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Optimizing the Use of Endocrine Therapy Partners in mBC

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: Thursday, Aug 02, 2018



Transcript: 

Hatem Soliman, MD: The up-front trials that included PALOMA-1, MONALEESA-2, and MONARCH 3 primarily focused on enrolling postmenopausal patients who had not seen any prior therapy for their metastatic disease. They could have had prior therapy for their breast cancer in the adjuvant setting and then have gone at least a year prior to relapsing with their metastatic disease, but all those frontline trials did not allow women who had had any kind of prior therapy. They focused on postmenopausal women. So, those are the general criteria for those upfront trials.

In contrast, the salvage trials that occurred in second-line therapy, such as MONARCH 2 or with PALOMA-3, allowed women who, in essence, were pretreated for their metastatic disease and had seen a prior line of endocrine therapy and enrolled them onto fulvestrant plus a CDK4/6 inhibitor. One differentiating factor between the PALOMA trial and the MONARCH 2 study was the PALOMA trial allowed patients to have at least 1 prior line of chemotherapy prior to entering, whereas MONARCH 2 did not allow that to happen. So the populations were slightly different there, which may in part contribute to some of the differences that were observed for progression-free survival across the 2 trials.

And so, the final group of patients who were enrolled in the later studies were a mix of premenopausal, perimenopausal, and postmenopausal patients. Whereas the first-line trials were only postmenopausal, some of the later salvage lines included women who were both premenopausal and perimenopausal. And we saw some of that data presented at ASCO with regard to MONARCH 2, showing the efficacy in the premenopausal and perimenopausal subset of patients.

For MONALEESA-3, in essence, the main difference there that was the main distinguishing factor of the study was that it allowed women who had failed or progressed on a prior line of endocrine therapy for their disease. But it also allowed women who were what we call de novo metastatic disease, and that was the main distinguishing factor of MONALEESA-3 in comparison with the other studies. And that’s a unique subset of patients whom we were looking to get additional data on for the strategy of fulvestrant plus a CDK4/6 inhibitor.

Debu Tripathy, MD: The trials that have looked at endocrine therapy and CDK inhibitors were based on the line of therapy patients were receiving. In the first-line therapy, people were generally receiving aromatase inhibitors with the trials and used aromatase inhibitors with or without CDK4/6 inhibitors. And in the second-line setting, they typically used fulvestrant plus or minus. But with the change in standards as to what one would use as the endocrine therapy in the first line, now allowing both fulvestrant or aromatase inhibitor, maybe even favoring fulvestrant in patients who had never had hormonal therapy, the practice is evolving a little bit, and I think now many physicians are going to choose to use fulvestrant in the first-line setting.

And so, the MONALEESA-3 was a study that allowed fulvestrant in either first- or second-line settings. So, I think the endocrine partner that we use now can be one of several, and so we do have some flexibility based on patients’ preferences. Some patients may have issues with compliance, and you may want to use fulvestrant in the first-line setting. Or based on the FALCON data, someone who has, say, nonvisceral disease, where the benefit of fulvestrant over AI seemed to be the biggest, one might choose to use fulvestrant in the first-line setting. And then finally based on the MONALEESA-7 data, one could even transition to tamoxifen if significant side effects are being seen with an aromatase inhibitor.

Hatem Soliman, MD: I think the data from FIRST, FALCON, and CONFIRM should be considered, especially with the latest data that have been generated and presented here at ASCO. The idea is if we know up front for certain subtypes of patients, particularly, it appears, those who have de novo metastatic disease, those with bone-only or nonvisceral disease, and those patients who appear in general to have a more indolent biology or a slower-growing biology may fair better when we start off with fulvestrant. That is an important management point in the treatment of hormone receptor–positive metastatic breast cancer that we have to consider. So, I think some physicians now are going to start having to integrate not only the patient’s treatment history but also hints about the biology of the cancer that they’re faced with in terms of selecting the appropriate partner with a CDK4/6 inhibitor. Another important point I wanted to highlight though, too, that I hadn’t mentioned previously is that especially in patients who had seen a prior line of therapy, doing next-generation sequencing assays on patients in order to identify acquired ESR1 receptor mutations is going to be critical because we have trials like SOPHIA with retrospective data that showed fulvestrant was more effective as a therapy in women who were known to harbor ESR1 mutations compared with an aromatase inhibitor.

Sara Hurvitz, MD: When we’re choosing which patients in whom to use the CDK4/6 inhibitor or which endocrine partner we should select, there are a number of factors we consider. Time to recurrence is kind of a nebulous factor because we’re not really sure where the cutoff is. Is it 6 months from endocrine therapy in the adjuvant setting where we really think they’re going to be resistant to that agent? Is it 12 months? Is it 24 months? Typically, we say that if the patient has recurred within 12 months of being on an adjuvant AI, we should consider them resistant. There are more recent data suggesting that 2 years is an indicator of resistance versus sensitivity. More and more we are using next-generation sequencing to look for markers of resistance, such as ESR1 mutations, which may help us determine whether we should be using fulvestrant versus an AI.

Transcript Edited for Clarity 
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Transcript: 

Hatem Soliman, MD: The up-front trials that included PALOMA-1, MONALEESA-2, and MONARCH 3 primarily focused on enrolling postmenopausal patients who had not seen any prior therapy for their metastatic disease. They could have had prior therapy for their breast cancer in the adjuvant setting and then have gone at least a year prior to relapsing with their metastatic disease, but all those frontline trials did not allow women who had had any kind of prior therapy. They focused on postmenopausal women. So, those are the general criteria for those upfront trials.

In contrast, the salvage trials that occurred in second-line therapy, such as MONARCH 2 or with PALOMA-3, allowed women who, in essence, were pretreated for their metastatic disease and had seen a prior line of endocrine therapy and enrolled them onto fulvestrant plus a CDK4/6 inhibitor. One differentiating factor between the PALOMA trial and the MONARCH 2 study was the PALOMA trial allowed patients to have at least 1 prior line of chemotherapy prior to entering, whereas MONARCH 2 did not allow that to happen. So the populations were slightly different there, which may in part contribute to some of the differences that were observed for progression-free survival across the 2 trials.

And so, the final group of patients who were enrolled in the later studies were a mix of premenopausal, perimenopausal, and postmenopausal patients. Whereas the first-line trials were only postmenopausal, some of the later salvage lines included women who were both premenopausal and perimenopausal. And we saw some of that data presented at ASCO with regard to MONARCH 2, showing the efficacy in the premenopausal and perimenopausal subset of patients.

For MONALEESA-3, in essence, the main difference there that was the main distinguishing factor of the study was that it allowed women who had failed or progressed on a prior line of endocrine therapy for their disease. But it also allowed women who were what we call de novo metastatic disease, and that was the main distinguishing factor of MONALEESA-3 in comparison with the other studies. And that’s a unique subset of patients whom we were looking to get additional data on for the strategy of fulvestrant plus a CDK4/6 inhibitor.

Debu Tripathy, MD: The trials that have looked at endocrine therapy and CDK inhibitors were based on the line of therapy patients were receiving. In the first-line therapy, people were generally receiving aromatase inhibitors with the trials and used aromatase inhibitors with or without CDK4/6 inhibitors. And in the second-line setting, they typically used fulvestrant plus or minus. But with the change in standards as to what one would use as the endocrine therapy in the first line, now allowing both fulvestrant or aromatase inhibitor, maybe even favoring fulvestrant in patients who had never had hormonal therapy, the practice is evolving a little bit, and I think now many physicians are going to choose to use fulvestrant in the first-line setting.

And so, the MONALEESA-3 was a study that allowed fulvestrant in either first- or second-line settings. So, I think the endocrine partner that we use now can be one of several, and so we do have some flexibility based on patients’ preferences. Some patients may have issues with compliance, and you may want to use fulvestrant in the first-line setting. Or based on the FALCON data, someone who has, say, nonvisceral disease, where the benefit of fulvestrant over AI seemed to be the biggest, one might choose to use fulvestrant in the first-line setting. And then finally based on the MONALEESA-7 data, one could even transition to tamoxifen if significant side effects are being seen with an aromatase inhibitor.

Hatem Soliman, MD: I think the data from FIRST, FALCON, and CONFIRM should be considered, especially with the latest data that have been generated and presented here at ASCO. The idea is if we know up front for certain subtypes of patients, particularly, it appears, those who have de novo metastatic disease, those with bone-only or nonvisceral disease, and those patients who appear in general to have a more indolent biology or a slower-growing biology may fair better when we start off with fulvestrant. That is an important management point in the treatment of hormone receptor–positive metastatic breast cancer that we have to consider. So, I think some physicians now are going to start having to integrate not only the patient’s treatment history but also hints about the biology of the cancer that they’re faced with in terms of selecting the appropriate partner with a CDK4/6 inhibitor. Another important point I wanted to highlight though, too, that I hadn’t mentioned previously is that especially in patients who had seen a prior line of therapy, doing next-generation sequencing assays on patients in order to identify acquired ESR1 receptor mutations is going to be critical because we have trials like SOPHIA with retrospective data that showed fulvestrant was more effective as a therapy in women who were known to harbor ESR1 mutations compared with an aromatase inhibitor.

Sara Hurvitz, MD: When we’re choosing which patients in whom to use the CDK4/6 inhibitor or which endocrine partner we should select, there are a number of factors we consider. Time to recurrence is kind of a nebulous factor because we’re not really sure where the cutoff is. Is it 6 months from endocrine therapy in the adjuvant setting where we really think they’re going to be resistant to that agent? Is it 12 months? Is it 24 months? Typically, we say that if the patient has recurred within 12 months of being on an adjuvant AI, we should consider them resistant. There are more recent data suggesting that 2 years is an indicator of resistance versus sensitivity. More and more we are using next-generation sequencing to look for markers of resistance, such as ESR1 mutations, which may help us determine whether we should be using fulvestrant versus an AI.

Transcript Edited for Clarity 
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