I think the new rules make it much easier to start up and prosper in a very big airport, provided there are slots. I don't think there's as much difference in a medium sized airport, and of course it's always extremely tough if your chosen HQ is very short on slots.
It's easy to put 6 x turboprops on a 2000+ pax route, and get more or less full loads. An airline can still be forced to run at a loss on a 200 pax route by a bigger airline with more money also choosing to run at a loss on that route. But it can't be done on the larger routes, it's very easy to get a foothold, make good profits, and use that to build on. When my 9 seater experiment ended, I briefly started in ORD, using turboprops and then medium jets. I had big profit margins, no way I could have been driven to BK, even with a concerted effort by the huge airlines, but it was also boring, world only had ~6 years left, so I didn't stay.
I think fuel spikes claim the big, inefficient airlines even more than they hurt small startups. I saw 400+ plane airlines in DOTM go from big profits to terminal death spiral with one big spike. Keeps things more interesting, for sure.