Longer duration of prior CDK4/6 inhibitor results in a greater PFS benefit of elacestrant in patients with ER+/HER2- metastatic breast cancer

Previously, the EMERALD trial showed improved PFS of elacestrant vs. standard of care (SOC) in patients with ER+/HER2- metastatic breast cancer who had previously been treated with CDK4/6 inhibitors (CDK4/6i). At SABCS 2022, a new analysis of this trial demonstrated that the longer the duration of prior CDK4/6i, the greater the PFS benefit of elacestrant vs. SOC, a benefit that was even more pronounced in patients with ESR1-mutated tumours.

Endocrine therapy (ET) plus CDK4/6 inhibitor (CDK4/6i) is the standard of care (SOC) for the first-line treatment of patients with ER+/HER2- metastatic breast cancer (mBC). However, tumours eventually develop hormonal resistance, mainly through the onset of ESR1 mutations. Sequential endocrine monotherapy is associated with short progression-free survival (PFS) after CDK4/6i, while combination ET has a high rate of adverse events (AEs) and  discontinuation rates of around 25%. In this context, there is a significant need for a potent oral selective oestrogen receptor degrader (SERD) for monotherapy use.  Elacestrant is a next-generation oral SERD, which demonstrated to significantly improve PFS compared to single-agent ET in the EMERALD trial, including in patients with ESR1-mutated tumours. This analysis examined the impact of the duration of prior CDK4/6i on PFS, and shared updated safety results.

Study design

The phase 3 EMERALD trial enrolled patients with ER+/HER2- mBC that were previously treated with CDK4/6i. Prior use of chemotherapy, fulvestrant or more than one CDK4/6i therapy was permitted. Patients were randomised 1:1 to elacestrant (400 mg daily) or investigator’s choice SOC (fulvestrant, anastrozole, letrozole, or exemestane). The two primary endpoints in the trial were PFS in all patients and in the subgroup of patients with ESR1 mutations.  Since the length of duration of CDK4/6i is one of the parameters used to determine endocrine sensitivity, a post-hoc analysis was performed based on the duration of prior CDK4/6i therapy (≥ 6, ≥12 and ≥ 18 months) of patients receiving elacestrant vs. SOC.

Results

The results showed that the longer the duration of CDK4/6i therapy, the greater the PFS benefit from later lines of ET. This observation was more pronounced in the elacestrant arm. Median PFS was 2.79 vs. 1.91 months in the elacestrant and SOC arms at ≥6 months, 3.78 vs. 1.91 months at ≥ 12 months, and 5.45 vs. 3.29 months at ≥18 months.  PFS rates at different pre-specified time points demonstrated a consistent benefit of elacestrant vs. SOC, being nearly fivefold higher for elacestrant at 18 months (21.03% vs. 4.11%). The benefit of elacestrant was even more evident in patients with ESR1 mutations. Median PFS was 4.14 vs. 1.87 months in the elacestrant and SOC arms at ≥6 months, 8.61 vs. 1.91 months at ≥ 12 months, and 8.61 vs. 2.10  months at ≥18 months. There were no patients with ESR1-mutated tumours on the SOC arm who were progression-free at 18 months, while 30% of patients on elacestrant were progression-free at this time point. In order to further characterise endocrine sensitivity and the benefit of elacestrant, intervals of less than six months (<6, 6-12, 12-18 and ≥18 months) were analysed. Although the samples were smaller, the 6-12 months interval appeared to be a transition where ESR1 resistance starts to build. Of note, the benefit of elacestrant can already be observed in the <6 month-interval (mPFS of 3.55 vs. 1.87 months in all patients). Updated safety data were consistent with previously reported results. Most AEs, including nausea, were grade 1 and 2, and no grade 4 treatment-related AEs (TRAEs) were reported. Only 3.4% of patients receiving elacestrant and 0.9% of patients receiving SOC discontinued therapy due to any TRAE. No treatment-related deaths, haematologic safety signals and sinus bradycardia were observed in any of the arms. Anti-emetic use was low, 8% in the elacestrant arm, and 10.3% and 1.3% in the SOC arm (patients who had received previous aromatase inhibitor and fulvestrant, respectively).

Conclusions

EMERALD is the only pivotal trial in second/third-line mBC in which prior CDK4/6i therapy was mandatory. In this analysis, elacestrant consistently improved PFS vs. SOC in all pre-specified time points with a low rate of AEs. The longer the duration of prior CDK4/6i, the greater the PFS benefit of elacestrant vs. SOC, and this benefit was even more pronounced in patients with ESR1-mutated tumours. These promising results suggest that elacestrant can become an important oral endocrine monotherapy agent in the second/third-line and a safe and efficient alternative to combination therapies.

Reference

Bardia A, Bidard FC, Neven P, et al. 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. Presented at SABCS 2022; Abstract GS3-01.