Close encounters of the Serd kind

The idea of treating breast cancer with selective oestrogen receptor degraders, or Serds, has undergone a divergence. The pretreated setting looks increasingly driven by ESR1 mutation, but rather than focus on this the big pharma players are turning instead to front-line combination use.

An even stranger fact is that Radius Pharma, the only company so far that managed to design a second-line study geared at showing a benefit in ESR1-mutant disease – and which succeeded as a result – is not pursuing the first-line setting. Unless Radius moves quickly it will not have the upper hand for long.

Radius has this advantage as a result of the Emerald trial of its Serd, elacestrant, which succeeded in second-line ER-positive, Her2-negative breast cancer largely thanks to having been enriched for ESR1 mutation. There was a statistical PFS benefit versus standard of care (including Faslodex) in ESR1-positive patients, and these also drove a PFS benefit in all-comers.

Conversely, two subsequent studies in a similar setting – but not enriched for ESR1 – have failed recently. In March Sanofi’s amcenestrant flunked the Ameera-3 trial, and last week Roche’s giredestrant failed in Acelera.

Doomed to fail

Based on this trend the two remaining registrational Serd studies in the second-line setting now look doomed to fail; Astrazeneca’s Serena-2 trial of camizestrant reads out in the second half, while Lilly’s Ember-3 study of imlunestrant has a completion date of mid-2023. Neither enriches for ESR1 mutation, or tests for a benefit in this group as a primary endpoint.

Instead of amending trial designs the big pharmas are instead looking to position Serds in earlier settings of ER-positive Her2-negative breast cancer.

On April 28 Sanofi’s head of R&D, John Reed, said: “From the beginning we felt that the sweet spot for Serds was going to be in early lines of therapy. We took a swing in the late line [with amcenestrant], knowing the risks associated.”

On the same day Jake Van Naarden, head of Lilly’s Loxo division, stated: “The ultimate impact [for imlunestrant] is adjuvant, and we’re working on a trial design that we will share later in the year.” The company suggested that the failed second-line trials were underpowered.

For its part, Astra says there are differences between the projects. It is continuing with the now fully enrolled Serena-2 study, in which it expects 30-40% of patients to be ESR1-positive, and cites an earlier trial that showed camizestrant’s clinical activity in patients with and without ESR1 mutation.

Beating Faslodex

To understand why this debate has even arisen it is important to go back to the launch of the first Serd, Astra’s Faslodex. This now off-patent drug had poor bioavailability and was delivered intramuscularly, and only received a second-line label.

However, toxicity and poor bioavailability aside, there is no theoretical reason why Faslodex should not work first line, where the oestrogen receptor is thought to be an even bigger driver of disease than in later therapy lines, where resistance builds up.

Crucially, in patients with ESR1 mutations Faslodex is thought not to work as well as newer Serds. This might explain Radius’s success in the Emerald study: elacestrant and Faslodex alike might have proved efficacious in ESR1 wild-type patients, but the Radius project won out in those with ESR1 mutation.

More evidence of such a benefit comes from Roche’s failed Acelera trial: on April 25 Bill Anderson, the Swiss group’s head of pharma, said giredestrant yielded better progression-free survival versus standard of care in patients with baseline ESR1 mutations than in all-comers.

Sanofi says “most patients become ER-independent in their cancer journey”, and along with Roche and Astra is playing up the relevance of front-line studies that are already under way. With no need to beat Faslodex in these early lines the key for novel Serds will be to come out better than aromatase inhibition, in combination with other front-line drugs like Ibrance.

The debate about patient enrichment concerns earlier-stage biotechs too, including Arvinas and Zentalis; Stifel analysts recently wrote that the monotherapy setting looked increasingly like an ESR1-mutant story, and no doubt when these companies get around to designing registrational trials they will bear this in mind.

It is remarkable that so far only Radius has been able to score a second-line success. Roche, for instance, has been playing the Serd game for years with zero success so far; in 2014 it spent $725m buying Seragon, but both of this group’s lead Serd assets, RG6046 and RG6047, ended up in the bin. Giredestrant is the group’s third attempt.

But Radius now faces a big problem of its own. It is not running early-line elacestrant studies, saying these are the responsibility of its partner Menarini, and is focusing on getting its project approved second-line, where a filing is due in the current quarter.

Should any of Radius’s rivals score in the first-line setting elacestrant could see its second-line window close just as fast as it had opened.

This story has been amended to correct the design of Ameera-6.