Terry hasn’t written a Witches Discworld novel in years, and instead is covering that territory with Tiffany Aching. So yes, I think Agnes and Perdita are unlikely to return soon.
I disagree; I think Terry’s (sorta, kinda) setting Tiffany up to replace Granny Weatherwax. Granny’s been spending a long time as the “top gunfighter” witch (“You’d walk uneasily through life, always on the lookout for the next girl with a better broomstick and a quicker hand on the frog.”), and Tiffany’s ascention would give Terry a graceful way to take the burden off Granny’s shoulders.
Though I still think Granny/Nanny/Magrat/Agnes will be around for quite a spell (heh).
OTOH, I doubt he’ll scrap the “maid, mother, crone” configuration, and where does Tiffany fit into that? And who would succeed Weatherwax as the Lance crone?
Yes, RJ, but if the novel’s about them, rather than just using them as bit players, then as epic level magic users, they’ll need to face epic level problems to keep the conflict in the story interesting. Either that or they’d have to face problems that magic can’t fix.
And they were serious magic users, rather than whacky ones. Would you rather that they were whackied up, or that the story played with the difference between them and the UU wizards?
And I don’t think that Tiffany is ever going to become a Lancre witch. She’s destined for the Chalk. She’s getting training in Lancre, but will be going home eventually. She may become the unacknowledged best witch, eventually, but she’s shown no sign of joining up with older witches. She’s worked things through with her age-mates, and I think that, if anything, she’ll continue doing that.
Maybe she’ll become part of a coven when she’s old enough to be ‘the other one.’
Oh, and I also think that any coven she’d be in would be back on the Chalk. She’s working to increase acceptance of magic there.
That would be interesting!
But one point Pterry’s made now and then in more recent books is that the main purpose of UU is not to train wizards to do magic but to train them not to do magic, which is much harder. Everything is connected, and doing magic is like picking a card out of the bottom level of a house of cards; it’s not the card you’re reaching for that you have to worry about. So there’s no place for an ubermage like the kid in Sourcery. If Esk and Simon come back, they’ll have to come back as very disciplined, restrained wizards.
I’m not going anywhere, Guanoperson, and neither is Agnes thankyouverymuch! 
Just thought I’d throw a link out to the Terry Pratchett wiki here. 
It looks like it could use some more articles…
Oh, no disagreement from me here; Tiffany without the Chalk is as implausible as Nanny Ogg without a double entendre. 
I see it more as Tiffany’s proficiency would be a way to allow Granny Weatherwax a sort of quasi-retirement (as much as Discworld witches retire, anyway), since she wouldn’t need to appear in a plot when things in the countryside go all wahooni-shaped.
I suspect the Lancre coven might end up migrating to Nanny, Magrat, and Agnes, with Granny and Tiffany brought in as Special Guest Stars™ when the occasion arises. There’s also the possibility of Pterry finally Granny out of the books, though I’d rather that didn’t happen. I still miss Cohen. 
And to tie this back to the OP, could a novel featuring the return of Esk and Simon be centered around tying together “wizards’ magic” with “witches’ magic”? Geometry and rules vs. ritual and headology…
actually bringing Simon and Esk back could be kind of interesting (I can picture them turning up as sort of a “crunchy enlightened granola hippie” contrast to the stodgy, 12 meals a day non-magic doing wizards)
he’s managed to get a lot of mileage out of what started off as bit players like Ponder Stibbons, Agnes/Perdita, Detritus, the Igors so who knows, it might be a winner.
silenus, “ook ook ook ook, ook ook ook ook” (what happens in the menagerie, stays in the menagerie)
Magrat, for all her reliance on ear massages and flower based potions, has always been a fullfledged witch. Tiffany is still very much a witch in training, though most of her training is just getting old enough that people will respect her as a witch. The Chalk seems to have a tradition of single witches, not trios.
As for what or who the Librarian does in the menagerie…possibly he isn’t so set upon the distinctions of monkey, chimp, and orangutang in that place. He’s probably getting more action as an orangutang than he did as a human. I do often wonder just how much wizardly celibacy is enforced.