Treating Advanced Breast Cancer After Progression on CDK4/6 Inhibitors

The combination of abemaciclib (Verzenio) plus fulvestrant (Faslodex) significantly improved progression-free survival (PFS) versus fulvestrant alone in patients with hormone receptor-positive/HER2-negative advanced breast cancer who had disease progression on a CDK4/6 inhibitor and endocrine therapy, according to phase III data presented at the American Society of Clinical Oncology (ASCO) annual meeting.

MedPage Today brought together three expert leaders in the field for a virtual roundtable discussion: Moderator Hope S. Rugo, MD, of the University of California San Francisco (UCSF) Helen Diller Family Comprehensive Cancer Center, is joined by Joyce O’Shaughnessy, MD, of Baylor University Medical Center, Texas Oncology, in Dallas, and Sara Tolaney, MD, MPH, of Dana-Farber Cancer Institute in Boston. This second of four exclusive episodes focuses on the postMONARCH study.

Click here to watch the other videos from this ASCO roundtable series on breast cancer.

Following is a transcript of their remarks:

Rugo: We also saw another study that was really hotly awaited. Both of these trials were called postMONARCH and a lot of excitement came up when we saw the data from a phase II investigator-initiated multicenter trial, the MAINTAIN trial that Kevin Kalinsky did, really fabulous work looking at ribociclib [Kisqali] in patients who’d already had largely palbociclib [Ibrance] as first-line therapy with an endocrine treatment. But it’s a very heterogeneous population. Some had chemo, other endocrine therapies, etc., and a smaller trial relatively. But it did show a benefit, particularly in the subpopulation of patients that didn’t have mutations, a variety of mutations that all seemed to go together, ESR1 and other mutations.

So we’ve sort of been waiting to see what would postMONARCH tell us, and that trial, looked at abemaciclib in patients who just had their first-line endocrine therapy in a CDK4/6 inhibitor, and patients received fulvestrant with either abemaciclib or not. So Joyce, what did you think of the data from postMONARCH?

O’Shaughnessy: Well, I’m glad it was positive. It’s really good to have an option because prescribing a CDK post-CDK can be challenging in terms of insurance reimbursement, etc. So I’m really glad it’s a positive trial. I’d love to see it approved by the FDA.

If you look at the median improvement in progression-free survival, it’s really quite modest in the neighborhood of a month-ish. But there’s a tail on the curve that is around the 20% of patients going out over a year. And if you look at the forest plot, it appears to be more patients that are more endocrine-therapy sensitive, not so much the liver disease, although I like abemaciclib very much for liver disease. So I think it is a very welcome addition.

I think it does raise the question about whether if you had some intervening endocrine therapies in there, for example, or even a chemotherapy or two and come back to it, whether you might have more in the way of benefit from it.

But at any rate, I think it is a combination everybody’s very familiar with, the toxicity is well established, we know how to use it. And when you’re not ready to go on to chemotherapy for a patient and they don’t have a target, they don’t have ESR1, they don’t have a mutation in PI3 kinase pathway, it’s another option for them on the endocrine therapy armamentarium that I think will be welcomed by patients and doctors.

Rugo: It’s an interesting question because the other option for those patients right now is everolimus [Afinitor], and we don’t have an oral SERD [selective estrogen receptor degrader] to mix together with all these drugs, but we will in the not too distant future. So that will take care of this sort of ESR1 part.

But would you choose always in those patients, abema [abemaciclib] versus everolimus, and how would you decide? They looked at visceral mets [metastasis] versus not and it didn’t seem to work in that, but it worked a little in liver mets, which didn’t make a whole lot of sense. But Sarah, how would you put all that together?

Tolaney: I think the bottom line is we have a lot of choices post-CDK, so it’s very complicated. And as you pointed out, maybe someone who has an ESR1, you could do elacestrant [Orserdu], if someone has PI3K, P10, AKT, maybe you think about capivasertib [Truqap]. You could also think about alpelisib [Piqray] if they’re PI3K-mutant.

So then I feel like there becomes this other bucket of patients that maybe don’t have a targetable alteration, but you’re trying to do something with. So as you said, we could either think about continuing CDK beyond progression using fulvestrant-abema there, or you could think about fulvestrant-everolimus. And I guess maybe the way I would think about it is, we saw in postMONARCH that the benefits seemed to mostly be, as you said, in not the non-visceral population. So maybe someone who doesn’t have quite as much disease. Maybe I’m trying to think about CDK, someone who was on their first-line CDK for a really long time, progressed a little bit, that seems like the perfect person to put on fulvestrant-abema. But someone who maybe had more significant progression and maybe has more visceral involvement, I might think about mTOR [mammalian target of rapamycin] inhibition with everolimus in that situation.

Rugo: Yeah, we really do see those patients where there’s a little more uptake in the bone, and they’re not even that symptomatic and it’s hard to know.

O’Shuaghnessy: But the markers are creeping.

Rugo: The markers are creeping.

O’Shuaghnessy: Everybody’s getting nervous [laughter].

Rugo: And you’re thinking, what should we do? It’s almost like a non-change, especially when we have combination data with an oral SERD and everolimus for the more symptomatic and the oral SERD and abema for the less symptomatic. I mean, there’s already safety data with elacestrant, so I think it will be, we presented a poster here too, and a study we’ve worked on, and I think that that will be, now with fulvestrant and hopefully later with oral SERDs, this will be a good option for patients. Knowing you could go different ways is great.

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