Arvinas is pushing ahead with plans to expand development of its prostate cancer prospect ARV-766 into earlier-line settings. The biotech linked the protein degrader to declines in the PSA biomarker and partial responses in a phase 1/2 trial, providing early hints of its ability to overcome resistance mechanisms.
Connecticut-based Arvinas designed ARV-766 to degrade wild-type androgen receptor (AR) and clinically relevant LBD mutants that are linked to resistance to existing prostate cancer drugs. By degrading LBD mutants, ARV-766 may counter the drug resistance that can arise in patients taking AR inhibitors such as Astellas and Pfizer’s Xtandi and Johnson & Johnson’s Zytiga, thereby improving health outcomes.
Arvinas is putting that idea to the test in a clinical trial that enrolled 34 patients in its phase 1 stage and, as of the latest data cutoff, 13 patients in its phase 2 portion. The study is recruiting patients who have received at least one line of treatment with a novel hormonal agent such as Xtandi and Zytiga.
The trial is enrolling all comers, but Arvinas is particularly interested in the 13 patients, across both parts of the study, who have the AR LBD mutations targeted by ARV-766. In the latest update, Arvinas reported that 42% of patients with AR LBD mutations had a 50% or greater decline in PSA, a key biomarker. Two of the four evaluable LBD-mutated patients had partial responses, although one was unconfirmed.
Arvinas dug down into the type of AR LBD mutations possessed by the people who experienced a 50% drop in PSA. Of the five patients with L702H mutations, three had a 50% decline in PSA. The data point provides evidence that ARV-766 may address an increasingly important mutation. Arvinas shared data showing the prevalence of L702H mutations increased from 2% in 2016 to 11% in 2023.
ARV-766 is also designed to target T878X, H875Y and less frequent mutations. All three of the patients with co-occurring H875, T878 and L702H mutations had a 50% or greater reduction in PSA levels.
With the safety data coming in clean—no patients had grade 4 or 5 treatment-related adverse events or dose-limiting toxicities—Arvinas sees the evidence of efficacy as sufficiently encouraging to start gearing up for a study that will test ARV-766 in patients who are yet to take hormonal agents such as Xtandi and Zytiga. The trial, which is set to start this year, will test the candidate in combination with Zytiga.