Neurocognitive Impairment Associated with Traditional and Novel AR Signaling Inhibitors ± Androgen Deprivation Therapy - a Pharmacovigilance Study - Logan Briggs
January 30, 2023
Logan Briggs joins Alicia Morgans to delve into his research investigating the impact of androgen receptor-targeted drugs on cognitive function in prostate cancer patients. Dr. Briggs explains his team's use of VigiBase, a global pharmacovigilance database, to assess the neurotoxic effects of various hormone therapies, a relevant topic considering that approximately half of the 1 in 8 men diagnosed with prostate cancer will require hormone therapy. Their findings suggest all such therapies can cause neurotoxicity, with novel agents like enzalutamide presenting higher rates than traditional ones. Dr. Briggs acknowledges the study's limitations, noting its exploratory nature and the imperfect nature of the database. Yet, the results could inform medication choices based on patient history, and Dr. Morgans commends Dr. Briggs and his team for utilizing novel approaches to deepen understanding of the full effects of prostate cancer treatments.
Biographies:
Logan Briggs, MD, Chairman of Medicine in Motion, Urology, Resident Physician, Mayo Clinic AZ, Phoenix, AZ
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Biographies:
Logan Briggs, MD, Chairman of Medicine in Motion, Urology, Resident Physician, Mayo Clinic AZ, Phoenix, AZ
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Read the Full Video Transcript
Alicia Morgans: Hi, I'm so excited to be talking today with Dr. Logan Briggs, who is a recent Harvard Medical School graduate and who is starting his urology residency at Mayo Clinic in Arizona very, very soon. Thank you so much for talking with me today, Dr. Briggs.
Logan Briggs: Thanks so much for having me, Dr. Morgans. I'm really excited to be here and thanks to UroToday.
Alicia Morgans: Great. Well, Logan, I really wanted to talk with you a little bit about some of the work that you did as your medical school career was winding down. It was a really interesting investigation into cognitive function and how different drugs that target the androgen receptor may affect cognitive function in patients with prostate cancer. Can you tell me a little bit about what you studied and how you performed this work?
Logan Briggs: Yeah, absolutely. So, kind of like you touched on, we looked at the neurotoxicities associated with androgen or hormone therapies for prostate cancer. And it's a relevant question because about 1 in 8 men will be diagnosed with prostate cancer and about 50% of those will eventually need hormone therapy. So a lot of men end up getting these types of agents, and they're associated with all kinds of side effects, one of which is neurotoxicity. And so, we wanted to look at which types of hormone therapies are associated with the most neurotoxicity.
To answer this question, we looked at VigiBase, which is the world health organization's pharmacovigilance database. They pull drug safety reports from over 120 countries across the globe. And basically, we looked at the rates at which all types of hormone therapies cause neurotoxicity, and then we broke out the types of agents by more traditional agents, like the antigen deprivation therapies and the first-generation agents, and then we separately looked at the more novel, more potent androgen deprivation therapies.
Alicia Morgans: That's really interesting. And it's, I think, so important that you were actually able to use this database to go into understanding differences between different types of antigen receptor-directed therapies, the standard classic GnRH agonists and maybe antagonists, as well as the first-generation antigen receptor-targeted agents, and then some of our newer agents, which we use in intensified therapy. So, what did you find in this work?
Logan Briggs: Yeah, absolutely. We found that all types of hormone therapy are associated with neurotoxicity, which, in and of itself, is an interesting finding, but we also found that the novel agents have higher rates of neurotoxicity than the traditional agents. And, specifically, enzalutamide was the worst offender causing the most neurocognitive impairment compared to the other types of novel androgen deprivation therapies like apalutamide or abiraterone.
Alicia Morgans: That's also really interesting. What I think I'd like to point out is that this, of course, is a database that really is collecting adverse events that are being reported. So, we have to recognize the data set from which we're drawing these conclusions, and this is certainly not a prospective randomized trial, but does allow us to create some hypotheses around different effects that may exist.
In this setting, as you said, it's really interesting that a number of people reported that with any type of antigen deprivation therapy, there may be some cognitive change, but that may be emphasized in enzalutamide particularly, which we know does cross the blood-brain barrier. Certainly, this is not to say anything about how well this drug works on prostate cancer, and we all know that it has really favorable effects on prostate cancer, and for most patients, is a well tolerated agent, but there were some more adverse events reported for this agent as compared to others in an imperfect database, of course. But really, really interesting. How do you view this data when you think about applying these results to your clinical practice?
Logan Briggs: Yeah. As you started to touch on, there's a lot of different agents that are used for prostate cancer, and so the choice of agent is a salient choice. And when you're thinking about which type of medication you should prescribe, this data might help inform that decision. For example, maybe if you had a patient with some baseline neurocognitive impairment, memory issues, prone to seizures, those kinds of things, if all other things were equal, you might consider using something other than enzalutamide, versus if you have a patient with more cardiac history, there's some data on abiraterone and cardiac effects. So you might just kind of tailor the medication based on the patient's medical history.
Alicia Morgans: That's really interesting and so important in what we do, and certainly we're making those kinds of decisions in clinic every day. Just to make sure that we put this into context, what limitations do you want everyone to think about and recognizes they're interpreting what really is hypothesis generating and exciting, but exploratory set of data?
Logan Briggs: Yeah, exactly. And so that's a very important question. Thank you for asking that, because any pharmacovigilance analysis is not perfect at all. Like you said, it's exploratory, it's hypothesis driving, but there are significant limitations. Disproportionality analysis, it's the gold standard type of analysis used in this kind of pharmacovigilance analysis. But, basically what it does is it compares, it's not like a randomized control trial like you mentioned earlier, it basically compares the rates at which androgen deprivation therapy causes neurotoxicity versus the rate at which all other drugs in VigiBase cause neurotoxicity. So it's using all other drugs as a control, which is not a true control. But it gives you a reporting odds ratio and a measure of relative risk. So that's probably the biggest limitation.
There are some other limitations, including incomplete drug reporting. For example, when a physician fills out these safety reports, there's a form they fill out and they don't have to fill out the whole thing to submit it. And so often there's missing age data, became relevant in this paper, as you know. We couldn't control for age, which is important in this question, because a lot of older people end up taking androgen deprivation therapy, but other types of data can be missing as well.
Alicia Morgans: Great. Well, I sincerely congratulate you and your team for using this novel approach, this VigiBase database to really continue to ask questions about how these agents affect the patients that we care for. It is really exciting information, and like you said, information that is one step along the line of continued investigation to really understanding the full effects of these drugs, both in terms of their prostate cancer control activities, but also in terms of their side effect profiles. I sincerely appreciate your time and your expertise today.
Logan Briggs: Oh, thank you, Dr. Morgans. Thank you again for having me.
Alicia Morgans: Hi, I'm so excited to be talking today with Dr. Logan Briggs, who is a recent Harvard Medical School graduate and who is starting his urology residency at Mayo Clinic in Arizona very, very soon. Thank you so much for talking with me today, Dr. Briggs.
Logan Briggs: Thanks so much for having me, Dr. Morgans. I'm really excited to be here and thanks to UroToday.
Alicia Morgans: Great. Well, Logan, I really wanted to talk with you a little bit about some of the work that you did as your medical school career was winding down. It was a really interesting investigation into cognitive function and how different drugs that target the androgen receptor may affect cognitive function in patients with prostate cancer. Can you tell me a little bit about what you studied and how you performed this work?
Logan Briggs: Yeah, absolutely. So, kind of like you touched on, we looked at the neurotoxicities associated with androgen or hormone therapies for prostate cancer. And it's a relevant question because about 1 in 8 men will be diagnosed with prostate cancer and about 50% of those will eventually need hormone therapy. So a lot of men end up getting these types of agents, and they're associated with all kinds of side effects, one of which is neurotoxicity. And so, we wanted to look at which types of hormone therapies are associated with the most neurotoxicity.
To answer this question, we looked at VigiBase, which is the world health organization's pharmacovigilance database. They pull drug safety reports from over 120 countries across the globe. And basically, we looked at the rates at which all types of hormone therapies cause neurotoxicity, and then we broke out the types of agents by more traditional agents, like the antigen deprivation therapies and the first-generation agents, and then we separately looked at the more novel, more potent androgen deprivation therapies.
Alicia Morgans: That's really interesting. And it's, I think, so important that you were actually able to use this database to go into understanding differences between different types of antigen receptor-directed therapies, the standard classic GnRH agonists and maybe antagonists, as well as the first-generation antigen receptor-targeted agents, and then some of our newer agents, which we use in intensified therapy. So, what did you find in this work?
Logan Briggs: Yeah, absolutely. We found that all types of hormone therapy are associated with neurotoxicity, which, in and of itself, is an interesting finding, but we also found that the novel agents have higher rates of neurotoxicity than the traditional agents. And, specifically, enzalutamide was the worst offender causing the most neurocognitive impairment compared to the other types of novel androgen deprivation therapies like apalutamide or abiraterone.
Alicia Morgans: That's also really interesting. What I think I'd like to point out is that this, of course, is a database that really is collecting adverse events that are being reported. So, we have to recognize the data set from which we're drawing these conclusions, and this is certainly not a prospective randomized trial, but does allow us to create some hypotheses around different effects that may exist.
In this setting, as you said, it's really interesting that a number of people reported that with any type of antigen deprivation therapy, there may be some cognitive change, but that may be emphasized in enzalutamide particularly, which we know does cross the blood-brain barrier. Certainly, this is not to say anything about how well this drug works on prostate cancer, and we all know that it has really favorable effects on prostate cancer, and for most patients, is a well tolerated agent, but there were some more adverse events reported for this agent as compared to others in an imperfect database, of course. But really, really interesting. How do you view this data when you think about applying these results to your clinical practice?
Logan Briggs: Yeah. As you started to touch on, there's a lot of different agents that are used for prostate cancer, and so the choice of agent is a salient choice. And when you're thinking about which type of medication you should prescribe, this data might help inform that decision. For example, maybe if you had a patient with some baseline neurocognitive impairment, memory issues, prone to seizures, those kinds of things, if all other things were equal, you might consider using something other than enzalutamide, versus if you have a patient with more cardiac history, there's some data on abiraterone and cardiac effects. So you might just kind of tailor the medication based on the patient's medical history.
Alicia Morgans: That's really interesting and so important in what we do, and certainly we're making those kinds of decisions in clinic every day. Just to make sure that we put this into context, what limitations do you want everyone to think about and recognizes they're interpreting what really is hypothesis generating and exciting, but exploratory set of data?
Logan Briggs: Yeah, exactly. And so that's a very important question. Thank you for asking that, because any pharmacovigilance analysis is not perfect at all. Like you said, it's exploratory, it's hypothesis driving, but there are significant limitations. Disproportionality analysis, it's the gold standard type of analysis used in this kind of pharmacovigilance analysis. But, basically what it does is it compares, it's not like a randomized control trial like you mentioned earlier, it basically compares the rates at which androgen deprivation therapy causes neurotoxicity versus the rate at which all other drugs in VigiBase cause neurotoxicity. So it's using all other drugs as a control, which is not a true control. But it gives you a reporting odds ratio and a measure of relative risk. So that's probably the biggest limitation.
There are some other limitations, including incomplete drug reporting. For example, when a physician fills out these safety reports, there's a form they fill out and they don't have to fill out the whole thing to submit it. And so often there's missing age data, became relevant in this paper, as you know. We couldn't control for age, which is important in this question, because a lot of older people end up taking androgen deprivation therapy, but other types of data can be missing as well.
Alicia Morgans: Great. Well, I sincerely congratulate you and your team for using this novel approach, this VigiBase database to really continue to ask questions about how these agents affect the patients that we care for. It is really exciting information, and like you said, information that is one step along the line of continued investigation to really understanding the full effects of these drugs, both in terms of their prostate cancer control activities, but also in terms of their side effect profiles. I sincerely appreciate your time and your expertise today.
Logan Briggs: Oh, thank you, Dr. Morgans. Thank you again for having me.