It's the variety that makes a game like this dope. There are so many items that impact your character in various ways that you'll never have the same powers or playstyle for two playthroughs consecutively. Items you hold and how you play can impact what bosses you fight too, so there's an experiment and discovery method to the madness. Add that the maps are always different and now you're talking about a game where you're experimenting and finding out new things, but there's always a twist that makes certain items more or less useful. Gameplay is fun for old school heads as long as you get past the weirdness for sure.
All that said, I think a lot of the same aspects I loved in binding of isaac are included in Enter the Gungeon, but Gungeon combat is the one I favor and I find it even more challenging (plus it's light and humorous instead of dark and depressing). I still have a ton to unlock in Enter the Gungeon and it's basically replaced Binding of Isaac as the game I go back to when I'm just killing some time. I'm into all this pixel ish though. Steamworld Dig, Rogue Legacy, Spelunker, Binding of Isaac and Enter the Gungeon all get spins from me randomly even though I've played through them plenty.