I don't see the series ending yet, as there is a lot of questions, but I'd like Nefarious to get lost for a game or two, as this really isn't Crash Bandicoot with the same antagonist in every game. Nefarious isn't the main antagonist of the Lombaxes to say the least. But those, who have read the comics, know that
Tachyon is still alive.
I think he or another one of his kind or his kind in whole is the only worthy antagonist for the last game, being that Ratchet gets a contact to the other Lombaxes in their dimension of exile.
Anyway, the ending in A4O clearly indicates there will be more.
It was said in an interview that if done correcly, the series will never end, but I don't think so. The last (two) game(s) have to be epic and memorable to begin with, and also well sold and hyped. Who wouldn't try to get the last bucks of an ending series, and furthermore, try to do the last game the most memorable of them all.
Also, what if theykilled off the Plumber?
The series ends then 