Welcome to The Breastcancer.org Podcast, the podcast that brings you the latest information on breast cancer research, treatments, side effects, and survivorship issues through expert interviews, as well as personal stories from people affected by breast cancer. Here's your host, Breastcancer.org Senior Editor, Jamie DePolo.
Jamie DePolo: Hi, I’m Jamie DePolo, senior editor of Breastcancer.org, podcasting live from the 2023 San Antonio Breast Cancer Symposium. I’m with Dr. Stephanie Graff, director of breast oncology at the Lifespan Cancer Institute at Brown University and Co-Leader of the Breast Cancer Translational Research Disease Group. She just finished moderating an educational session on treatments after CDK 4/6 inhibitors.
Dr. Graff, so, could you summarize what was discussed, what did we learn, what are we doing now?
Dr. Stephanie Graff: Yeah. What are we doing now? Great question. I think that really the tenor of the conversation we just had is that treatment after CDK 4/6 inhibitors is a very evolving landscape, and so, what I just, you know, the phrase that I use with my patients is that we’re in the messy middle.
You know, right now what we have is some single agent oral SERDs approved, like elacestrant. Elacestrant is currently approved for patients that have an ESR1 mutation. ESR1 is detected using a blood-based assay called Guardant360. It’s a mechanism of resistance. So, it’s best detected after a patient has had disease progression.
That’s one option, but elacestrant probably isn’t maybe the best SERD. It’s also maybe not best as a single agent. It’s maybe going to be best in combination with other things. There are numerous other SERDs in development, and we’ll hear about those as San Antonio unfolds. We’ll hear about those at ASCO and ESMO and on and on and on.
A second option we have is the family of drugs that target PI3 kinase. We’ve had apelisib approved for a while. We’ve recently received approval for capivasertib. Capivasertib targets not just PI3 kinase but everything in the AKT altered pathway, which includes PI3 kinase, AKT, and PTEN, and so, that is detected on tissue and it’s an activating mutation.
So, patients typically have that within their tumor from the time that they’re diagnosed with metastatic disease. So, we can test patients for that alteration early and sort of be ready and waiting in the wings, knowing that that’s going to be an option for them. Right now both apelisib targeting PI3 kinase and capivasertib targeting the AKT-altered tumors are approved in combination with endocrine therapy and after progression and CDK 4/6 inhibitors, and so, whether we should use those before or after elacestrant for patients that have both mutations, no one knows.
Most of us are saying probably elacestrant first, PI3 kinase or AKT-targeting second, just based on where we currently are in the landscape of knowledge. For patients that don’t have an alteration, if you have a germ line BRCA1 or BRCA2, we do still have PARP inhibitors. Again, if you have no alteration, we still have fulvestrant as a single agent. We can always add everolimus to that. Dr. Ruth O’Regan just did a great job reminding us that everolimus actually is a really great drug. It has some side effects.
Every single thing we talk about has side effects, and so, Abigail Johnston, who was the patient advocate who just spoke so powerfully said, you know, that’s a huge part about what we should be doing as clinicians and what we should be doing as the patient community, is coming together to say where’s that rub, what matters to us as humans, what matters to us as clinicians, what matters to us as patients, in terms of the tradeoff of what we’re willing to give up, what we’re willing to gain, and how those pieces work together to optimize treatment in that second line.
I think someday we’ll get to a different place where we know better…how those sequence better, how to use these agents in combination, but that’s where we landed right now.
Jamie DePolo: Thank you. I just have one more question. So, it sounded like from the presentation that giving a different CDK 4/6 inhibitor if one stopped working isn’t perhaps the best option.
Dr. Stephanie Graff: Yeah. So, right now, you know, I think that most of the time… we have three CDK 4/6 inhibitors approved, palbociclib, ribociclib, and abemaciclib, at the time…I’m sorry, this is a long, meandering answer to what should have been an easy question.. palbociclib had sort of the lion’s share of experience, and so, most of the sequencing data we have, most patients have had palbociclib first.
Palbociclib, as the data has matured, did not show an overall survival advantage, so now that share is starting to shift. We’re seeing that more and more patients are getting either ribociclib or abemaciclib as their first CDK 4/6 inhibitor.
In the sequencing CDK 4/6 inhibitors, so, CDK 4/6 inhibitor one and on progression you get CDK 4/6 inhibitor two, data, we have seen that continuing palbociclib…palbociclib after palbociclib, which was called the PACE study, did not work. So, we don’t do that.
Jamie DePolo: Okay.
Dr. Stephanie Graff: Changing from palbociclib to ribociclib, which was the MAINTAIN trial, did work, but we don’t really know for somebody who starts on ribociclib, if changing them to abemaciclib, for example, or palbociclib for that matter, would make a difference. And so, there’s a third trial called the postMONARCH study that we expect to report out probably at ASCO next year…
Jamie DePolo: Okay.
Dr. Stephanie Graff: …which hopefully will give us some clarity, but even on that study we may not see a huge population of patients that didn’t get first-line…we still think most of those patients will probably be first-line palbociclib patients, again, just because of the timing of that study taking patients on. So, that may give us some clarity today. It may not give us a lot of clarity for two years from now as the prescribing patterns change.
Jamie DePolo: Okay. All right. Dr. Graff, thank you so much. This has been very helpful and I know we don’t have a lot of answers but we have a little bit more clarity. Thank you.
Dr. Stephanie Graff: Thanks.
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