Isaac co-starred with Natalie Portman in the film adaptation of the novel "Annihilation", playing her character's husband. Directed by Alex Garland, the role is Isaac's second collaboration with the director, after "Ex Machina". In late-January 2019, Isaac was cast as Duke Leto Atreides in the upcoming Denis Villeneuve film "Dune". In 2019, Isaac was cast in the Paul Schrader film "The Card Counter" and starred in the action-adventure film "Triple Frontier" directed by J. C. Chandor as Pope, an ex-CAG operative. Isaac will star in and produce "The Great Machine", an adaptation of the comic "Ex Machina". He will also star in "London," a science fiction film to be directed by Ben Stiller. Isaac is also in talks for the role of Moon Knight for a Disney+ series being developed by Marvel Studios and was confirmed in January 2021 to have been cast in the role. In December 2020, it was announced that Isaac would star as Solid Snake in the film adaptation of "Metal Gear Solid" directed by Jordan Vogt-Roberts.