1 Elacestrant Versus Fulvestrant or Aromatase Inhibitor in a Phase 3 Trial Evaluating Elacestrant, an Oral Selective Estrogen Receptor Degrader Versus Standard-of- Care Endocrine Monotherapy for ER+/HER2– Advanced/Metastatic Breast Cancer

Background

Elacestrant is a novel, oral selective estrogen receptor degrader (SERD). The phase 3 EMERALD trial compared the efficacy and safety of elacestrant to standard-of-care (SOC) endocrine therapy of investigator’s choice (fulvestrant or aromatase inhibitor [AI]) in patients with ER+/HER2– locally advanced or metastatic breast cancer (mBC) following progression on prior endocrine and cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy. Elacestrant demonstrated significantly prolonged progression-free survival (PFS) compared to SOC in all patients and in patients whose tumors harbored ESR1 mutations (ESR1-mut). Here, we report a post-hoc subgroup analysis from EMERALD separately comparing the efficacy of elacestrant to fulvestrant and to AI.

Materials and Methods

EMERALD (NCT03778931) is a randomized, open-label, phase 3 trial. Patients were randomized 1:1 to elacestrant (400 mg orally daily) or SOC consisting of investigator’s choice of fulvestrant or AI. For the SOC arm, the protocol provided the following guidance regarding therapy selection:

• Patients who have not previously received fulvestrant should be treated with fulvestrant.
• Patients who have progressed on prior fulvestrant therapy should be treated with an AI.
  • The selection of an AI should be based on prior AI therapy and any known contraindications.
  • If the patient has previously progressed on a non-steroidal AI (anastrozole or letrozole) but has not received exemestane, the preferred option would be exemestane.
  • If the patient has previously progressed on exemestane but has not received a nonsteroidal AI, the preferred option would be a nonsteroidal AI.

Results

Of 477 patients enrolled in the trial:

• n = 239 received elacestrant, n = 238 received SOC.
• n = 165 (69%) received fulvestrant (159 patients were pretreated with AI).
• n = 73 (31%) received AI (69 patients were pretreated with fulvestrant).

Baseline characteristics were balanced between the elacestrant and SOC groups. CDK4/6i are frequently combined with AI in the 1st-line ER+/HER2– mBC setting; therefore, patient disposition showing more fulvestrant (69%) vs AI (31%) in EMERALD reflects the real-life setting and that the therapy selection guidance in the protocol was followed by the sites. A greater proportion of AI-treated patients had received 2 prior endocrine therapies (71.2%) vs fulvestrant-treated patients (27.3%).

Conclusions

Elacestrant demonstrated statistically significant and clinically meaningful improvement in PFS vs SOC endocrine therapy in a randomized global phase 3 study in patients with ER+/HER2- mBC in the 2nd/3rd-line post-CDK4/6i setting. The sequencing guidance provided in the protocol regarding the selection of therapy in the control arm represents real-world therapeutic strategy for patients with ER+/HER2- mBC in the 2nd/3rd-line post-CDK4/6i setting. In this post hoc subgroup analysis, elacestrant improved PFS compared with fulvestrant as well as AI consistently at 6, 12, and 18 months, highlighting a superior efficacy of elacestrant regardless of the type of endocrine therapy. Elacestrant has a predictable and manageable safety profile consistent with other endocrine therapies.

AFFILIATIONS:

Philippe Aftimos,¹ Javier Cortes,² Francois Clement Bidard,³ Virginia Kaklamani,⁴ Aditya Bardia,⁵ Alberto J. Montero,⁶ Joo Hyuk Sohn,⁷ Giulia Tonini,⁸ Krzysztof J. Grzegorzewski,⁹ Patrick Neven¹⁰

¹Institut Jules Bordet – Université Libre de Bruxelles, Brussels, Belgium.

²International Breast Cancer Center (IBCC), Quiron Group, Barcelona Spain.

³Instit Curie, Paris and Saint Cloud, France.

⁴University of Texas Health Sciences Center, Houston, TX.

⁵Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA.

⁶University Hospitals Seidman Cancer Center – Case Western Reserve University, Cleveland, OH.

⁷Yonsei Cancer Center, Yonsei University Health System – Medical Oncology, Seoul, Republic of Korea.

⁸Menarini Group, Florence, Italy.

⁹Stemline Therapeutics/Menarini Group, New York, NY.

¹⁰Universitaire Ziekenhuizen (UZ) – Leuven Cancer Institute, Leuven, Belgium.