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Role of the Androgen Receptor in TNBC

Panelists: Aditya Bardia, MD, MPH, Massachusetts General Hospital Center; Claudine Isaacs, MD, Lombardi Comprehensive Cancer Center; Joyce OShaughnessy, MD, Baylor University Medical Center Texas Oncology; Tiffany Traina, MD, Memorial Sloan Kettering Cancer Center
Published: Monday, Apr 09, 2018



Transcript: 

Joyce A. O’Shaughnessy, MD: Let’s move on to the androgen receptor. Thankfully, we have Tiffany here who can tell us all about it. And, also, of course, you’ve led all the clinical trials, but do you ever get it in standard practice, ever?

Tiffany Traina, MD: I always try to have a trial available.

Joyce A. O’Shaughnessy, MD: But how often do we find it?

Tiffany Traina, MD: So, I guess I would start with saying just the challenges of looking. We are in the androgen receptor world when we were, decades ago, in the ER-positive world. Really, this story started almost 10 years ago already. Back in 2006 or 2007, we had some of the first papers from MSK and the group in France, Farmer and colleagues, just even identifying the subset of ER-appearing–negative cancers that had a hormonal signature.

And, as we’re learning now over a decade of study, not only is there a hormonal gene expression signature, but phenotypically, these patients just appear different than overall triple-negative breast cancer patients. Perhaps, however you define it molecularly, the basal type, or phenotypically, those are more rapidly progressing cancers. So, we have identified this subset. How we define it by IHC has evolved over the years as well. There’s no standard, agreed-upon assay. And so, in different labs, you’ll find different results. But IHC testing has yielded probably about 50% of TNBCs being considered AR-positive. And whether that’s setting your bar at AR greater than 0 or AR greater than 10%, the range is probably about 50% and could be even as high as 70% in some of these different trials that have been done.

It’s unclear if IHC is the best surrogate or predictor of benefit to anti-androgens, and this development really has gone hand in hand with trying to find the optimal diagnostic biomarker and finding response to these anti-androgen therapies. There has been a tremendous amount of work in looking at gene expression signatures of androgen dependence perhaps as a better predictor. And that’s still all ongoing work right now.

Joyce A. O’Shaughnessy, MD: But there have been some data, right? You brought out a couple of trials for us, which we do brush off in the clinic from time to time, I must say. And you’ve published the both of them now, right?

Tiffany Traina, MD: Yes. So, there has been, I’d say, 4 trials now that have looked at targeting androgen signaling pathways in AR-driven TNBC. The first date back to looking at bicalutamide. This is an AR antagonist, sort of the tamoxifen equivalent for an AR-driven cancer. And bicalutamide was tested in women with AR greater than 10%, metastatic TNBC, and that was through the TBCRC trial. It was really a nationwide effort to find and screen these patients and treat them with single-agent anti-androgen. And that was a proof-of-concept study where only about 15% of those patients screened were found to be AR-positive, but patients received a clinical benefit rate on the order of about 20% in that trial of patients who had received prior cytotoxic chemotherapy as a standard of care. And so, that was an encouraging first signal for a very well-tolerated hormonal agent to treat metastatic triple-negative breast cancer.

And that then led into the much larger study of enzalutamide, another AR antagonist, a later-generation version of bicalutamide. That was a global study looking at using single-agent enzalutamide in patients who had AR greater than 0% by IHC as their eligibility criterion coming on trial. And, with that treatment, clinical benefit rate was about 30% to 35% in the evaluable population. What was really compelling was the partnering of development of a gene signature biomarker when you could begin to enrich for a population that seemed to really derive greatest benefit. And, in that case, we were seeing much higher clinical benefit rate at 16 weeks and 24 weeks, improved progression-free survival over what we would have otherwise ordinarily expected, and even longer overall survival. So, what remains an unanswered question is, how much of this is natural biology and how much of this is related to the drug? And that ultimately will take a randomized phase III trial against a control to really tease that out.

The third trial that has been published is looking at abiraterone. Now, abiraterone, rather than being an AR antagonist, actually blocks the production of androgens. It’s a less-specific CYP17 inhibitor. So, you have reduced androgen production, probably like an aromatase inhibitor for the ER-positive paradigm. And that was a trial led by our French colleagues through UNI Cancer that also looked at patients with AR greater than 10% by IHC, so subtle differences here in eligibility trial to trial. And they found about 30% of the patients that they screened were AR-positive. And the clinical benefit rate, again, was tracking in the low 20%, so very comparable to the bicalutamide data. So, really, growing evidence through multiple studies that there’s something here that really requires more evaluation.

The fourth study that has data, now just presented in abstract form, is looking at seviteronel, or VT-464. So, I like to think of this drug as a combination of AR antagonism and CYP17 inhibition all rolled into one. And it both reduces your androgen production and blocks the androgen receptor. And this has had encouraging results in the AR-positive TNBC subset, and it also has cohorts looking at ER-positive breast cancer, even male breast cancer, based on its mechanism of action.

Joyce A. O’Shaughnessy, MD: So, there are really definite signals there and such an unmet medical need, too. And what are the next steps? You’re doing some pilot work in an earlier-stage group of patients. Because, gosh, it’s tempting for, like, the no path CRs that maybe have this phenotype or what have you. But you’re piloting some things, aren’t you?

Tiffany Traina, MD: We are, absolutely. So, there are a couple of different irons in the fire, if you will. In metastatic disease, we think there’s opportunity to do better, clearly. And I would like you to just think about AR-driven triple-negative breast cancer as a hormonal cancer. There’s evidence that CDK4/6 inhibition may have a role in this luminal-driven cancer that has presence of RB. And so, we have a study of bicalutamide in combination with palbociclib. There’s another study in the country of bicalutamide and ribociclib. So, clearly, an area to explore. In thinking about these patients a little bit differently, there is a high degree of coexpression with PI3-kinase mutations in an androgen-driven triple-negative breast cancer.

And so, TBCRC also has a study going on of enzalutamide with an oral PI3-kinase inhibitor. And so, a lot of interesting combination treatments for advanced disease. And it really feels as a natural progression to move earlier and follow the paradigm of adjuvant endocrine therapy for our patients with AR-driven TNBC. Not surprisingly, in the neoadjuvant dataset, a luminal AR-positive triple-negative breast cancer has the worst path CR rate, on the order of about 10%, not unlike ER-positive disease in response to preop chemotherapy. And so, we think that this is really a role for piloting the feasibility of adjuvant enzalutamide. That trial is nearing completion of 1 year of adjuvant enzalutamide with the option to extend to 2 years, trying to really span that period of highest risk of recurrence in about the 2- to 3-year range. And so, yes, that’s open and accruing.

Joyce A. O’Shaughnessy, MD: That’s real nice to know there’s a randomization, right? If you’re AR-positive, you can go on that. And I know in HER2-positive, ER-negative, about half of those are AR-positive. And wasn’t there kind of a pilot safety early? I think it was Ian Crop who had some data of trastuzumab with enzalutamide, right?

Tiffany Traina, MD: Sure. Also, a phase II study that has completed accrual, but we have yet to see the results of that. But there’s really nice work out of Boston showing the importance and integration of AR signaling and HER2 and HER3.

Joyce A. O’Shaughnessy, MD: Yes, that’ll be nice to watch that done in that space.

Transcript Edited for Clarity 

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Transcript: 

Joyce A. O’Shaughnessy, MD: Let’s move on to the androgen receptor. Thankfully, we have Tiffany here who can tell us all about it. And, also, of course, you’ve led all the clinical trials, but do you ever get it in standard practice, ever?

Tiffany Traina, MD: I always try to have a trial available.

Joyce A. O’Shaughnessy, MD: But how often do we find it?

Tiffany Traina, MD: So, I guess I would start with saying just the challenges of looking. We are in the androgen receptor world when we were, decades ago, in the ER-positive world. Really, this story started almost 10 years ago already. Back in 2006 or 2007, we had some of the first papers from MSK and the group in France, Farmer and colleagues, just even identifying the subset of ER-appearing–negative cancers that had a hormonal signature.

And, as we’re learning now over a decade of study, not only is there a hormonal gene expression signature, but phenotypically, these patients just appear different than overall triple-negative breast cancer patients. Perhaps, however you define it molecularly, the basal type, or phenotypically, those are more rapidly progressing cancers. So, we have identified this subset. How we define it by IHC has evolved over the years as well. There’s no standard, agreed-upon assay. And so, in different labs, you’ll find different results. But IHC testing has yielded probably about 50% of TNBCs being considered AR-positive. And whether that’s setting your bar at AR greater than 0 or AR greater than 10%, the range is probably about 50% and could be even as high as 70% in some of these different trials that have been done.

It’s unclear if IHC is the best surrogate or predictor of benefit to anti-androgens, and this development really has gone hand in hand with trying to find the optimal diagnostic biomarker and finding response to these anti-androgen therapies. There has been a tremendous amount of work in looking at gene expression signatures of androgen dependence perhaps as a better predictor. And that’s still all ongoing work right now.

Joyce A. O’Shaughnessy, MD: But there have been some data, right? You brought out a couple of trials for us, which we do brush off in the clinic from time to time, I must say. And you’ve published the both of them now, right?

Tiffany Traina, MD: Yes. So, there has been, I’d say, 4 trials now that have looked at targeting androgen signaling pathways in AR-driven TNBC. The first date back to looking at bicalutamide. This is an AR antagonist, sort of the tamoxifen equivalent for an AR-driven cancer. And bicalutamide was tested in women with AR greater than 10%, metastatic TNBC, and that was through the TBCRC trial. It was really a nationwide effort to find and screen these patients and treat them with single-agent anti-androgen. And that was a proof-of-concept study where only about 15% of those patients screened were found to be AR-positive, but patients received a clinical benefit rate on the order of about 20% in that trial of patients who had received prior cytotoxic chemotherapy as a standard of care. And so, that was an encouraging first signal for a very well-tolerated hormonal agent to treat metastatic triple-negative breast cancer.

And that then led into the much larger study of enzalutamide, another AR antagonist, a later-generation version of bicalutamide. That was a global study looking at using single-agent enzalutamide in patients who had AR greater than 0% by IHC as their eligibility criterion coming on trial. And, with that treatment, clinical benefit rate was about 30% to 35% in the evaluable population. What was really compelling was the partnering of development of a gene signature biomarker when you could begin to enrich for a population that seemed to really derive greatest benefit. And, in that case, we were seeing much higher clinical benefit rate at 16 weeks and 24 weeks, improved progression-free survival over what we would have otherwise ordinarily expected, and even longer overall survival. So, what remains an unanswered question is, how much of this is natural biology and how much of this is related to the drug? And that ultimately will take a randomized phase III trial against a control to really tease that out.

The third trial that has been published is looking at abiraterone. Now, abiraterone, rather than being an AR antagonist, actually blocks the production of androgens. It’s a less-specific CYP17 inhibitor. So, you have reduced androgen production, probably like an aromatase inhibitor for the ER-positive paradigm. And that was a trial led by our French colleagues through UNI Cancer that also looked at patients with AR greater than 10% by IHC, so subtle differences here in eligibility trial to trial. And they found about 30% of the patients that they screened were AR-positive. And the clinical benefit rate, again, was tracking in the low 20%, so very comparable to the bicalutamide data. So, really, growing evidence through multiple studies that there’s something here that really requires more evaluation.

The fourth study that has data, now just presented in abstract form, is looking at seviteronel, or VT-464. So, I like to think of this drug as a combination of AR antagonism and CYP17 inhibition all rolled into one. And it both reduces your androgen production and blocks the androgen receptor. And this has had encouraging results in the AR-positive TNBC subset, and it also has cohorts looking at ER-positive breast cancer, even male breast cancer, based on its mechanism of action.

Joyce A. O’Shaughnessy, MD: So, there are really definite signals there and such an unmet medical need, too. And what are the next steps? You’re doing some pilot work in an earlier-stage group of patients. Because, gosh, it’s tempting for, like, the no path CRs that maybe have this phenotype or what have you. But you’re piloting some things, aren’t you?

Tiffany Traina, MD: We are, absolutely. So, there are a couple of different irons in the fire, if you will. In metastatic disease, we think there’s opportunity to do better, clearly. And I would like you to just think about AR-driven triple-negative breast cancer as a hormonal cancer. There’s evidence that CDK4/6 inhibition may have a role in this luminal-driven cancer that has presence of RB. And so, we have a study of bicalutamide in combination with palbociclib. There’s another study in the country of bicalutamide and ribociclib. So, clearly, an area to explore. In thinking about these patients a little bit differently, there is a high degree of coexpression with PI3-kinase mutations in an androgen-driven triple-negative breast cancer.

And so, TBCRC also has a study going on of enzalutamide with an oral PI3-kinase inhibitor. And so, a lot of interesting combination treatments for advanced disease. And it really feels as a natural progression to move earlier and follow the paradigm of adjuvant endocrine therapy for our patients with AR-driven TNBC. Not surprisingly, in the neoadjuvant dataset, a luminal AR-positive triple-negative breast cancer has the worst path CR rate, on the order of about 10%, not unlike ER-positive disease in response to preop chemotherapy. And so, we think that this is really a role for piloting the feasibility of adjuvant enzalutamide. That trial is nearing completion of 1 year of adjuvant enzalutamide with the option to extend to 2 years, trying to really span that period of highest risk of recurrence in about the 2- to 3-year range. And so, yes, that’s open and accruing.

Joyce A. O’Shaughnessy, MD: That’s real nice to know there’s a randomization, right? If you’re AR-positive, you can go on that. And I know in HER2-positive, ER-negative, about half of those are AR-positive. And wasn’t there kind of a pilot safety early? I think it was Ian Crop who had some data of trastuzumab with enzalutamide, right?

Tiffany Traina, MD: Sure. Also, a phase II study that has completed accrual, but we have yet to see the results of that. But there’s really nice work out of Boston showing the importance and integration of AR signaling and HER2 and HER3.

Joyce A. O’Shaughnessy, MD: Yes, that’ll be nice to watch that done in that space.

Transcript Edited for Clarity 
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