Everolimus for HR+ Metastatic Breast Cancer

Transcript:Adam M. Brufsky, MD, PhD: Where does everolimus fit now? We have CDK4, and we’ve got fulvestrant alone. Where are you giving everolimus? Do we have any data that have come out recently at San Antonio, the PrECOG study, for example, of fulvestrant with everolimus? And we have another trial of everolimus and exemestane. Aditya, what do you do now? What do you think of that phase II trial, the PrECOG?

Aditya Bardia, MD, MPH: I think that was an interesting trial, which looked at fulvestrant plus/minus everolimus for second-line and beyond. Patients who had progressed on an aromatase inhibitor were randomized to receive fulvestrant as a single agent versus fulvestrant plus the mTOR inhibitor. In design, it was very similar to the BOLERO-2 design, which looked at exemestane plus/minus everolimus, but instead of exemestane, it was fulvestrant in this trial. As one would potentially predict, the fulvestrant-plus-everolimus arm did better than the fulvestrant arm. So, I think it provides us an additional option of potentially combining an mTOR inhibitor with fulvestrant as opposed to exemestane. And I think this might have value because if the first-line at this time is letrozole plus palbociclib, and if you have a patient who progresses on letrozole/palbociclib, it’s unclear what to do at this time. You could use exemestane plus everolimus in that setting, but this trial would potentially allow you to switch both the partners, switch the AI to fulvestrant, plus switch the CDK4/6 inhibitor to mTOR. But we just don’t have enough data at this time because this trial did not look at patients who had received prior CDK4/6. But I think, in practice, it’s potentially a combination that we would consider.

A second point to consider would be this subtype of ER-positive breast cancer, which harbors ESR1 mutations. We do know that patients who receive prior AIs tend to develop a mutation in the estrogen receptor, which causes the tumor to become estrogen independent. So, if one of the mechanisms by which patients progress on letrozole, palbociclib, or other AIs is through ESR1 mutations, I would be more excited to use a SERD like fulvestrant in the second-line setting as opposed to discontinuing the AI.

Adam M. Brufsky, MD, PhD: And just note that having the ESR mutation does not interfere with the efficacy of the CDK4 inhibitor. We have data from ASCO, from the SOPHIA trial, as well as from PALOMA-3 trial, that an ESR mutation doesn’t affect your response.

Transcript Edited for Clarity