Sanofi has ceased the development of amcenestrant, an oral selective estrogen receptor degrader (SERD), following the disappointing results of the phase 3 AMEERA-5 trial. This decision marks a significant setback for Sanofi's breast cancer pipeline and raises questions about the broader potential of SERDs in the first-line treatment setting.
The AMEERA-5 trial evaluated amcenestrant in combination with palbociclib versus letrozole in combination with palbociclib as a first-line therapy for patients with HR-positive/HER2-negative advanced breast cancer. The interim analysis revealed that the amcenestrant arm did not demonstrate a significant improvement in efficacy compared to the letrozole arm, leading to the termination of the trial.
This setback follows the earlier failure of the AMEERA-3 phase 2 study, where amcenestrant was compared to physician's choice of endocrine therapy in patients with HR+/HER2- breast cancer who had progressed after prior hormonal therapy. The drug failed to meet its primary endpoint in this earlier trial as well.
Impact on SERD Development
The failure of amcenestrant in the first-line setting is a worrying development for other companies developing SERDs, some of whom are also conducting trials in previously untreated patients. Roche's giredestrant also failed in the phase 2 ACELERA trial in relapsed/refractory HR+/HER2- breast cancer, leading the company to focus on first-line and adjuvant settings. Radius Health and Menarini's elacestrant is currently the only SERD to demonstrate efficacy as a second-line therapy for HR+/HER2- breast cancer, particularly in patients with ESR1 mutations.
The Role of ESR1 Mutations
Roche's ACELERA trial showed better results with giredestrant in a subgroup of patients with ESR1 mutations, suggesting that the failure of amcenestrant may be due to its all-comer recruitment strategy in both AMEERA-3 and AMEERA-5. ESR1 mutations are commonly found in patients who have developed resistance to aromatase inhibitors, indicating that SERDs may be more effective in the second-line setting.
Several other companies are exploring the potential of SERDs in breast cancer treatment. AstraZeneca is conducting the non-enriched phase 2 SERENA-2 trial of camizestrant in the second-line setting, as well as two phase 3 studies in previously untreated subjects – SERENA-4 and SERENA-6, with the latter including ESR1 enrichment. Lilly is also in development with a non-enriched phase 2 second-line study called EMBER-3.
Sanofi has announced that all other studies of amcenestrant will be discontinued, including the late-stage AMEERA-6 trial, which was comparing amcenestrant to tamoxifen in early-stage HR+ breast cancer patients who had discontinued aromatase inhibitor therapy due to toxicity.
