Alexander Zverev and Daniil Medvedev both suffered upsets against Dutch opponents in the second round of the Canadian Open on Wednesday, while fellow title contender Taylor Fritz also crashed out in Montreal.
World number three Zverev, playing his first match since losing to Jannik Sinner in last month's Wimbledon final, was beaten 6-7(3) 6-2 6-4 by Tallon Griekspoor, who arrived in Canada with one win in his last eight tour-level matches.
The defeat comes as a setback to the German's preparations for the U.S. Open, which begins on August 30.
"I've been very close to throwing in the towel a couple of times," world number 69 Griekspoor said after claiming his third victory over French Open champion Zverev.
"I've been working harder and harder lately and I've reached quite a good level in practice over the past couple of weeks.
"I felt like it was just a matter of time. This one is special, especially against a player like Sascha."
Fourth seed Medvedev lost 6-3 7-6(5) to Botic van de Zandschulp, who scored his first win over the 2021 US Open champion.
"I played him a couple of times, and it has always been tough," said the Dutchman. "I never beat him before, but today ... I had to change it up, go out of my comfort zone and I think I did it well."
After winning his biggest title in nearly four years at the Washington Open last week, US seventh seed Fritz lost 7-5 6-3 to Argentine Thiago Agustin Tirante.
Their departures left the ATP 1000 event with just four of the top 10 seeds still in the draw. Sixth seed Flavio Cobolli and 10th seed Andrey Rublev lost their opening matches while fifth seed Felix Auger-Aliassime pulled out with a back injury.
World number one Sinner and 24-times Grand Slam champion Novak Djokovic decided to skip the US Open tune-up tournament, while world number two Carlos Alcaraz is nursing a wrist injury that also ruled him out of the Cincinnati Open.

Fujairah to host World Junior Chess Championship
Salah signs two-year deal with Trabzonspor
Uruguay appoint Forlan as head coach after World Cup debacle
Real Madrid agree deal to sign Diomande until 2033
Arsenal and Emirates renew landmark partnership
