As far as I know, the size of any source file is irrelevant in relation to the limitations of Zip files.
Before data is archived, Duplicati breaks the source files into small chuncks of 100 KB (or another value that is set by the user, but never more than a few MB’s).
So backing up a 20GB source file results in a Zip file containing a bunch of 100 KB files. The large source file has already been split up in small files before it is stored in the Zip file.
The only limitations are the size of the upload volume (not more than 4 GB), the number of block files in one upload volume (not more than 65535) and the size of the file list in the DLIST file (not more than 4 GB).
On the other hand, I don’t think defaulting to Zip64 can’t do any harm to existing backups, apart from potentional issues when combining Zip and Zip64 in existing backups.