So, as one of many hopping on the trend, I've decided to make work of backing up my GOG installers to disc and giving them nice cases. However, one thing I am running into is that not all installers work flawlessly.

My main example here is Stardew Valley. When I burn it to a disc, get the autorun.inf and everything set up, it needs to spin up for a very, very long time before being able to be opened. Compare that to Rayman 2: The Great Escape, which opens almost instantly with the exact same setup. Now the only difference between the two is that Stardew Valley is a 600mb .exe file while Rayman 2: is a 1mb .exe file and an extra .bin file. This leads me to believe the "large" .exe file is the problem here since it doesn't happen with Rayman 2: The Great Escape or even Fallout New Vegas, which is about 14 times bigger than Stardew Valley.

Has anyone run into this problem? Is there a way to fix it?

Your guess sounds correct. If the .exe file has to be read in its entirety to run, then an installer with a 1MB .exe + 599MB .bin will start much faster than a 600MB single-piece .exe. This effect is hidden on devices with high read speeds, but much more visible on media with low-read speeds (optical + much lower real-world read speeds if a lot of random seeks are involved).

Personally, I use BD-R's more as a "tertiary" backup (ie, an extra emergency 'layer' of backup in the event both sets of HDD's backups die and I need something else to restore from to rebuild a HDD backup set from scratch). I don't actually use them as a main backup where I'll be "running" installers directly, for reasons you described. Even though you're reading the same amount of data, it's still faster to copy installer files as large sequential files to an external HDD and run them from that, than run them directly from optical when that involves many more random seeks when finding & decompressing thousands of tiny files from installers run from media with very low random seek speeds (if that makes sense).