Ajay Dhakal MBBS

The clinical benefit of fulvestrant as a second-line treatment after tumor progression with CDK4/6i-based therapy has been discouraging, highlighting an unmet need for a better SERD in this space.¹ Multiple oral SERD are currently in trials. The EMERALD trial is a phase 3 study that randomly assigned 477 patients with ER+/HER2- mBC in a 1:1 ratio to elacestrant, an oral SERD, vs standard of care (SOC) endocrine therapy (ET). Enrolled patients had received one to two prior ET and one or less chemotherapy treatments in the metastatic disease settings. All patients had prior treatment with a CDK4/6i. Fulvestrant-naive patients were required to have fulvestrant as the SOC ET. In contrast, patients previously treated with fulvestrant received an AI, the selection of which was based on prior AI therapy. Primary endpoints were progression-free survival (PFS) in all patients and in patients with detectable ESR1 mutation. The median PFS in the elacestrant arm was 2.8 months vs 1.9 months in the control arm [hazard ratio (HR) 0.70; 95% CI 0.55-0.88; P = .002]. The 6-month PFS was 34% vs 20% in all patients and 41% vs 19% in patients with detectable ESR1 mutation, favoring the elacestrant arm. In the subgroup analysis among patients who received fulvestrant in the control arm, the 6-month PFS was 34% vs 21% in all patients and 41% vs 19% in patients with ESR1 mutation. Grade 3 or 4 adverse events developed in 27% patients in the elacestrant arm compared with 20% in the SOC arm. More patients in the elacestrant arm developed nausea, vomiting, and liver function abnormalities compared with patients in the SOC arm.

This is the first phase 3 trial demonstrating statistically significant prolongation of PFS associated with an oral SERD compared with SOC ET in patients with ER+/HER2- mBC who had prior treatment with a CDK4/6i. A new drug application has been submitted to the US Food and Drug Administration based on this data. If approved, elacestrant may be favored over fulvestrant as the standard ET for ER+/HER2- mBC after progression on a CDK4/6i-based therapy.

Patients with breast cancer brain metastasis (BrM) have a poor prognosis. Systemic therapies with good central nervous system (CNS) permeability and strong activity against BrM are much needed. An exploratory subset of the phase 3 BEACON trial demonstrated improvement in overall survival (OS) with etirinotecan pegol, a long-acting polymer conjugate of irinotecan, compared with physicians' choice chemotherapy in patients with mBC with treated and stable BrMs.²

Based on this data, a large phase 3 study (the ATTAIN study) was conducted. Patients with mBC with treated and stable BrM (n = 178) were randomly assigned to receive etirinotecan pegol vs physicians' choice of chemotherapy (eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel). The primary endpoint of OS was similar in both groups (etirinotecan pegol 7.8 months; chemotherapy 7.5 months; HR 0.90; 95% CI 0.61-1.33; P = .60). Median PFS for mBC with CNS metastases (etirinotecan pegol vs chemotherapy) were 3.9 vs 3.3 months (HR 0.59; 95% CI 0.33-1.05; P = .07) and for non-CNS metastases were 2.8 vs 1.9 months (HR 0.72; 95% CI 0.45-1.16; P = .18). Adverse events were grade 3 or 4 in 57% patients receiving etirinotecan pegol compared with 64% receiving SOC chemotherapy.

This trial failed to meet its primary endpoint. The possible explanations proposed by the investigators are a protocol amendment that reduced the power of the trial to 80%, some key differences in the patient population in the ATTAIN trial compared with the BEACON trial, and the possibility of the BEACON trial exploratory analysis result being a false positive. The OS of around 7 months highlights the unmet need for better systemic therapy for patients with BrM breast cancer, especially those with HER2- breast cancer.

Additional References

1. Lindeman GJ, Fernando TM, Bowen R, et al. VERONICA: Randomized phase II study of fulvestrant and venetoclax in ER-positive metastatic breast cancer post-CDK4/6 inhibitors – Efficacy, safety, and biomarker results. Clin Cancer Res. 2022 (June 21). Doi: 10.1158/1078-0432.CCR-21-3811
    
2. Cortés J, Rugo HS, Awada A, et al. Prolonged survival in patients with breast cancer and a history of brain metastases: Results of a preplanned subgroup analysis from the randomized phase III BEACON trial. Breast Cancer Res Treat. 2017;165:329-341. Doi: 10.1007/s10549-017-4304-7

The clinical benefit of fulvestrant as a second-line treatment after tumor progression with CDK4/6i-based therapy has been discouraging, highlighting an unmet need for a better SERD in this space.¹ Multiple oral SERD are currently in trials. The EMERALD trial is a phase 3 study that randomly assigned 477 patients with ER+/HER2- mBC in a 1:1 ratio to elacestrant, an oral SERD, vs standard of care (SOC) endocrine therapy (ET). Enrolled patients had received one to two prior ET and one or less chemotherapy treatments in the metastatic disease settings. All patients had prior treatment with a CDK4/6i. Fulvestrant-naive patients were required to have fulvestrant as the SOC ET. In contrast, patients previously treated with fulvestrant received an AI, the selection of which was based on prior AI therapy. Primary endpoints were progression-free survival (PFS) in all patients and in patients with detectable ESR1 mutation. The median PFS in the elacestrant arm was 2.8 months vs 1.9 months in the control arm [hazard ratio (HR) 0.70; 95% CI 0.55-0.88; P = .002]. The 6-month PFS was 34% vs 20% in all patients and 41% vs 19% in patients with detectable ESR1 mutation, favoring the elacestrant arm. In the subgroup analysis among patients who received fulvestrant in the control arm, the 6-month PFS was 34% vs 21% in all patients and 41% vs 19% in patients with ESR1 mutation. Grade 3 or 4 adverse events developed in 27% patients in the elacestrant arm compared with 20% in the SOC arm. More patients in the elacestrant arm developed nausea, vomiting, and liver function abnormalities compared with patients in the SOC arm.

This is the first phase 3 trial demonstrating statistically significant prolongation of PFS associated with an oral SERD compared with SOC ET in patients with ER+/HER2- mBC who had prior treatment with a CDK4/6i. A new drug application has been submitted to the US Food and Drug Administration based on this data. If approved, elacestrant may be favored over fulvestrant as the standard ET for ER+/HER2- mBC after progression on a CDK4/6i-based therapy.

Patients with breast cancer brain metastasis (BrM) have a poor prognosis. Systemic therapies with good central nervous system (CNS) permeability and strong activity against BrM are much needed. An exploratory subset of the phase 3 BEACON trial demonstrated improvement in overall survival (OS) with etirinotecan pegol, a long-acting polymer conjugate of irinotecan, compared with physicians' choice chemotherapy in patients with mBC with treated and stable BrMs.²

Based on this data, a large phase 3 study (the ATTAIN study) was conducted. Patients with mBC with treated and stable BrM (n = 178) were randomly assigned to receive etirinotecan pegol vs physicians' choice of chemotherapy (eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel). The primary endpoint of OS was similar in both groups (etirinotecan pegol 7.8 months; chemotherapy 7.5 months; HR 0.90; 95% CI 0.61-1.33; P = .60). Median PFS for mBC with CNS metastases (etirinotecan pegol vs chemotherapy) were 3.9 vs 3.3 months (HR 0.59; 95% CI 0.33-1.05; P = .07) and for non-CNS metastases were 2.8 vs 1.9 months (HR 0.72; 95% CI 0.45-1.16; P = .18). Adverse events were grade 3 or 4 in 57% patients receiving etirinotecan pegol compared with 64% receiving SOC chemotherapy.

This trial failed to meet its primary endpoint. The possible explanations proposed by the investigators are a protocol amendment that reduced the power of the trial to 80%, some key differences in the patient population in the ATTAIN trial compared with the BEACON trial, and the possibility of the BEACON trial exploratory analysis result being a false positive. The OS of around 7 months highlights the unmet need for better systemic therapy for patients with BrM breast cancer, especially those with HER2- breast cancer.

Additional References

1. Lindeman GJ, Fernando TM, Bowen R, et al. VERONICA: Randomized phase II study of fulvestrant and venetoclax in ER-positive metastatic breast cancer post-CDK4/6 inhibitors – Efficacy, safety, and biomarker results. Clin Cancer Res. 2022 (June 21). Doi: 10.1158/1078-0432.CCR-21-3811
    
2. Cortés J, Rugo HS, Awada A, et al. Prolonged survival in patients with breast cancer and a history of brain metastases: Results of a preplanned subgroup analysis from the randomized phase III BEACON trial. Breast Cancer Res Treat. 2017;165:329-341. Doi: 10.1007/s10549-017-4304-7

The clinical benefit of fulvestrant as a second-line treatment after tumor progression with CDK4/6i-based therapy has been discouraging, highlighting an unmet need for a better SERD in this space.¹ Multiple oral SERD are currently in trials. The EMERALD trial is a phase 3 study that randomly assigned 477 patients with ER+/HER2- mBC in a 1:1 ratio to elacestrant, an oral SERD, vs standard of care (SOC) endocrine therapy (ET). Enrolled patients had received one to two prior ET and one or less chemotherapy treatments in the metastatic disease settings. All patients had prior treatment with a CDK4/6i. Fulvestrant-naive patients were required to have fulvestrant as the SOC ET. In contrast, patients previously treated with fulvestrant received an AI, the selection of which was based on prior AI therapy. Primary endpoints were progression-free survival (PFS) in all patients and in patients with detectable ESR1 mutation. The median PFS in the elacestrant arm was 2.8 months vs 1.9 months in the control arm [hazard ratio (HR) 0.70; 95% CI 0.55-0.88; P = .002]. The 6-month PFS was 34% vs 20% in all patients and 41% vs 19% in patients with detectable ESR1 mutation, favoring the elacestrant arm. In the subgroup analysis among patients who received fulvestrant in the control arm, the 6-month PFS was 34% vs 21% in all patients and 41% vs 19% in patients with ESR1 mutation. Grade 3 or 4 adverse events developed in 27% patients in the elacestrant arm compared with 20% in the SOC arm. More patients in the elacestrant arm developed nausea, vomiting, and liver function abnormalities compared with patients in the SOC arm.

This is the first phase 3 trial demonstrating statistically significant prolongation of PFS associated with an oral SERD compared with SOC ET in patients with ER+/HER2- mBC who had prior treatment with a CDK4/6i. A new drug application has been submitted to the US Food and Drug Administration based on this data. If approved, elacestrant may be favored over fulvestrant as the standard ET for ER+/HER2- mBC after progression on a CDK4/6i-based therapy.

Patients with breast cancer brain metastasis (BrM) have a poor prognosis. Systemic therapies with good central nervous system (CNS) permeability and strong activity against BrM are much needed. An exploratory subset of the phase 3 BEACON trial demonstrated improvement in overall survival (OS) with etirinotecan pegol, a long-acting polymer conjugate of irinotecan, compared with physicians' choice chemotherapy in patients with mBC with treated and stable BrMs.²

Based on this data, a large phase 3 study (the ATTAIN study) was conducted. Patients with mBC with treated and stable BrM (n = 178) were randomly assigned to receive etirinotecan pegol vs physicians' choice of chemotherapy (eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel). The primary endpoint of OS was similar in both groups (etirinotecan pegol 7.8 months; chemotherapy 7.5 months; HR 0.90; 95% CI 0.61-1.33; P = .60). Median PFS for mBC with CNS metastases (etirinotecan pegol vs chemotherapy) were 3.9 vs 3.3 months (HR 0.59; 95% CI 0.33-1.05; P = .07) and for non-CNS metastases were 2.8 vs 1.9 months (HR 0.72; 95% CI 0.45-1.16; P = .18). Adverse events were grade 3 or 4 in 57% patients receiving etirinotecan pegol compared with 64% receiving SOC chemotherapy.

This trial failed to meet its primary endpoint. The possible explanations proposed by the investigators are a protocol amendment that reduced the power of the trial to 80%, some key differences in the patient population in the ATTAIN trial compared with the BEACON trial, and the possibility of the BEACON trial exploratory analysis result being a false positive. The OS of around 7 months highlights the unmet need for better systemic therapy for patients with BrM breast cancer, especially those with HER2- breast cancer.

Additional References

1. Lindeman GJ, Fernando TM, Bowen R, et al. VERONICA: Randomized phase II study of fulvestrant and venetoclax in ER-positive metastatic breast cancer post-CDK4/6 inhibitors – Efficacy, safety, and biomarker results. Clin Cancer Res. 2022 (June 21). Doi: 10.1158/1078-0432.CCR-21-3811
    
2. Cortés J, Rugo HS, Awada A, et al. Prolonged survival in patients with breast cancer and a history of brain metastases: Results of a preplanned subgroup analysis from the randomized phase III BEACON trial. Breast Cancer Res Treat. 2017;165:329-341. Doi: 10.1007/s10549-017-4304-7