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Role of Everolimus in HR+ Metastatic Breast Cancer

Insights From: Debu Tripathy, MD, MD Anderson Cancer Center; Sara Hurvitz, MD, UCLA Jonsson Comprehensive Cancer Center; Hatem Soliman, MD, H. Lee Moffitt Cancer Center & Research Institute
Published: Monday, Aug 20, 2018



Transcript: 

Sara Hurvitz, MD: The PrECOG 0102 clinical trial was evaluating the use of fulvestrant in combination with everolimus, an mTOR inhibitor, versus fulvestrant alone. And in this clinical trial, patients with AI-resistant metastatic hormone receptor–positive breast cancer were enrolled. And what this showed was that actually the combination of fulvestrant and everolimus significantly improved median progression-free survival. It basically doubled it. The objective response rate itself wasn’t significantly improved but the clinical benefit rate was higher with everolimus. There were no new safety signals highlighted in this clinical trial. I really like the design of this clinical trial because I feel like in my patients whose disease is resistant to an AI, I’d rather switch them to fulvestrant. And it shows that the combination of fulvestrant and everolimus is really quite good, and this is now going to be my recommendation for a patient who has had resistance to an AI—for example, first-line AI with a CDK4/6 inhibitor.

What the trial doesn’t address is how well this works in patients whose disease has progressed on a CDK4/6 inhibitor, because the study was designed and enrolled before CDK4/6 inhibitors were being used so routinely. In my own clinical practice that’s not holding me back from using this combination, and I’ve actually seen it be quite effective in a number of my own patients.

Hatem Soliman, MD: The BOLERO-6 trial’s main purpose or stated purpose was a postregulatory commitment that was made to authorities by Novartis to interrogate the benefit of everolimus with an AI known as Aromasin versus using everolimus by itself. And one of the issues that we wanted to look at was, how much does exemestane add to the benefit observed by using everolimus in the hormone receptor–positive, HER2-negative metastatic setting in women who have failed or progressed on prior lines of endocrine therapy? So, that was the primary endpoint of the BOLERO-6 study. They also had an additional arm of the study, which compared the efficacy with capecitabine in that line as well. And so, it enrolled a little over 300 patients, and they treated about 100 patients per arm for each of those 3 arms across an everolimus and exemestane combination, everolimus alone, and capecitabine.

And they looked at progression-free survival, safety and toxicity, efficacy, and other readouts. It has to be clarified though that the trial was not designed and statistically powered to allow for head-to-head comparison between the 3 different arms. So, it was purely intended just to show the relative magnitude of improvement for the combination of everolimus and exemestane compared with everolimus alone.

In the trial, they were able to demonstrate that the hazard ratio for the combination of everolimus and exemestane was 0.74. So, it resulted in approximately a 26% reduction in the hazard rate of progression for women who got the combination compared with those who got everolimus alone, suggesting that there is a role for continuing to suppress estrogen production in a woman who is getting everolimus, and that the benefit isn’t solely with the everolimus alone. And so, I believe that it did not necessarily change practice as it currently stands. However, it does provide us additional clarity and information around the relative contribution of each of the partners in the therapy and what benefit they bring to the table.

Transcript Edited for Clarity 
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Transcript: 

Sara Hurvitz, MD: The PrECOG 0102 clinical trial was evaluating the use of fulvestrant in combination with everolimus, an mTOR inhibitor, versus fulvestrant alone. And in this clinical trial, patients with AI-resistant metastatic hormone receptor–positive breast cancer were enrolled. And what this showed was that actually the combination of fulvestrant and everolimus significantly improved median progression-free survival. It basically doubled it. The objective response rate itself wasn’t significantly improved but the clinical benefit rate was higher with everolimus. There were no new safety signals highlighted in this clinical trial. I really like the design of this clinical trial because I feel like in my patients whose disease is resistant to an AI, I’d rather switch them to fulvestrant. And it shows that the combination of fulvestrant and everolimus is really quite good, and this is now going to be my recommendation for a patient who has had resistance to an AI—for example, first-line AI with a CDK4/6 inhibitor.

What the trial doesn’t address is how well this works in patients whose disease has progressed on a CDK4/6 inhibitor, because the study was designed and enrolled before CDK4/6 inhibitors were being used so routinely. In my own clinical practice that’s not holding me back from using this combination, and I’ve actually seen it be quite effective in a number of my own patients.

Hatem Soliman, MD: The BOLERO-6 trial’s main purpose or stated purpose was a postregulatory commitment that was made to authorities by Novartis to interrogate the benefit of everolimus with an AI known as Aromasin versus using everolimus by itself. And one of the issues that we wanted to look at was, how much does exemestane add to the benefit observed by using everolimus in the hormone receptor–positive, HER2-negative metastatic setting in women who have failed or progressed on prior lines of endocrine therapy? So, that was the primary endpoint of the BOLERO-6 study. They also had an additional arm of the study, which compared the efficacy with capecitabine in that line as well. And so, it enrolled a little over 300 patients, and they treated about 100 patients per arm for each of those 3 arms across an everolimus and exemestane combination, everolimus alone, and capecitabine.

And they looked at progression-free survival, safety and toxicity, efficacy, and other readouts. It has to be clarified though that the trial was not designed and statistically powered to allow for head-to-head comparison between the 3 different arms. So, it was purely intended just to show the relative magnitude of improvement for the combination of everolimus and exemestane compared with everolimus alone.

In the trial, they were able to demonstrate that the hazard ratio for the combination of everolimus and exemestane was 0.74. So, it resulted in approximately a 26% reduction in the hazard rate of progression for women who got the combination compared with those who got everolimus alone, suggesting that there is a role for continuing to suppress estrogen production in a woman who is getting everolimus, and that the benefit isn’t solely with the everolimus alone. And so, I believe that it did not necessarily change practice as it currently stands. However, it does provide us additional clarity and information around the relative contribution of each of the partners in the therapy and what benefit they bring to the table.

Transcript Edited for Clarity 
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Miami Breast Cancer Conference®: Attendee Tumor Board OnlineNov 30, 20181.5
Community Practice Connections™: 1st Annual Paris Breast Cancer Conference™Dec 31, 20181.5
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