Guys, this is easy. A prequel 50,000 years in the past. We get to play out the Reaper-Prothean war.
It's perfect. It gets to be another galaxy-spanning apocalyptic conflict without stepping on the toes of the trilogy. We get to learn a whole lot more about the protheans, who seemed pretty interesting when I was talking with Javik. We could even get multiple races to play, since he said that the prothean empire was actually composed of many species all calling themselves prothean.
There are so many ways to do this. It could be a galaxy-wide RTS setup, with each planet having its own forces and resources that you employ to hold off the reapers as long as you can, with the occasional possibility of a victory to keep the player going in the face of ultimate defeat. It could be another personal Shepard-style story, where you play one of the prothean avatars, or whatever Javik called himself, like the embodiment of hope or something. It could even include some space combat, something the series has always had the opportunity to do but never has.
This would be a great example of how to do dark, end-of-the-world tension. We know that the protheans WILL LOSE. It's a game built on the hope of our protagonists that we know will end in genocide; but that even this ultimate defeat will result in the slightest glimmer of hope with the conduit from ME1. I really think this is the best option available. It avoids the problems that any sequel will run into, and it mostly avoids the problems of a prequel set in the same cycle. In this case, we also know the ultimate outcome, but none of the details that led to it. It just seems like a perfect setup to me.
