There's already been several departures from the shows. LEGENDS seems designed to survive changes to the line-up and still continue--it helps keep the show interesting. But ARROW and SUPERGIRL have not benefitted from the loss of actors and have become the worse for it. As long as FLASH, SUPERGIRL and ARROW have their star, I guess they can keep going. On that front I think Melissa Benoist is the most likely to exit to pursue other opportunities in Hollywood and on Broadway.
It does seem like Melissa Benoist is the only one getting meaningful work outside of Supergirl. I don't think Stephen Amell doing professional wrestling counts as meaningful work and I haven't heard of Grant Gustin doing
anything outside of The Flash. I think Supergirl will probably get five seasons and then wrap up. Or maybe just continue the show without her. Call it DEO. Sort of like how when Kyra Sedgwick didn't want to do
The Closer anymore so they kept all the other actors and changed it to Major Crimes. I think a show with an agency tasked with investigating extra-ordinary phenomena could work. It could sort of be like X-Files.