Cup kings Llanelli also went out after losing 22-12 at home to Pontypridd. The visitors ran in four tries in the second half to overturn a 12-3 interval deficit. 13-times winners Llanelli had a depleted side out as six of their players were away with the Wales U20 squad and a further three were with the Wales Sevens squad.
Last year's beaten finalists Cardiff were comfortable victors over Carmarthen Quins and left wing Nathan Rees ran in a four tries as Cardiff eased through 43-15.
Bedwas overcame poor league form to rout Bonymaen 43-0, and Bridgend powered their way to a 45-10 victory at Builth Wells, running in six tries past the Bulls lightweight defence.
In the all-Premier clash at Llynfi Road, Glamorgan Wanderers defeated Maesteg 22-0, Andrew Coomber went over three times for Newport in their 59-17 success over One East outfit Llanharan, Cross Keys won 44-19 at Merthyr, and Ebbw Vale beat Caerphilly 31-14 with wing Andrew Bevan crossing for a try hat-trick.