Clinical Implications of SERENA-2 Trial Data

Conversation centered around the clinical implications of recently presented data from the randomized, multi-dose phase II SERENA-2 trial.

Dr. Ian Krop: So why don't we start talking about the SERDS. We had updated data from EMERALD using Elacestrant and then we had this SERENA-2 trial looking at Camizestrant. I thought that the Camizestrant data were very compelling showing this drug. Clearly, this was looking at Fulvestrant versus one of two different doses of Camizestrant. Both showing substantial improvements in progression free survival over single agent Fulvestrant, and what I thought was a relatively clean or relatively - an adverse event profile that looked like this was a drug that was pretty well tolerated. I haven't used the drug in any of the trials. I don't know what your thoughts are, had experience with the drug itself, but I thought the data were encouraging.

Dr. Charles Geyer: I mean it was some of these phase two studies that the companies have set up really have been kind of risky, you know with the Giredestrant, the Genentech Roche. Their study didn't meet the specified criteria, is actually larger than this study. But with base 75 patients per arm, they were able to, as you say, show that the patients getting the Camizestrant, that the AstraZeneca SERD did better and there was a pretty consistent improvement around 0.6, 0.65 with both groups. They also showed that was in the tougher patients, those with liver Mets and some other things, when they looked at subsets, so that was good. The unusual thing about this drug side effect wise, is this photopsia, that was there in about twenty percent of the higher dose and ten percent of the lower dose, its grade one, grade two. It's just kind of a little bit of flashing lights, from what I understand, as you go from dark to light, light to dark, sort of changing, that I think is going to maybe throw in a few little extra wrinkles into the early development. But I think the data is consistent and I think we will see development of Camizestrant just accelerate as based on this study.

Dr. Ian Krop: I think the question I'm struggling with; you know with the data from Elacestrant, with The Emerald studies, the furthest along. It's the, positive phase three, which may lead to approval, is how we're actually going to use these in clinic based on these first set of trials that are coming out? What do you think?

Dr. Charles Geyer: I think we'll just start using it instead of Fulvestrant. This would be my expectation. I mean, you will run into a little bit of the approval challenge if you try and give it in combination with something that's there initially. But they're active and so I think, would you? If you could give an oral SERD with Capivasertib, would you? As opposed to injections with Fulvestrant, assuming that we've seen the safety data which, I think will be forthcoming, I think that's where it's going to go. I think there will be these challenges of payors, that we will work through, but initially it'll get approved as single agent therapy, where it was designed in the trials. And the other thing is the guidelines do now, more and more impact on payor, so it's not quite as tightly tied to the label as it used to be.

Dr. Ian Krop: Right. I mean, getting from a clinical standpoint, I think many of us aren’t using single agent Fulvestrant as much as we used to. So, I think that's what you were alluded to, is that you know in practice, it would be nice to be able to use these drugs instead of Fulvestrant in the way we typically use Fulvestrant now, which is in combination with some other agent, either Alpelisib or perhaps in the future, you know Capivasertib, or Everolimus. I think we're going to need. I mean, there are studies asking those doublet questions with the SERDs and they'll be, hopefully those will come out soon, so we can use them. Because I think that's going to make the SERDs much more impactful in the clinic to allow those kind of combination usage to happen. And interestingly, it seems like most of the data so far with these SERDs, has been showing at least is a good benefit. In fact, usually more benefit in the patient with ESR1 mutations, compared to the ESR1 wildtype patients which is good, kind of consistent with their mechanism of action and from a clinical standpoint, a nice thing to see since we know that the ESR1 mutant patients oftentimes have at least somewhat worse outcome when treated with standard underground therapy.

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