I ride a Giant Defy Advanced 2 primarily. I'm the type of person that when I ride I want to go, and go, and go. I've found that I need to force myself to stop and get out of the saddle and stretch my legs a little. The longest ride I'll do now without stopping and getting out of the saddle is 40 miles and even at that, the last mile or two, I'm feeling it. This year I rode my first century, I forced myself to stop every 25-30 miles and give my butt a break. I was on the bike for nearly 7 hours that day, but I had no problems as far as comfort in the saddle were concerned. For what it's worth, I have a Brooks B17 that I have about 3k miles on. Here's another valuable lesson that I learned. Midway thru the summer I raised my saddle just a little bit to try and get a little more extension for my legs thinking that it would reduce leg fatigue. After a while I started to get a really sore left sit bone after about 20 miles. I tried switching saddles with some others that I have on hand but I didn't see a big improvement. I decided to lower my seat again after realizing that the pain started occurring not long after I raised my saddle. Voila! The pain went away. I'm talking about less than a 1/2" difference in saddle height was what was causing me pain.
The other thing you don't mention is whether you ride with padded shorts or not. That's also something to consider if you don't ride with them currently.
One more thing, I'm also 220 lbs. I ride Continental GP5K at 85psi.