Twin engined aircraft flights from SYD to JNB would basically have to fly further north than the QF B744 flights. This would be to remain within the "still air" ETOPS range ((calculated at a fast single engine speed), which I believe is a little over 5 hours for the B777-300ER) of suitable alternate airports such as Perth, Cocos Is, St Denis, Mauritius, Durban etc. The planned route would have to look at the depressurisation case so that at all times the aircraft remains within range of a suitable airport flying at 14,000'/10,000' after loss of pressurisation.
The route flown from SYD to JNB by a twin would on most occasions be significantly longer than the four engined route - not only in the distance flown over the earths surface but also because it would require flying into stronger headwinds/jetstreams. Often, the optimum SYD-JNB route involves flying a long way south over the Antarctic land mass but QF operations limit the flights to remain north of the continent (approx 65 degrees South) due to depressurisation issues - Antarctica has a very high plateau in that area.
The twin engined aircraft would not be at a disadvantage on the return flight from JNB as the optimum route is normally further north to take advantage of the tailwinds ie within the ETOPS/depressurisation limits.