The first effect of Powerful Foes triggers once during setup as soon as you choose the class deck, which is corroborated by the preview article. There is no indication that it works any other way.
You Will definitely have to carefully plan out your setup choices to get the most out of the deck, including your Agenda deck and the traits of your chosen villain. You'll want to choose villains with complimentary costs and abilities. Taking two super expensive villains like Vader and Boba won't work out well. I love that the deck has cards to support bruiser villains like Inquisitor and Bossk or support villains like Kayn and Sorin.
I agree. Maybe the highlight of the boxset. And that's saying A LOT.
My only concern is the deplete ability of Powerful Foes: if you deplete the card, doesn't that also mean the villains are no longer earned?
Plus, Shyla's reward is worded funny in my opinion. "Before you declare an attack" is a weird timing instance. Not sure why it's worded like that.