Arvinas’s degrader disappoints

Arvinas had hoped that its Protac estrogen receptor degrader vepdegestrant would be able to work where other SERDs have not – but the project has produced a similar result to its rivals.

In the Veritac-2 trial in second-line ER-positive HER2-negative breast cancer, vepdegestrant hit one of its dual primary endpoints, showing a progression-free survival benefit in ESR1 mutants. However, the project failed to show any improvement in the intent-to-treat population, Arvinas and its partner Pfizer said on Tuesday.

The topline release echoes previous data with SERDs, which have so far only prevailed in ESR1 mutants. Still, some investors were clearly surprised by the result, with Arvinas’s stock opening down 40% on Tuesday morning.

Perhaps investors wanted more details, but the companies are saving the data for a future medical meeting – a move Arvinas telegraphed during its fourth-quarter earnings last month. For now all the partners are saying is that, in the ESR1m population, “the results exceeded the pre-specified target hazard ratio of 0.60”.

Overall survival, a secondary endpoint, was immature at the time of the analysis.

SERDs & Protacs

While traditional SERDs passively degrade the oestrogen receptor, Protacs like vepdegestrant are designed to promote degradation actively. Ahead of the data release Arvinas’s chief medical officer, Noah Berkowitz, told ApexOnco that this could lead to more potent degradation, giving vepdegestrant a better chance in ESR1 wild-types.

However, this theory has not worked out. Berkowitz flagged the presence of other driver mutations in wild-type patients as a potentially confounding factor, so it will be interesting to see if there are any details on patients’ mutation status when the full data are released.

Vepdegestrant now joins the likes of Menarini’s Orserdu and Lilly’s imlunestrant in only showing a benefit in ESR1 mutants. One pivotal second-line trial yet to read out involves Olema’s palazestrant, which that company says is both a SERD and a complete ER antagonist (CERAN). Whether this will make any difference is a big question.

AstraZeneca is now making similar claims about its contender camizestrant. That project recently claimed a win in the Serena-6 switch study, which monitored first-line patients receiving standard of care for development of ESR1m.

Meanwhile a true first-line readout is approaching, from Roche’s Persevera study of giredestrant – which also failed in the second-line setting – plus Pfizer’s CDK4/6 inhibitor Ibrance. Arvinas and Pfizer are also looking at the front line, recently disclosing plans to test vepdegestrant alongside Pfizer’s investigational CDK4 inhibitor atirmociclib.

Oral SERD studies in 2nd-line ER-positive HER2-negative breast cancer

Note: *also includes imlunestrant + Verzenio arm. Source: OncologyPipeline & clinicaltrials.gov.