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

Background

• Endocrine therapy plus CDK4/6i is the mainstay for the management of ER+/HER2- mBC as 1st-line therapy.¹
• Tumors eventually develop hormonal resistance, mainly through the development of ESR1 mutations.
• In current practice, sequential endocrine monotherapy or combination therapies are used in the 2nd/3rd line.
• Sequential endocrine monotherapy is associated with low PFS after CDK4/6i (1.94 months).² In addition, fulvestrant has low bioavailability and an IM injection burden.
• Main combinations such as everolimus + exemestane and alpelisib + fulvestrant can be associated with significant toxicity with discontinuation rates around 25%.^3,4
• In this context, there is a significant need for potent oral SERDS for monotherapy use and for enabling oral-oral combinations.
• Elacestrant is a next-generation oral SERD, which has demonstrated a statistically significant improvement in PFS compared with single-agent endocrine therapy in the EMERALD trial, including in patients with ESR1 mutated tumors. EMERALD is the only pivotal oral SERD trial where prior CDK 4/6i usage was mandated.⁵

Study Design

• Phase III randomized trial evaluating elacestrant (400 mg daily) vs investigator’s choice (fulvestrant, anastrozole, letrozole, exemestane) in men and postmenopausal women with ER-positive, HER2-negative advanced metastatic breast cancer who have progressed or relapsed on or after 1 or 2 lines of endocrine therapy for advanced disease, one of which was given in combination with a CDK4/6i
• Stratification Factors: ESR1-mutation status; Prior treatment with fulvestrant; Presence of visceral metastases
• Two Primary Endpoints:PFS in all pts; PFS in ESR1-mut

Results

• Baseline characteristics well matched between the two arms; all patients had received prior treatment with a CDK4/6i
• All Patients: PFS by Duration of CDK4/6i – Improvement demonstrated with elacestrant vs standard of care
  • Duration on CDK4/6i in the metastatic setting, at least 12 months: 3.78 months, elacestrant vs 1.91 months, SOC hormonal therapy [95% CI, HR .613 (453-.828)]
  • Duration on CDK4/6i in the metastatic setting, at least 18 months: 5.45 months elacestrant vs 3.29 months SOC hormonal therapy [95%, CI, HR .703 (.482-1.019)]
• Patients with ESR1-mut Tumors: PFS by Duration of CDK4/6i – Improvement demonstrated with elacestrant vs standard of care
  • Duration on CDK4/6i in the metastatic setting, at least 12 months: 8.61 months, elacestrant vs 1.91 months, SOC hormonal therapy [95% CI; HR .410 (.262-.634)]
  • Duration on CDK4/6i in the metastatic setting, at least 18 months: 8.61 months, elacestrant vs 2.10 months, SOC hormonal therapy [95% CI; HR .466 (.270-.791)]
• Updated safety data consistent with previously reported results

Conclusion

• EMERALD is the only pivotal trial in 2nd/3rd-line mBC with 100% prior CDK4/6i usage.
• Duration of CDK4/6i was associated with PFS in the EMERALD trial. The longer the duration of prior CDK4/6i, the longer PFS on elacestrant as compared with SOC.
• This was even more pronounced in patients with ESR1-mut tumors, where patients who had at least 12 months of prior CDK4/6i duration achieved a mPFS of 8.6 months with elacestrant vs 2 months mPFS with SOC.
• No new safety signals were identified. Low-grade nausea was common in both treatment arms, but antiemetic usage was low with both drugs: 8% on elacestrant and 10.3% on AIs. There was no incidence of bradycardia.
• These results showed that elacestrant significantly prolongs PFS vs SOC with a low rate of adverse events.
• Elacestrant can become an important oral endocrine monotherapy agent in 2nd/3rd line as an alternative to combination therapies that are associated with challenging safety profiles.

References

Moy B, et al. J Clin Oncol. 2021:JCO2101374; 2. Lindeman GJ et al. J Clin Oncol 2021,39(suppl 15):1004-1004; 3. Everolimus US Prescribing Information; 4. Alpelisib US Prescribing Information 5. Bidard FC, et al. J Clin Oncol. 2022;40(28):3246-3256.

Funding supported by Stemline Therapeutics. Content independently developed by OncLive.