I don't think the question necessarily is "Will Book X turn a profit?" I think most of their published books will turn some profit. The question is "Will Book X turn enough of a profit?" Keep in mind, that any time WotC decides to publish a particular book, it redirects resources away from another book/project/etc. In other words, there's a limit to the number of products that WotC can release in a given time period.
So the question then becomes, how does WotC maximize profit? (For better or worse they are a business who's primary goal is to make money). When looking at setting specific books, I think you immediately have to consider that you are looking at a reduced maximum profit potential. Theorhetically, the maximum any book would sell would be 1 per consumer (i.e. every player/DM buys said book). Books like the PHBs, Martial Power, etc. will theorhetically maximize the profit potential (i.e. everyone will want to buy the PHB).
Setting books though inherently limit the profit potential. Not everyone likes FR, Eberron, or Dark Sun for instance. In fact, there are people who despise FR or other settings. The people who hate FR will not buy a FR book, regardless of whether its a campaign setting, player's guide, or Guide to Baldur's Gate. The general FR books though (CS and Players Guide) at least have the chance of being purchased by all of the FR fans. Each subsequent FR book though will gradually see a reduction in the profit potential. If you are running a Kara-Tur campaign for instance, you won't be too interested in a detailed book on Icewind Dale. Likewise, the group that is running a campaign based in Icewind Dale, likely might not have much interest in a book on the Dalelands. Why drop $30 on a product you won't use?
All that being said, I think that the best idea (as has already been expressed) is to supplement those "core" books with Dragon and Dungeon articles. Personally, even though I might not use all of them, I would not have a problem if there was 1 or 2 articles/adventures/etc. in each issue dedicated to a given setting, so long as there was still plenty of generic setting support in each issue. This would really, in my opinion, be the best of both worlds. The FR/Eberron/DS fans get their content while the homebrewers/POL's get their content. Everyone should, in theory, go home happy. By putting the content in the online magazines, WotC also saves a bunch on production cost which makes the reduced profit potential less of an issue.
So the question then becomes, how does WotC maximize profit? (For better or worse they are a business who's primary goal is to make money). When looking at setting specific books, I think you immediately have to consider that you are looking at a reduced maximum profit potential. Theorhetically, the maximum any book would sell would be 1 per consumer (i.e. every player/DM buys said book). Books like the PHBs, Martial Power, etc. will theorhetically maximize the profit potential (i.e. everyone will want to buy the PHB).
Setting books though inherently limit the profit potential. Not everyone likes FR, Eberron, or Dark Sun for instance. In fact, there are people who despise FR or other settings. The people who hate FR will not buy a FR book, regardless of whether its a campaign setting, player's guide, or Guide to Baldur's Gate. The general FR books though (CS and Players Guide) at least have the chance of being purchased by all of the FR fans. Each subsequent FR book though will gradually see a reduction in the profit potential. If you are running a Kara-Tur campaign for instance, you won't be too interested in a detailed book on Icewind Dale. Likewise, the group that is running a campaign based in Icewind Dale, likely might not have much interest in a book on the Dalelands. Why drop $30 on a product you won't use?
All that being said, I think that the best idea (as has already been expressed) is to supplement those "core" books with Dragon and Dungeon articles. Personally, even though I might not use all of them, I would not have a problem if there was 1 or 2 articles/adventures/etc. in each issue dedicated to a given setting, so long as there was still plenty of generic setting support in each issue. This would really, in my opinion, be the best of both worlds. The FR/Eberron/DS fans get their content while the homebrewers/POL's get their content. Everyone should, in theory, go home happy. By putting the content in the online magazines, WotC also saves a bunch on production cost which makes the reduced profit potential less of an issue.