Warning: SPOILERS ahead for the Supergirl season 2 finale
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While worldbuilding and stage-setting are all the rage for the superhero genre - especially on episodic TV - Supergirl opted to focus its second season finale on wrapping up the seasonal storylines and keeping the setups for new status-quos in the realm of character relationships (specifically, Kara is now the lone single person among a cast of characters that have almost all paired-up at this point), rather than comic-book references or mythology details. If anything, it's main "big" change (Mon-El is gone for parts unknown, with Earth's atmosphere rendered toxic to Daxamites for the foreseeable future) served to take things back closer to their season 1 starting point.
At least right up to the ending, where the somber final shot of Supergirl flying off to work out her newfound loneliness through crime-fighting (and the reveal that the returning Cat Grant has sussed-out her secret identity) cut abruptly to a flashback of the destruction of Krypton and the reveal that at least one more baby... "something" had been loaded into an escape pod and shot off to Earth before the planet went up in smoke. We didn't get to see it, but whoever was doing the loading left us with one word: "Reign."
While Supergirl is a show that often thrives on misdirection (the much-hyped word of General Zod turning up in the finale turned out to be references to a hallucination), "Reign" would seem very much to suggest that this incoming new nemesis will indeed be drawn once again from the character's comic book incarnation. But while the majority of the enemies faced by Kara Zor-El over her first two seasons have been modernized versions of classic Superman/Supergirl foes, the character most associated with the name Reign is a fairly recent creation of DC's now-concluding "New 52" era.
WORLDKILLERS
As incarnated in the pages of Supergirl's 6th DC Comics Universe incarnation - which featured an aloof, distant Kara who was fixated on her Kryptonian heritage and largely distrustful/dismissive of humanity - Reign is a female superhuman created by Krypton scientists but actually "built" from the fetal stage up from genetic experiments on a creature from an unknown alien world. She had comparable powers to Supergirl herself (flight, superhuman strength, super-speed, invulnerability and additionally was a master of weapons-based combat) and was later revealed to be the nominal leader of an entire four person team of similarly-created bio-weapons called "Worldkillers," which also included members named Perillus, Deimax and Flower of Heaven.
The gradual reveal of the Worldkillers' powers and origin were spread over a three issue Supergirl storyline that made them the first significant new nemeses the Girl of Steel faced in her New 52 continuity, which at the time was meant to exist in the absence of any prior storylines and center this particular Kara as one of the most recently-emerged figures in the new "streamlined" DC Universe. However, allusions to characters and events that had come before were still common; and more than a few fans took notice that the Worldkillers' origin as monsters made by cruel Kryptonian experimentation made them very similar to the villain of the infamous Death of Superman storyline - Doomsday.
This connection was teased out further when Supergirl, having worked out the "trick" that the Worldkiller's were vulnerable to one another's attacks, pushed them to the brink of defeat. In retreat, Reign revealed that a fifth yet-unseen Worldkiller existed somewhere in the universe - leaving fans to speculate that this could become the origin of the eventual New 52 version of Doomsday himself... while others speculated that Reign may actually have been referring to Kara.
IS THIS DOOMSDAY?
Ever since the character was created, Superman adaptations have tended to be in a hurry to get a version of Doomsday into the mix. Given that the DCEU TV world's version of Supergirl has leaned harder than most on establishing Kara as a direct parallel of her more famous cousin (with much of Superman's presence in the Season 2 finale serving to reinforce the idea that she is, in fact, the more powerful of the two), it's not hard to imagine the showrunners deciding that the next logical step in terms of enemies is to have Kara encounter a Doomsday analog of her own. If so, Reign - a female character with an extremely similar origin story - would seem to fit the bill for such a role almost too perfectly.
If this is the case, the question Supergirl fans will have to ask themselves while they wait for Season 3 to start delivering answers is what purpose a Doomsday-like character will play. In this particular series, villains' goals and motives tend to be secondary to what effect they'll have on Kara and her compatriots on an emotional/character level - and with Kara now having lost her main love interest and seemingly set to be re-focused on the superheroic side of her identity, a Doomsday-style encounter sets her up for intriguing and potentially character turns.
Doomsday, of course, was the character who killed (or, rather, appeared to have killed) Superman. No one really expects Supergirl to "kill off" its title character (at least not without a similar "just kidding" denouement); but the broader fallout of that storyline, which involved various "pretender" Supermen vying for the position of one true hero and an overall question of whether the "returned" original had changed for the worse. Is Reign set to be an excuse for Supergirl to work through some of the Reign (there's that word again...) of The Supermen story-beats? It seems possible - but we'll have to wait for season 3 to find out.