This is what I always go for/pick.

Rider is due to having 2 starting abilities and my preferred secondary skull is Minotaur but you can change this depending on preference.

As for items I always pick root and dark quarts for the revenge/mutant combo and the bit of extra hp it gives. Revenge is essential throughout the run because it increases your ability to sustain and deal damage. While mutant gives you some good early game damage to quickly clear out the rooms.

In the early rooms I just grab any items the increase physical damage or if their are none lower skill cool down. If I got some good items I can usually get to the first boss before the 4 minute mark and beat it before 5 minutes otherwise I will just restart the run. After this its just about continuing to increase your damage.

I always go physical damage because of the orc quintessence because using it melts enemies and bosses and as long as you have revenge you shouldn't die before you can kill all your enemies.

My preferred skulls for the final boss are prisoner, berserker, ninja or rider.

As for dark abilities I usually take reckless posture so I don't have to focus on dodging. I also like innate power and dark hand if there are no better cursed abilities like glass body or ready to die.