Elacestrant Shows PFS Benefit For Patients With ER+/HER2-, ESR1-Mutated Breast Cancer and Prior CDK4/6 Treatment History

Virginia G. Kaklamani, MD

A subgroup analysis of the phase 3 EMERALD trial (NCT03778931) showed that patients who have estrogen receptor (ER)–positive/HER2-negative, non-detected ESR1-mutated breast cancer who experienced disease progression within 6 months of CDK4/6 inhibitor treatment plus endocrine therapy achieved better progression-free survival rates with elacestrant (Orserdu) vs standard-of-care therapy (SOC). Findings, which were presented during the 2023 American Society of Clinical Oncology Annual Meeting, demonstrated that increased PFS rates were most pronounced among patients who had received at last 12 months of CDK4/6 treatment.

Data also showed a manageable safety profile for the next generation oral SERD. 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.” Kaklamani 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-mutant group. 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

1. 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
2. FDA approves elacestrant for ER-positive, HER2-negative, ESR1-mutated advanced or metastatic breast cancer. FDA. January 27, 2023. Accessed June 4, 2023. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-elacestrant-er-positive-her2-negative-esr1-mutated-advanced-or-metastatic-breast-cancer