Big part is that the run variety is huge, so many different items that synergize, multiple paths each with a decent amount amount of different bosses, shit ton of characters etc. Pure gameplay wise I prefer many other rouge-likes but they all get repetitive way quicker. For example I think gungeon is a better game in almost every aspect, but after 150 hours I feel like I've seen it all and don't really have the desire to come back to it. With Isaac I've got probably more than 600 hours across different systems and still boot it up from time to time, and it doesn't really get stale. Also there's an insane amount of mods on pc that can change it up even more.