Astra stakes a claim for early camizestrant

AstraZeneca, one of several companies to demonstrate that second-line treatment of ER-positive HER2-negative breast cancer with an oral SERD works only in patients whose tumours have an ESR1 mutation, has made an argument for early testing for this mutation, courtesy of a phase 3 trial.

That trial is Serena-6, a relatively low-profile pivotal study of camizestrant, whose unique feature was early detection of the development of ERS1 mutation, a key resistance pathway. On Wednesday this was toplined positive for PFS, a result that raises several questions, including about the complexity of adding ctDNA analysis to routine treatment, and over the reliability of a win solely on PFS.

Serena-6 has a switch design, taking first-line patients undergoing standard treatment with CDK4/6 and aromatase inhibitors, and monitoring for development of ESR1m. This monitoring is carried out using ctDNA analysis as part of routine tumour scanning; patients in whom ESR1m is detected – but who haven't had disease progression – are then given camizestrant plus the CDK4/6 inhibitor, or continue on their original therapy.

Big win?

On Wednesday Astra heralded a "highly statistically significant and clinically meaningful improvement in PFS", Serena-6's primary endpoint.

This in itself shouldn't come as a huge surprise. Several second-line trials, including Ember-3 of Lilly’s imlunestrant, and camizestrant's own Serena-2, have shown SERDs (selective ER degraders) to work only in ESR1-mutant disease. The US label of Menarini's Orserdu, the only such approved drug, is limited to ESR1-positive second-line disease.

But Astra's argument for early diagnosis of ESR1 mutation is subtle. The typical second line is where patients have progressed on CDK4/6 and aromatase inhibition, but the company is positioning camizestrant in a setting slightly before this. Some might simply ask: why not just give camizestrant first line? It won't go unnoticed that Astra is calling Serena-6 a "first-line" win.

The first-line setting is important since this is now the key battleground for oral SERDs, the first of which, Roche's giredestrant, could yield data from the Persevera trial this year. Camizestrant's first-line Serena-4 study won't read out until late 2026, so Astra making the case for early use could be a smart way of seizing a first-mover advantage of sorts.

Not so fast

However, until full Serena-6 data are revealed significant doubts remain. Perhaps most important is that a PFS benefit alone will count for little if patients who do progress via ESR1 resistance can then simply be given Orserdu, with no detriment to their overall survival. So far Astra says Serena-6's OS result is immature at this interim analysis.

And it should be stressed that Serena-6's active camizestrant cohort compares this only against the first-line standard without disease progression at baseline. The study doesn't compare SERD plus standard of care while still in response, versus SERD plus standard of care after disease progression.

A separate detail will be especially noteworthy to Olema, whose own SERD palazestrant is in a second wave of projects, with plans to enter a pivotal first-line Kisqali combo study only announced recently. In recent years Olema started referring to palazestrant as a CERAN/SERD (complete ER antagonist and SERD), arguing that ER degradation alone isn't enough. 

Astra is now in on the act too, claiming that camizestrant is the first next-generation "oral SERD and complete ER antagonist" to demonstrate a first-line benefit in combination with widely approved CDK4/6 inhibitors.

Key trials of camizestrant

Notes: AI=aromatase inhibitor; *phase 2; others are phase 3. Source: OncologyPipeline.