The Kazakh rider bridged to the lone remaining breakaway rider, Antoine Duschene (Direct Energie), before riding alone for the final 16km of the stage to Salon-de-Provence.
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In a tough start to the stage, the breakaway gained over eight minutes on the peloton as they climbed some of the way up Mont Ventoux, with sprinter Andre Greipel pulling out of the race on the climb.
With two steep second category climbs in the final 30km, Duschene attacked alone off the front of the breakaway on the first one and looked to be in prime position to hold his lead to the line.
With a lead of nearly a minute’s lead over the peloton on the flat run-in to the line, Duschene was joined by Lutsenko with 17km to go and left behind just a kilometre later.
The chasing peloton couldn’t work together enough to catch Lutsenko, despite the wide open and smooth road, with the Kazakh maintaining a comfortable gap over the bunch for the entire final 10km.
Matthews sprinted for third after seeing his lead cut, with Tom Dumoulin (Giant-Alpecin) now 18 seconds off the lead in third. A summit finish on the Col de Madone outside Nice on Saturday will decide the general classification, with the likes of Dumoulin, Geraint Thomas and Ion Izagirre looking to eliminate their time gaps on the infamous climb.
Paris-Nice stage five result, Saint-Paul-Trois-Châteaux – Salon-de-Provence (198k)
1. Alexey Lutsenko (Kaz) Astana, 5-00-26
2. Alexander Kristoff (Nor) Katusha, at 21s
3. Michael Matthews (Aus) Orica-GreenEdge, st
4. Davide Cimolai (Ita) Lampre-Merida, st
5. Sep Vanmarcke (Bel) LottoNL-Jumbo, st
6. Pieter Serry (Bel) Etixx-Quick Step, st
7. Vicente Reynes (Esp) IAM Cycling, st
8. Leonardo Duque (Col) Delko Marseille Provence KTM, st
9. Olivier Naesen (Bel) IAM Cycling, st
10. Arnold Jeannesson (Fra) Cofidis, st
Overall standings after stage five
1. Michael Matthews (Aus) Orica-GreenEdge, 19-24-58
2. Alexey Lutsenko (Kaz) Astana, at 6s
3. Tom Dumoulin (Ned) Giant-Alpecin, at 18s
4. Patrick Bevin (NZl) Cannondale, at 23s
5. Ion Izagirre (Esp) Movistar, st
6. Geraint Thomas (GBr) Team Sky, st
7. Lieuwe Westra (Ned) Astana, at 28s
8. Dries Devenyns (Bel) IAM Cycling, at 29s
9. Rafal Majka (Pol) Tinkoff, at 31s
10. Richie Porte (Aus) BMC, st