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Page 8 of 22 Droste et al. J Cancer Metastasis Treat 2023;9:2 https://dx.doi.org/10.20517/2394-4722.2022.94

next-generation, orally effective SERDs with improved efficacy and potency by optimizing the molecule’s
[58]
ability to saturate ERα, antagonizing its activity, and reducing its degradation .
Elacestrant is the first oral SERD that demonstrated better efficacy than endocrine therapy in patients with
[59]
advanced HR-positive breast cancer . The novel SERD functions by degrading ERα and inhibiting
estradiol-dependent estrogen receptor-related gene transcription and tumor growth with improved
pharmacological properties compared to fulvestrant [59-62] . The phase III EMERALD trial investigated the
efficacy and safety of elacestrant in postmenopausal women with HR-positive, HER2-negative advanced or
metastatic breast cancer who had progression after first- or second-line treatment with a combination of
CDK4/6 inhibitor plus endocrine therapy . Elacestrant was administered orally daily, and efficacy was
[59]
compared with standard-of-care (SOC) endocrine therapy (fulvestrant/anastrozole/letrozole/exemestane
monotherapy) . Bidard et al. reported a significantly prolonged progression-free survival in patients
[59]
treated with elacestrant compared to the SOC-cohort after a median follow-up of 15.1 months (HR 0.7;
[59]
P = 0.002) . Kaplan-Meier curves revealed six-month progression-free survival rates of 34.3% vs. 20.4% for
the elacestrant vs. SOC arm . The ESR1 mutation status was assessed using cell-free circulating DNA. Of
[59]
the 477 patients, 47.8% had detectable ESR1 mutations . ESR1-mutated patients had a significant
[59]
improvement of progression-free survival with elacestrant compared with SOC endocrine therapy (HR 0.55;
[59]
P = 0.005) . In a subgroup analysis, the efficacy of elacestrant was also higher than in patients receiving
fulvestrant as SOC . An interim analysis of overall survival rates demonstrated hazard ratios of 0.75
[59]
(95%CI: 0.54-1.04; P = 0.08) in the overall population and 0.59 (95%CI: 0.36-0.96; P = 0.03) in the ESR1-
[59]
mutated cohort . The most common adverse events observed with elacestrant were nausea (35.0%), fatigue
(19.0%), decreased appetite (14.8%), and arthralgia (14.3%), and grade 3 and 4 adverse events were reported
in 27.0% of patients in the elacestrant arm vs. 20,5% in the SOC arm .
[59]

The EMERALD trial reported superior progression-free survival rates of elacestrant compared to fulvestrant
in this selected population and might give a first hint that elacestrant could be an orally available alternative
to the intramuscular injections of fulvestrant, especially for ESR1-mutated breast cancers .
[59]

Several promising oral SERDs are currently being investigated in numerous clinical trials. Table 5 provides a
brief overview of selected clinical trials on oral SERDs, although not all studies have reported results.
Recently, the first results of the phase II acelERA trial were reported. The study evaluated the efficacy and
safety of giredestrant compared with endocrine therapy (fulvestrant or an AI) in patients with HR-positive,
HER2-negative advanced breast cancer who progressed after one or two lines of systemic therapy . Prior
[63]
treatment with fulvestrant and a CDK4/6 inhibitor was allowed. The study did not meet its primary
endpoint of investigator-assessed progression-free survival; however, monotherapy with giredestrant
showed a numerical improvement of progression-free survival compared with endocrine therapy of
physician’s choice (5.6 months vs. 5.4 months; HR 0.81; P = 0.1757) . A higher clinical benefit rate and
[63]
objective response rate were reported with giredestrant . In the cohort of patients with proven ESR1
[63]
mutation (39% of patients), the benefit in progression-free survival was even more pronounced (HR 0.60;
P = 0.0610) . By contrast, negative results were recently reported by the phase II AMEERA-3 trial .
[63]
[64]
Amcenestrant is another oral SERD that showed promising antitumor activity in phase I/II studies
regardless of the ESR1 mutation status [65,66] . The efficacy of amcenestrant compared to endocrine therapy of
physician’s choice was investigated in the phase II AMEERA-3 trial in postmenopausal women with HR-
positive, HER2-negative advanced breast cancer who received ≤ 2 prior lines of endocrine therapy and ≤ 1
prior chemotherapy or ≤ 1 targeted therapy for advanced disease . Unfortunately, the study did not meet
[64]
its primary endpoint, as progression-free survival was similar in both cohorts (median progression-free