I create a new homebrew setting for every campaign, and run in it 4-7 years historically. Part of the campaign process is thinking about what stories can be explored in that setting that can't in other settings, and those themes get woven in.
For example in my current Masks of the Imperium campaign, a couple of the things we are exploring are:
1. A worn out Imperium in a worn out world - literally there is not enough magic to cast spells of 6th level and higher.
2. Colonizing a new world, but one that already has civilizations at "similar tech" - not like Europe colonizing the Americas.
3. Characters all starting as agents of the Imperium, having woken one of the 101 semi-sentient artifact masks that will grow with them. Between that and being able to requisition any mundane equipment it has been the least loot-focused and non-murder-hobo campaign I've ever run.
4. Exploring genocide (of the Dwarves) and the ethics of created servitor races (Drow and Haliflings).
Plus of course other heroic aspects that could be found elsewhere, like dealing with an usurper, etc.