The pair fought last September and it was Usyk who came out on top, outpointing Joshua in London the win the WBA, IBF and WBO titles.
In doing so, Usyk became just the third fighter to win world titles at cruiserweight and heavyweight after Evander Holyfield and David Haye.
The winner will hope to meet Tyson Fury towards the end of this year to determine the division's first undisputed heavyweight champion since Lennox Lewis in 1999.
Despite Fury confirming his retirement, many believe he will be enticed to fight one more time.
Ukraine's Usyk will enter the contest against Joshua as a favourite and should he win again, there will be question marks about whether his British opponent is finished when it comes to fighting at elite level.
"I mean it kind of is yeah, if he loses this one then he'll find himself in the position of having to kind of call for fights," Clarke told Planet Sport when asked if it was win or bust for Joshua.
"And I don't know how well that will kind of sit with him. He might get another world title fairly quickly because if there is a fight for undisputed and they get it done for the end of the year.
"I'm being very optimistic, but let's say Usyk wins and Usyk-Fury happens in December, there's no particular reason why that couldn't happen, but we know how complicated these things can be.
"That first fight would get sanctioned by all the governing bodies but say there was a rematch clause which you would imagine there would be, there always is now," Clarke continued.
"Then a second fight for all the belts might not get sanctioned by them all and they might start to fragment at that point, because unless obviously, it's a draw in the first fight then it wouldn't be a unification so it could all just blow wide open couldn't it.
"And then he'll right up there in the rankings you would've thought to get a fight for a world title again. There will always be fights out there for him but if he loses to Usyk again, then maybe his days at that very top level are kind of over."