Saddle setback determines your balance over your cranks, which in many ways directly determines long-distance comfort and endurance.

Being more "in front of" the cranks will get you a position more akin to time-trialing, or even standing. It will also cause you to "fall" forward into your handlebars, accelerating hand, shoulder, and neck fatigue.

Your saddle setback should be in a place that allows you to ride mostly relaxed with bent elbows. If you are locking out your arms to support yourself as a result of being too far forward, you will not be happy for long. Oh, and your steering inputs will suffer.