1 or 2 intensity. The most common adverse event was nausea, reported in 2.5% of patients with a severity score of 3. Importantly, no instances of cardiac or ocular damage were documented, which is a significant advantage over other SERDs.

Comparative Efficacy: Elacestrant vs. Standard Endocrine Therapy

Elacestrant has shown a median PFS of 2.8 months compared to 1.9 months with standard care, representing a 30% relative decrease in the risk of progression or death. In patients with ESR1 mutations, this improvement was even more pronounced, with a median PFS of 3.8 months for elacestrant versus 1.9 months for standard therapy.

Market Potential and Future Outlook

The global breast cancer drug market is expected to reach $43.4 billion by 2024, with SERDs like elacestrant poised to capture a significant share. The convenience of oral administration, coupled with its efficacy in ESR1-mutated tumors, positions elacestrant as a game-changer in the treatment landscape of advanced breast cancer.

ER+/HER2- breast cancer frequently harbors ESR1 mutations, particularly in metastatic settings, contributing to endocrine therapy resistance and disease progression. Nearly 1 out of 2 (~50%) people with ER+/HER2- metastatic breast cancer may develop an ESR1 mutation after progression on hormone therapy. From an overall perspective, ESR1 mutations are found in approximately 22% of metastatic ER+/HER2- breast cancer samples but are less common in primary tumors, with a prevalence of less than 3%. This suggests that 22% * 70% * 91% of postmenopausal female breast cancer patients (assuming the average age of menopause is ~50 years old) are eligible for Elacestrant treatment. Using 2022's data, there were approximately 2.3 million * 22% * 70% * 91% = 322,322 potential target patients. In addition, 50~70% of ER+ patients would respond clinically to endocrine therapy of whom 40~50% would relapse, which gives 87,027 patients that would consider elacestrant for the following treatment. 

The US and European Market

Elacestrant is approved in the US by the FDA in Jan 2023, and by the EMA in Nov 2023. Therefore, let's examine the potential impact in these key regions..

In the US, breast cancer is the second leading cause of cancer-related deaths among women, surpassed only by lung cancer. Despite preventive efforts, breast cancer continues to be prevalent, accounting for roughly 30% of all newly diagnosed cancers in American women. In 2021, the US anticipated approximately 330,840 new breast cancer cases, including about 281,550 invasive and 49,290 noninvasive (in situ) cases. During the same period, an estimated 43,600 American women were expected to succumb to the disease. 

The situation in Europe is equally concerning. In 2020, European women faced approximately 576,300 new breast cancer cases and 157,100 deaths from the disease. However, projections suggest that breast cancer mortality rates across Europe may converge to more uniform levels by 2025. The United Kingdom is expected to see the most significant decrease in breast cancer mortality, with predictions estimating a rate of 12.2 per 100,000 women in 2025. This reduction could potentially prevent 150,000 breast cancer deaths in the UK between 1994 and 2025. In the rest of Europe, an estimated 470,000 breast cancer deaths could be avoided during the same period.

Based on these statistics and applying relevant calculations, the current market ceiling for Elacestrant is estimated at 34,324 eligible patients. This figure represents the potential reach of the treatment in its approved markets, highlighting the significant opportunity for Elacestrant to make a meaningful impact in breast cancer care.

Conclusion

Elacestrant's approval marks a significant advancement in the treatment of ER+, HER2-, ESR1-mutated breast cancer. Its oral formulation offers patients a more convenient and potentially more adherent treatment option. As ongoing trials continue to explore its potential in various therapeutic scenarios, elacestrant holds promise for improving outcomes and quality of life for patients battling this disease.

Disclaimer: This article is for informational purposes only and should not be considered medical advice. Always consult with a healthcare professional before making any decisions related to treatment.

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