As a matter of fact, I'm in the process of writing an exploration and combat based space game, with an astronomical number of locations. (Much, much greater than billions) These locations will also contain procedurally generated alien technologies that can be incorporated into ship designs, resulting in emergent ship capabilities and gameplay.
Such a large universe also means that there will always be a frontier for someone to strike-out into and establish their own industrial infrastructure/empire. (Once certain thresholds are reached, such factions become visible in "Hyperspace" to other large factions.)