Boss Rush and ??? can provide additional chances at good items.
As a result of beginning the challenge with both Key Pieces, Angel Rooms are much more likely to appear than normal.
It is somewhat easier to beat this challenge with The Polaroid (which doesn't appear after the Mom fight in Afterbirth †) than it is with The Negative, as Isaac is an easier fight than Satan in this challenge. Furthermore, the Chest can provide many chances at useful items that the Dark Room does not.
Aside from beating Mega Satan for the first time, the player must also unlock all starter items in the challenge. That is, ??? or The Lamb must be beaten to unlock the Key Pieces (which is a prerequisite requirement to defeat Mega Satan anyway) and Satan must be beaten with Isaac to unlock Mom's Knife. In addition, although not explicitly stated, The Negative must also be unlocked by defeating Satan 5 times, as the challenge requires you to go to the Dark Room and then fight Mega Satan. Mega Satan can be defeated before unlocking The Negative and vice versa; the challenge will be unlocked immediately once all requirements are met.
Despite being forced to take The Negative, the Cathedral can still be accessed; however, once Isaac is defeated and the chest is entered, the run will simply end and will not count as a completion of the challenge.