Amcenestrant and Endocrine Therapy Led to Similar Risk of Disease Progression in Endocrine-Resistant, ER-Positive Advanced Breast Cancer


The phase 2 AMEERA-3 trial revealed no progression-free survival benefit of amcenestrant vs physician’s choice of endocrine monotherapy in patients with endocrine-resistant, estrogen receptor–positive, HER2-negative advanced breast cancer.

Results of the phase 2 AMEERA-3 trial (NCT04059484) presented during the 2022 European Society for Medical Oncology Congress (ESMO) showed that amcenestrant (SAR439859) did not result in a significant improvement in progression-free survival (PFS) vs physician’s choice of endocrine monotherapy in patients with endocrine-resistant, estrogen receptor (ER)–positive, HER2-negative advanced breast cancer, although the results were numerically comparable.

Findings indicated that the median PFS with the oral selective estrogen receptor degrader (n = 143) was 3.6 months (95% CI, 2.0-3.9) by independent central review (ICR) vs 3.7 months (95% CI, 2.0-4.9) with endocrine therapy (n = 147) in the intention-to-treat (ITT) population (HR, 1.05; 95% CI, 0.789-1.4; 1-sided P value, 0.6437).

However, a numerically longer PFS was reported with amcenestrant (n = 65) vs endocrine therapy (n = 55) in those who harbored ESR1 mutations, at a median of 3.7 months (95% CI, 1.9-7.2) vs 2.0 months (95% CI, 1.9-4.3), respectively (HR, 0.90; 95% CI, 0.565-1.435).

“Although AMEERA-3 did not achieve its primary objective, there was a numerically similar PFS that was observed with amcenestrant compared with treatment of physician’s choice endocrine monotherapy in patients with endocrine-resistant, ER-positive, HER2-negative advanced breast cancer,” Sara M. Tolaney, MD, MPH, lead study author as well as chief of the Division of Breast Oncology and associate director of Susan F. Smith Center for Women’s Cancers, said in a presentation on the data. “This was in a population of patients where 80% were being treated in the second-line metastatic setting. Eighty percent had a prior CDK4/6 inhibitor and [around] 90% in the control arm received fulvestrant [Faslodex].”

Amcenestrant is a competitive ER antagonist that possesses a dual mechanism of action that is characterized by ER binding and degradation resulting in robust ER signaling inhibition.

Pre/peri- and postmenopausal women and men with ER-positive, HER2-negative advanced breast cancer were enrolled to AMEERA-3. Patients were required to have an ECOG performance status of 0 or 1. They could not have received more than 2 previous lines of endocrine treatment or more than 1 chemotherapy or targeted agent for advanced disease. They must have experienced disease progression on or following endocrine treatment in the adjuvant or advanced settings.

A total of 290 participants were randomly assigned 1:1 to receive oral amcenestrant at a once-daily dose of 400 mg as part of a 28-day cycle or physician’s choice of endocrine therapy in the form of fulvestrant, tamoxifen, or an aromatase inhibitor (AI) such as anastrozole, letrozole, or exemestane.

Key stratification factors included the presence of visceral metastases (yes vs no), previous treatment with a CDK4/6 inhibitor where available (yes vs no), and performance status (0 vs 1).

PFS served as the primary end point for the trial, and a key secondary end point was overall survival.

Regarding baseline patient characteristics, Tolaney, who is also a senior physician at Dana-Farber Cancer Institute and an associate professor of medicine at Harvard Medical School, noted that the 2 treatment arms were generally well balanced.

The median age in those who received the oral SERD was 58 years (range, 29-84) vs 60 years (range, 28-66) in those given endocrine treatment; 81.8% and 87.7% of patients, respectively, were postmenopausal. Most patients in the investigative and control arms, respectively, were White (71.3% vs 69.4%), had an ECOG performance status of 0 (67.8% vs 63.9%), had secondary resistance to endocrine therapy (94.4% vs 95.9%), and measurable disease (90.2% vs 85.0%).

In the amcenestrant arm, 53.6% of patients (n = 75) had ESR1 wild-type disease, and 46.4% had ESR1-mutated disease; these rates were 60.7% and 39.3%, respectively, in the endocrine-therapy arm. Visceral metastases were present in 63.6% of those who received the oral SERD vs 63.9% of those given endocrine therapy. Moreover, 79.7% of those in the investigative arm previously received CDK4/6 inhibition in the advanced setting vs 78.2% of those in the control arm; 81.8% vs 82.3% of patients, respectively, received 1 prior line of endocrine treatment in the advanced setting.

“When looking at the choice of treatment utilized in the control arm, you can see that the vast majority of patients are on fulvestrant; this was [about] 90% of patients in that arm,” Tolaney noted. In the control arm, 89.8% of patients received fulvestrant, 6.8% received an AI, and 3.4% received tamoxifen.

Additional data shared during the Congress showed that PFS treatment effect in other key patient subsets proved to be generally consistent with what had been observed in the primary analysis.

Moreover, investigator-assessed PFS was found to be consistent with ICR-assessed PFS in the amcenestrant and endocrine therapy arms, at a median PFS of 3.7 months vs 3.5 months, respectively (HR, 0.944; 95% CI, 0.735-1.228).

“Amcenestrant given at 400 mg was well tolerated with no new safety signals identified,” Tolaney said. “[We did not see] clinically significant bradycardia, acute QTc prolongation, or visual disturbances.”

Treatment-emergent adverse effects (TEAEs), which occurred in 82.5% of those who received amcenestrant and 76.2% of those given endocrine therapy, were mostly grade 1 or 2 in severity across the treatment arms. Treatment-related AEs (TRAEs) occurred in 44.8% of those who received the oral SERD and 31.3% of those given physician’s choice of therapy; these effects were grade 3 or higher in 4.9% and 0.7% of patients, respectively.

The most common all-grade TRAEs reported in the investigative and control arms were nausea (14.0% vs 4.1%, respectively), vomiting (8.4% vs 1.4%), arthralgia (4.9% vs 2.7%), back pain (0.7% vs 2.0%), headache (4.2% vs 2.7%), fatigue (5.6% vs 6.1%), and diarrhea (4.2% vs 2.0%). In the amcenestrant arm, 1 patient experienced grade 3 or higher fatigue.

Two patients in the investigative arm discontinued treatment because of TRAEs in the form of grade 1 or 2 dyspepsia and grade 3 rash. No patients on the control arm discontinued therapy due to TRAEs.

Serious AEs (SAEs) were experienced by 16.1% of those who received amcenestrant vs 10.2% of those given endocrine therapy. Grade 3 treatment-related SAEs in the form of gastritis and angina pectoris were experienced by 1 patient in the amcenestrant arm and 1 patient in the endocrine therapy arm, respectively.

One toxicity-related death occurred during the on-treatment period in 1 patient on the control arm who was receiving fulvestrant, although this was not determined to be related to the treatment.

“Given the outcome of the prespecified interim analysis of the phase 3 AMEERA-5 trial [NCT04478266], Sanofi is discontinuing the global clinical development program of amcenestrant,” Tolaney concluded.


Tolaney SM, Chan A, Petrakova K, et al. AMEERA-3, a phase 2 study of amcenestrant versus endocrine treatment of physician’s choice (TPC) in patients with endocrine-resistant ER+/HER2– advanced breast cancer (aBC). Ann Oncol. 2022;33(suppl 7):S88-S121. doi:10.1016/annonc/annonc1040

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