Will Roche's Perseverance pay off?

Camizestrant's toplined hit in AstraZeneca's unusually designed phase 3 Serena-6 study puts the spotlight on a rival SERD, Roche's giredestrant, in a true first-line setting. Giredestrant's Persevera trial ends soon, and should deliver data at some point this year.

The readout is important because it involves the first pivotal study of an oral SERD (selective ER degrader) in first-line ER-positive, HER2-negative breast cancer. Yet to be determined is the best CDK4/6 inhibitor to combine with and the importance of ERS1 mutations, while key considerations include giredestrant's second-line failure, and the hand grenade Serena-6 just threw into the front-line setting.

There is much doubt still surrounding the last point, given that Serena-6, a switch-design study, has only been toplined for PFS and relies on a new screening paradigm, and without seeing full data it's unclear precisely what it says about treatment sequencing. However, if it is deemed that patients should be given a SERD only after showing evidence of the ESR1 resistance mutation this would reduce the first-line opportunity – for giredestrant, camizestrant and others.

The ESR1 effect

The first SERD battleground was second-line breast cancer, and here Menarini's Orserdu came out on top, securing approval in ESR1-mutant disease after failure of endocrine therapy.

Other SERDs, including camizestrant and most recently Lilly's imlunestrant, showed a second-line benefit only in ESR1m patients. Roche itself failed in the Acelera trial; while that too revealed a signal in ESR1m disease, the second-line setting is no longer being pursued, and Roche and others have effectively turned to earlier disease.

One possibility is that ESR1 mutation will have a different impact in the front line, where tumours are still ER dependent. The hope is that giving a SERD up front in addition to standard of care could cut the emergence of this resistance mutation, and thus deliver a survival benefit versus standard of care alone in all-comers.

But what is the standard of care? First-line patients typically receive endocrine therapy combined with a CDK4/6 inhibitor, but there are several of the latter to choose from, including Pfizer's Ibrance, Novartis’s Kisqali and Lilly’s Verzenio.

Persevera, in line with Astra's first-line Serena-4 trial, uses Ibrance, but it's notable that Olema is combining its latecomer palazestrant with Kisqali, while Pfizer/Arvinas have turned away from Ibrance in favour of the CDK4-selective molecule atirmociclib. All the first-line trials use PFS as primary endpoint.

Oral SERDs in first-line breast cancer

Note: *CDK4 inhibitor. Source: OncologyPipeline.

Beyond efficacy, a key consideration for giredestrant is safety. A 100mg dose was earlier associated with grade 1 asymptomatic bradycardia, with the rate deemed related to giredestrant being 13%.

A subtle detail is that Persevera actually tests a lower, 30mg giredestrant dose, which has shown clinical benefit without bradycardia. Whether any bradycardia are seen in Persevera – and, if not, whether 30mg is high enough to deliver strong enough efficacy – therefore remain open questions.

Last September Roche said giredestrant had sales potential of over CHF3bn a year, so clearly the group is counting on the molecule to turn around its run of bad luck in oncology drug development. For this to play out Persevera must read out positively.