Mix ground beef, panko breadcrumbs, egg, ketchup, mustard, garlic powder, onion powder, salt, and pepper, then form into 4 patties about ½ inch thick.
Toast buttered buns with a sprinkle of garlic powder in a skillet over medium heat about 2 minutes until golden.
Cook patties in a hot skillet 3–4 minutes, flip and cook 2–3 minutes more, then add mozzarella and cheddar and cover briefly to melt.
Spread 1 tablespoon marinara on each bun bottom, add the cheesy patty, top with 3 pepperoni slices, oregano, basil, and extra mozzarella if desired.
Add optional toppings like pickles, onions, basil, or extra cheese, then close with the top bun and serve warm.