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ONCAlert | Upfront Therapy for mRCC

Is There Still a Role for Fulvestrant Hormone Monotherapy?

Debu Tripathy, MD
Published Online:12:26 PM, Tue July 10, 2018

Debu Tripathy, MD: The FIRST trial and the FALCON trial were 2 trials that randomized patients to either fulvestrant or an aromatase inhibitor in the first-line setting, anastrozole being the aromatase inhibitor. The FIRST trial was a smaller trial, and the follow-up was incomplete. They had to go back and do more follow-up, but that did suggest an improvement in progression-free and even overall survival.

The FALCON trial, however, was a much larger study and a little bit more exclusive. It was for patients who had not received any prior hormonal therapy for the advanced setting, and it did allow prior chemotherapy, although very few patients had that. And so, it was a less endocrine-pretreated group of patients. That study did show a clear improvement in progression-free survival in the fulvestrant arm. It was particularly more dramatic in the subgroup of patients who had nonvisceral disease. What that means for us is for that population of patients in particular, fulvestrant may be the optimal monotherapy if one is using monotherapy. Now, one can extend this a little bit into assuming that if you combine it with CDK4/6 inhibitors, you would still get an advantage over fulvestrant. Until we have randomized data, I think it’s a reasonable thing to assume. And so, I think it is a very legitimate first-line therapy. In fact, in the view of some people, it should be the preferred first-line therapy.

There are some unknowns there. What do you do after you progress on fulvestrant? Can you then go on an aromatase inhibitor? I think you can, but we really don’t have any data. I think there are some missing pieces in our knowledge before we start to routinely make these decisions. But I think that in a very short order of time, we will have more data on the sequence of therapies and what makes the most sense.

Most people feel that endocrine therapy alone could be a perfectly reasonable option. We know that with the addition of CDK inhibitors, we are doubling progression-free survival and have not yet identified a subgroup of patients that we can reliably say will be as well served with endocrine therapy alone. But there are many pieces of information that are missing right now. For example, what if you start someone on endocrine therapy and then add a CDK4/6 inhibitor? Some studies have looked at this. The TREND study didn’t quite ask that question, but did suggest that it’s probably better to start off with both. But we need more information and more biomarkers.

We do know that there are some patients who do very well. Patients who are de novo. Patients who have a very long disease-free interval. Patients who have very low-burden disease, maybe bone-only disease, tend to do well. And while the CKD4/6 inhibitors do improve things, they are still likely to do quite well with endocrine therapy. Finally, you have to factor in the patient’s preferences. Some patients don’t want to have a visit every month and have their blood drawn every month. They may not want the additional fatigue and some hair loss. These have to be discussed in advance with the patient, and their values have to be taken into account, as well.

First of all, I think that the development of targeted therapies with endocrine therapies is a big advance, and it’s really a sign of success that by studying the biology, we will eventually develop a targeted therapy that is appropriate for that population. We’ve known that growth factor receptors and the cell cycle are important, especially in hormone receptor–positive disease, and probably in other subtypes, as well. That has been now applied to improve the patient’s outcome.

The other point is that when one looks at this from the patient perspective, we now have some data with quality of life that tell us the deterioration the patients may experience over the course of their treatment for metastatic cancer seems to be less of a decline when one uses a CDK4/6 inhibitor, so that’s a positive, as well.

And finally, I think that we have a long way to go. We have not yet shown a survival advantage. These trials were not designed to show a survival advantage; they didn’t have the right number of patients. Because these patients live a long time, it is very difficult to show that at the current point in time. But nevertheless, we would like to see more dramatic improvements. We would like to see what happens to patients when they become resistant to CDK4/6 inhibitors. What happens when they become resistant to everolimus and have better targeted therapies for afterward? We’ve got some preliminary data from PI3 kinase inhibitors and from AKT inhibitors. They have their issues in terms of side effects, but they may find their roles once we have more data.

I think that the field is improving in the sense that our patients’ lives are normal for longer. That’s what we want to see. Of course we want to eradicate breast cancer, and I’m optimistic that at some point, we will. But what we want to see, at least in the next few years, is that we’re extending things out and that patients can continue to live their lives and continue to have a high quality of life, with drugs that don’t interfere with their lives but clearly extend the time that they may have to move to another therapy or to more toxic treatment.

I think the field is moving at a more rapid pace when you just look at the CDK4/6 inhibitors and how quickly 3 drugs got approved in different settings. I think that speaks to our optimism that these new developments will actually come at a faster pace.

Transcript edited for clarity.

Debu Tripathy, MD: The FIRST trial and the FALCON trial were 2 trials that randomized patients to either fulvestrant or an aromatase inhibitor in the first-line setting, anastrozole being the aromatase inhibitor. The FIRST trial was a smaller trial, and the follow-up was incomplete. They had to go back and do more follow-up, but that did suggest an improvement in progression-free and even overall survival.

The FALCON trial, however, was a much larger study and a little bit more exclusive. It was for patients who had not received any prior hormonal therapy for the advanced setting, and it did allow prior chemotherapy, although very few patients had that. And so, it was a less endocrine-pretreated group of patients. That study did show a clear improvement in progression-free survival in the fulvestrant arm. It was particularly more dramatic in the subgroup of patients who had nonvisceral disease. What that means for us is for that population of patients in particular, fulvestrant may be the optimal monotherapy if one is using monotherapy. Now, one can extend this a little bit into assuming that if you combine it with CDK4/6 inhibitors, you would still get an advantage over fulvestrant. Until we have randomized data, I think it’s a reasonable thing to assume. And so, I think it is a very legitimate first-line therapy. In fact, in the view of some people, it should be the preferred first-line therapy.

There are some unknowns there. What do you do after you progress on fulvestrant? Can you then go on an aromatase inhibitor? I think you can, but we really don’t have any data. I think there are some missing pieces in our knowledge before we start to routinely make these decisions. But I think that in a very short order of time, we will have more data on the sequence of therapies and what makes the most sense.

Most people feel that endocrine therapy alone could be a perfectly reasonable option. We know that with the addition of CDK inhibitors, we are doubling progression-free survival and have not yet identified a subgroup of patients that we can reliably say will be as well served with endocrine therapy alone. But there are many pieces of information that are missing right now. For example, what if you start someone on endocrine therapy and then add a CDK4/6 inhibitor? Some studies have looked at this. The TREND study didn’t quite ask that question, but did suggest that it’s probably better to start off with both. But we need more information and more biomarkers.

We do know that there are some patients who do very well. Patients who are de novo. Patients who have a very long disease-free interval. Patients who have very low-burden disease, maybe bone-only disease, tend to do well. And while the CKD4/6 inhibitors do improve things, they are still likely to do quite well with endocrine therapy. Finally, you have to factor in the patient’s preferences. Some patients don’t want to have a visit every month and have their blood drawn every month. They may not want the additional fatigue and some hair loss. These have to be discussed in advance with the patient, and their values have to be taken into account, as well.

First of all, I think that the development of targeted therapies with endocrine therapies is a big advance, and it’s really a sign of success that by studying the biology, we will eventually develop a targeted therapy that is appropriate for that population. We’ve known that growth factor receptors and the cell cycle are important, especially in hormone receptor–positive disease, and probably in other subtypes, as well. That has been now applied to improve the patient’s outcome.

The other point is that when one looks at this from the patient perspective, we now have some data with quality of life that tell us the deterioration the patients may experience over the course of their treatment for metastatic cancer seems to be less of a decline when one uses a CDK4/6 inhibitor, so that’s a positive, as well.

And finally, I think that we have a long way to go. We have not yet shown a survival advantage. These trials were not designed to show a survival advantage; they didn’t have the right number of patients. Because these patients live a long time, it is very difficult to show that at the current point in time. But nevertheless, we would like to see more dramatic improvements. We would like to see what happens to patients when they become resistant to CDK4/6 inhibitors. What happens when they become resistant to everolimus and have better targeted therapies for afterward? We’ve got some preliminary data from PI3 kinase inhibitors and from AKT inhibitors. They have their issues in terms of side effects, but they may find their roles once we have more data.

I think that the field is improving in the sense that our patients’ lives are normal for longer. That’s what we want to see. Of course we want to eradicate breast cancer, and I’m optimistic that at some point, we will. But what we want to see, at least in the next few years, is that we’re extending things out and that patients can continue to live their lives and continue to have a high quality of life, with drugs that don’t interfere with their lives but clearly extend the time that they may have to move to another therapy or to more toxic treatment.

I think the field is moving at a more rapid pace when you just look at the CDK4/6 inhibitors and how quickly 3 drugs got approved in different settings. I think that speaks to our optimism that these new developments will actually come at a faster pace.

Transcript edited for clarity.
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