Use of elacestrant (Orserdu) for patients with estrogen receptor (ER)-positive HER2-negative non-detected ESR1 mutated breast cancer prolonged progression-free survival (PFS) compared to standard-of-care (SOC) within 6 months of CDK4/6 inhibitor treatment plus endocrine therapy. These findings from a subgroup analysis of the phase 3 EMERALD trial (NCT03778931) also demonstrated that patients with ESR1 mutations treated with elacestrant who received 12 months or more of prior CDK4/6 inhibitor therapy experienced increased PFS rates, according to data presented during the 2023 ASCO Annual Meeting.1
These data showed a manageable safety profile for the next generation oral SERD as well. With elacestrant’s January 2023 FDA approval backed by the EMERALD trial for patients with ER-positive HER2-negative ESR1 mutated breast cancer who have experienced disease progression following prior endocrine therapy, elacestrant has already provided an efficacious treatment option for a subgroup of patients.2
Diving deeper into findings from EMERALD in this post-hoc analysis presentation, Virginia G. Kaklamani, MD, said “duration of prior CDK4/6 inhibitor [treatment] in the metastatic setting was shown to be a predictor of efficacy in patients with ESR1 mutations receiving elacestrant.” Kaklaman is a professor of medicine and leader of the Breast Cancer Program at UT Health San Antonio MD Anderson Cancer Center in Texas.1
She noted that these differences may be attributed to a development of resistance to CDK4/6 inhibitors and other clinical trials, such as the phase 2 MAINTAIN study (NCT02632045), have shown similar patterns.
Non-Detected ESR1-Mutant Tumors
A benefit was seen for patients given elacestrant (n = 20) vs SOC (n = 21) who received less than 6 months of treatment with a CDK4/6 inhibitor. The median PFS was 5.32 months (95% CI, 1.94-15.34) vs 1.87 months (95% CI, 1.71-2.20), respectively, and the PFS rate at 12 months was 26.17% (95% CI, 0.00%-54.59%) vs 16.11% (95% CI, 0.00%-32.77%), respectively (HR, 0.518; 95% CI, 0.216-1.165).
However, those receiving elacestrant (n = 99) vs SOC (n = 103) who had prior treatment with a CDK4/6 inhibitor for 6 months or more experienced a median PFS in the elacestrant arm of 1.91 months (95% CI, 1.87-3.42) compared with 1.97 months (95% CI, 1.87-3.61) in the SOC arm. The PFS rate at 12 months was 15.31% (95% CI, 4.99%-25.63%) vs 6.06% (95% CI, 0.00%-15.75%), respectively (HR, 0.911; 95% CI, 0.640-1.298).
ESR1-Mutant Tumors
Patients with ESR1 mutations who received 12 months or more of prior treatment with a CDK4/6 inhibitor achieved a median PFS of 8.61 months (95% CI, 4.14-10.84) with elacestrant (n = 78) compared with 1.91 months (95% CI, 1.87-3.68) for those given SOC (n = 81) for an absolute difference of 6.7 months. The PFS rate at 12-months was 35.81% (95% CI, 21.84%-49.78%) vs 8.39% (95% CI, 0.00%-17.66%), respectively (HR, 0.410; 95% CI, 0.262-0.634).
Patients who received at least 18 months of treatment with a CDK4/6 inhibitor and were in the elacestrant (n = 55) and SOC (n = 56) arms achieved a median PFS of 8.61 months (95% CI, 5.45-16.89) and 2.10 months (95% CI, 1.87-3.75), respectively. At 12 months, the PFS rates were 35.79% (95% CI, 19.54%-52.05%) in the elacestrant group vs 7.73% (95% CI, 0.00%-20.20%) in the SOC group (HR, 0.466; 95% CI, 0.270-0.791).
Finally, patients receiving elacestrant (n = 103) and SOC (n = 102) who had previous treatment with a CDK4/6 inhibitor for at least 6 months experienced a median PFS of 4.14 months (95% CI, 2.20-7.79) and 1.87 months (95% CI, 1.87-3.29), respectively. The PFS rate at 12 months was 26.02% (95% CI, 15.12%-36.92%) vs 6.45% (95% CI, 0.00%-13.65%), respectively (HR, 0.517; 95% CI, 0.361%-0.738%).
Safety Profile
Investigators noted that safety data of patients with non-detected ESR1 mutations were consistent with previously reported results for all patients.
There were no treatment-related deaths or grade 4 adverse events (AEs) in either arm, most AEs were grade 1 and 2, and there was no hematologic safety signal observed. The discontinuation rate was low with 3.4% of patients who received elacestrant and 0.9% of patients treated with SOC discontinuing treatment due to a treatment-related AE. Additionally, no patients had sinus bradycardia.
Regarding nausea, in the elacestrant (n = 237) and SOC (n = 230) arms, there were grade 2 events (2.5% vs 0.9%) and antiemetics were used (8.0% vs 14%). Treatment-related dose reduction rates (1.3% vs not applicable) and discontinuation rates (1.3% vs 0.0%) were also reported.
Patient Characteristics
Baseline characteristics were generally well balanced in the elacestrant arm between all those receiving elacestrant (n = 239) and the ESR1-mutant group (n = 115), as well as in the SOC arm between all patient who received therapy (n = 239) and those with ESR1 mutations (n = 113).
In the all-patient population in the elacestrant arm and in the SOC arm, ECOG scores were 0 (59.8% vs 56.5%), 1 (40.2% vs 43.1%), or less than 1 (0% vs 0.4%), patients had visceral metastases (68.2% vs 71.1%), and had received no prior lines of chemotherapy (79.9% vs 75.3%) or 1 prior line (20.1% vs 24.7%). The median age of patients was 63.0 years (range, 24-89) vs 63.0 (range, 32-83), respectively.
Further, the all patient elacestrant group was 97.5% female and the ESR1-mutant group was 100% female. The SOC group was 99.6% and 100% female, respectively. Prior lines of endocrine therapy received were 1 (54.0% and 63.5% vs 59.4% and 61.1%) or 2 (46.0% and 36.5% vs 40.6% and 38.9%) in the elacestrant arm for all patients and the ESR1 mutation group as well as in the SOC arm for all patients and the ESR1-mutantgroup. Aromatase inhibitors were the most received endocrine therapy overall at approximately 84.0% with fulvestrant following at approximately 27.0% and tamoxifen at approximately 7.5%.
Elacestrant in the Treatment Landscape
The FDA approved elacestrant in January 2023 based on the EMERALD trial for postmenopausal women or adult men with ER-positive HER2-negative ESR1-mutated advanced or metastatic breast cancer who experienced disease progression following at least 1 line of endocrine therapy.2 Ongoing clinical trials evaluating elacestrant in patients with ER-positive HER2-negative breast cancer include ELEVATE (NCT05563220), ELECTRA (NCT05386108), and ELCIN (NCT05596409).1
The first line treatment SOC for this patient population is endocrine therapy plus a CDK4/6 inhibitor, but because tumors develop hormonal resistance which can be a result of ESR1 mutations, sequential endocrine therapies are used in the second line. However, sequential endocrine monotherapy has been associated with low PFS rates following treatment with a CDK4/6 inhibitor.
Investigators wrote that because “main combinations such as everolimus [Afinitor] and exemestane [Aromasin] and alpelisib [Piqray] and fulvestrant can be associated with significant toxicity with discontinuation rates around 25%, in this context, there is a significant need for potent oral SERDs for monotherapy use and for enabling oral-oral combinations.”
Additionally, preclinical data demonstrated that elacestrant showed growth inhibition in ESR1 wild-type cells that were resistant to CDK4/6 inhibitors.
References
Kaklamani VG, Bidard FC, Neven P, et al. Oral elacestrant vs standard-of-care in estrogen receptor-positive, HER2-negative (ER+/HER2-) advanced or metastatic breast cancer (mBC) without detectable ESR1 mutation (EMERALD): Subgroup analysis by prior duration of CDK4/6i plus endocrine therapy (ET). J Clin Oncol. 2023;41(suppl 16):1070. doi:10.1200/JCO.2023.41.16_suppl.1070
FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. January 27, 2023. Accessed June 4, 2023.