Sanofi’s oral SERD fails in AMEERA-3 trial, plans to discontinue the development of amcenestrant in Breast Cancer

Metastatic breast cancer is essentially a Stage IV breast cancer wherein cancer originates in breast tissue and then spreads to other body parts. The steroid hormone, estradiol, plays a vital role in breast cancer progression, and a majority of human breast cancers start as estrogen-dependent and express the estrogen receptor (ER). ERα is the major ER subtype in the mammary epithelium and plays a critical role in mammary gland biology and breast cancer progression. Estrogen receptor alpha (ERα), encoded by the ESR1 gene, is a member of the nuclear hormone receptor superfamily that is expressed in ∼70% of newly diagnosed breast cancers.

Amcenestrant (formerly known as SAR439859) is an investigational oral selective estrogen receptor degrader (SERD) dosed once daily. It antagonizes and degrades the estrogen receptor (ER), in turn blocking the ER signaling pathway. Amcenestrant is a potent, oral selective estrogen receptor α-(ERα) degrader, dosed once daily. The drug has received fast-track designation from FDA. 

AstraZeneca’s Faslodex remains a backbone treatment for most of the CDK 4/6 inhibitor classes treating HR-positive, HER2-negative breast cancer patients for the last 2 decades. Moreover, in 2017, the drug received a label expansion as a solo treatment for advanced HR+HER2- breast cancer patients who have not undergone endocrine therapy. Despite its not-so-good bioavailability and intramuscular administration, it is the first and only SERD approved for Breast Cancer until now. The drug had already hit a 1 billion mark in revenue globally in 2018, which was the last full year for the drug before its generic entered in 2019. Even though it might not be a celebration for AstraZeneca in terms of revenue, we can foresee its increased access among patients considering the price dip. 

Presently, the emergence of oral Next-Generation SERDs looks bleak, considering the disappointing results of Sanofi’s amcenestrant and Roche’s giredestrant. This time-lapse will only benefit Faslodex (both brand and generic) and Radius Health, which has already filed Elacestrant in the ESR1 mutated breast cancer setting, an area with a high unmet need. 

Describing the details of Sanofi’s AMEERA-3 trial, the efficacy findings indicated that the median PFS with the oral selective estrogen receptor degrader was 3.6 months by independent central review (ICR) vs. 3.7 months with endocrine therapy in the intention-to-treat (ITT) population. However, a numerically longer PFS was reported with amcenestrant vs. endocrine therapy in those who harbored ESR1 mutations, at a median of 3.7 months vs. 2.0 months respectively. Moreover, PFS served as the primary endpoint for the trial, and a key secondary endpoint was overall survival. In addition, 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. 

In terms of safety results, the Treatment-related AEs (TRAEs) occurred in 44.8% of those who received the oral SERD and 31.3% of those given a physician’s choice of therapy; these effects were grade 3 or higher in 4.9% and 0.7% of patients, respectively. Serious AEs (SAEs) were experienced by 16.1% of those who received amcenestrant vs. 10.2% of those given endocrine therapy. Apparently, 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. No patients on the control arm discontinued therapy due to TRAEs. Due to the caveats in the AMEERA-3 trial design, it is high time that rival companies developing SERDS should also take it as a learning opportunity.

Expert Opinion: “Although AMEERA-3 did not achieve its primary objective, there was a numerically similar PFS that was observed with amcenestrant compared with the treatment of physician’s choice endocrine monotherapy in patients with endocrine-resistant, ER-positive, HER2-negative advanced breast cancer”

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

For more insights: ER positive HER2 negative Breast Cancer Market, ESR1 Mutated Metastatic Breast Cancer Market, Triple Negative Breast Cancer Market, Metastatic castration-resistant prostate cancer (mCRPC) Market, ovarian cancer Market, pancreatic cancer Market, and others