Supernatural still has the God card to play; despite some theories that "The Writer" was God (personally, I don't think so, and more think he was a prophet who ascended when his work was done).
It's a good hook, really. The ground has been laid for the characters to question the cosmology of the Supernatural universe and the point of the whole war between good, evil, humans, monsters, etc.
Basically, I wouldn't be surprised if we see an Incarnations of Immortality-type ending where the cosmos is reset, maybe even literally a new God (or no God!) takes over, and we end the story with a hopeful note that the world will actually progress to a better state.
Right now, Supernatural's universe is a very grim one without much hope in sight - it is doomed to be the battleground between immortal forces that just want to use humanity as war materials to control the higher dimensions.
However, once the God plot is resolved, that SHOULD be it. The end. There's nothing they can do to top it, or to make the quest of supernatural adventurers relevant any further.