This issue only happens with PRTG, and I can't figure out the key reason why.
I set up a Reverse Proxy on the DMZ, which points to the PRTG Core Server. All good, verified external access and it works.
It's not until a few hours later, that I attempt to log on to PRTG externally, and I can't access the login page. I check if it's running internally by connecting to our VPN, and PRTG is running just fine, no changes in the configuration.
So I figured out that if I send out an unsolicited ARP request on the Firewall through SSH for the public IP address that PRTG is associated with, all of a sudden PRTG works instantly externally.
Any explanation why this keeps happening. At first I thought it was because of odd metric settings within Server 2016, but now that I completely reconfigured the access to PRTG according to the following guide, I am still experiencing the issues: