I have been running Ascension since shortly after it came out. The party is an Interrogator (recently moved to Inquisitor), Vindicare Assassin, Psyker Primaris, Sage and Death Cult Assassin (all are Rank 10-11). Yes, each Ascended Class has its obvious strengths and a list of weaknesses. As a GM, I let them go crazy with their powers and abilities but I make sure their major story encounters are populated with equally powerful baddies. When the story calls for "and out of the alley comes a group of 20 thugs with clubs and stub pistols…" I don't even throw dice, I just asked how they respond and storytell what happens. Only for the epic fights, etc. do I get the miniatures and the mat out and roll dice.
Some tips without changing (much) any rules:
1. Let the psyker go nuts and burn minions to a crisp the first round. Just make sure he feels the pressure of his actions as he is targeted as the biggest threat. People hate psykers and people with guns kill psykers although you might have to find the right one like a heavy flamer (Burn the Witch! anyone?)
2. Vindicare Assassins are still vulnerable to autofire and even large blast weapons not to mention squads of 10 Imperial guards men all shooting at semi-auto because they have heard the lethal rumours of the Vindicare. A compareable swordsman can tie him up in melee. Also, psykers work well since WP checks are easily failed (possession and then use him against the party psyker is fun). Oh, and even though the Vindicare can hit just about every target he aims at, baddies can still dodge his overpriced bullets (Trust me, at Unique, the Vindicare doesn't get his special ammo back often). And really who cares?? The Vindicare Assassin is usually good for only one kill a turn… not a lot when the party is up against 20-30 baddies. (Same goes for the Death Gult Assassin who carves up 1 baddie a turn.)
3. The only rule I got rid of was "This One Thing I Ask.." I changed it so that the party could burn 1 Influence to get +10 on an Influence test (up to +60 max. bonus).
4. I never say no, but do not let your party get a hold of any force fields… but let your big baddies have them, which can be destroyed when the psyker goes too far and burns the baddie and all his belongings :-) Also, any baddie with any Intelligence gets Dodge +20, because they didn't get to be that bad by standing there to get hit. Also, no hexagrammic wards, etc. Warp Weapons make people pay attention. Limit Blessed, Sanctified, etc. weapons (there is a short story called Sacrifice by Ben Counter where they talk about how blessed weapons, etc. are made and their rarity… good information)
5. If you have them, use the NPC stats from the Deathwatch or Rogue Trader books for Ascension level DH characters and even these should be tailored a bit. I don't use the Horde Rules, I make them kill each baddie dead (yes, lots of numbers for me but your Primaris Psyker thins the horde quickly).
6. Traps work. People forget that things like a covered pit still catch people off guard when you are not actively looking. With science you can make up all sorts of fun stuff. I love servitors… yes, they are slow and have lower stats but 6 of them with a mix of heavy bolters, multi-meltas and heavy flamers means someone is bound to get hit. Add armour, immune to fear, etc. and they are great to put fear back in a party… oh and those heavy weapons are not really useable by the party when the servitor dies. Same goes for servo skulls with boltguns and flamers (of course GW has the miniatures for all these).
The thing to keep in mind about Ascension is that it is Epic. Your players are not taking on a cult cell, they are taking on the Fortress of Evil. Look at the NPC examples given in Ascension, one is a planetary governor. Also, the normal person is afraid of the Inquisition, Assassins, Psykers, etc. so if the party comes out blowing things up, people hide… investigations become harder because people stay hidden, bad guys run away (yes, let them get away and they can come back again or you can let the Calaxian Conclave remind the party of their failure… too many failures and they might suspect the Agents are Heretics themselves.)
Let your players know that Ascension becomes less of about combat than basic DH and more about intrigue and politics. My party upset an Inquisitor Lord who wanted to capture Haarlock and his secrets instead of banishing him to the nether which the party did in the Haarlock Legacy. They make Influence tests that "pass" and my Inquisitor Lord makes Influence Tests (yes, I actually roll for him) to block their access to things… not to mention he sent his own Vindicare Assassin who shot and "killed" the Interrogator. Also, after completely the Apostasy Gambit trilogy there are Ecclesiarchy and Imperials who think the part killed St. Drusus and zealots never forgive… or even listen to explanations.
Note: GMs play different ways, players have different attachments to characters but with the ability to burn Fate points to "escape death", I feel if you are not "killing" a player character from time to time (esp. when they do something really brave… i.e. dumb) then you are not doing something right. No matter how powerful they become, they should fear death. It is a dangerous universe, people die. All of my characters (but 1) have some sort of cyber limb (or lungs) because the Critical damage killed them and they Burned a Fate Point to survive it … yes, they lived but usually at a cost.
Also, Do Not Forget Insanity and Corruption. At the Ascension level, even with Jaded, characters should be worried about Mental Disorders and Mutations. They have seen some serious **** and it should always leave a mark. (My party's newly minted Inquisitor has 81 Corruption… the Ordo Malleus NPC is a Puritan and refuses to deal with him and the party's Holier-than-thou-art Death Cult Assassin is inching closer to sacrificing him in the name of the Emperor).
Wow, sorry so much, but hope it helps.
-Cynr