End of the line for Sanofi’s SERD amcenestrant as it fails first-line trial

Sanofi has called time on breast cancer candidate amcenestrant – at one time one of its top pipeline prospects – after it missed the mark in another clinical trial.

The decision to abandon development of the oral selective oestrogen receptor degrader (SERD) comes after an interim analysis of the phase 3 AMEERA-5 trial failed an interim analysis. It was comparing the drug to letrozole – both given on top of Pfizer’s Ibrance (palbociclib) – as first-line therapy for patients with HR-positive/HER2-negative advanced breast cancer.

The demise of amcenestrant hasn’t come out of the blue, as it also flunked a potentially registration phase 2 study earlier this year called AMEERA-3, which was comparing it to physician’s choice of endocrine therapy in patients with the same form of breast cancer who had progressed after prior hormonal therapy.

Sanofi said all other studies of amcenestrant will now be discontinued, including the late-stage AMEERA-6 trial pitting amcenestrant against tamoxifen in early-stage HR+ breast cancer patients who have discontinues aromatase inhibitor therapy due to toxicity.

This is the first failure for the SERD class in the first-line treatment setting, and will be a worrying development for other developers, some of whom are also running trials in previously-untreated patients.

Like amcenestrant, Roche’s giredestrant failed the phase 2 ACELERA trial in relapsed/refractory HR+/HER2- breast cancer, and the company has said it will now focus its efforts on the first-line and adjuvant treatment settings.

Radius Health and Menarini’s elacestrant is so far the only drug in the category to show efficacy as a second-line therapy for HR+/HER2- breast cancer, which the companies reckon is a result of selecting a patient population enriched with subjects whose tumours harbour ESR1 mutations. They are however not focused at the moment on developing the drug in the first-line setting.

Roche meanwhile also pointed to better results in ACELERA with giredestrant in a subgroup of patients with ESR1 mutants, suggesting that the failure of Sanofi’s drug to show efficacy could have been a result of its all-comer recruitment strategy, which was used in both AMEERA-3 and AMEERA-5.

ESR1 mutations are seen in patients who have developed resistance to aromatase inhibitors, which might indicate SERDS will have greater utility in a second-line setting.

The AMEERA-5 failure makes the focus by some developers on first-line use look a little shaky, unless of course they can show activity in patients both with and without ESR1 mutations.

It’s worth noting that neither of Roche’s phase 3 trials – PERSEVERA in the first-line setting and LIDERA as adjuvant treatment – appear to have ESR1 enrichment built into the design.

Meanwhile, AstraZeneca is running the non-enriched phase 2 SERENA-2 trial of second-line camizestrant, and two phase 3 studies in previously-untreated subjects – SERENA-4 and SERENA-6 – with the latter study including ESR1 enrichment.

At the moment, Lilly is a little further back in development, with a non-enriched phase 2 second-line study on the go called EMBER-3.

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