Penn Medicine oncologist Vivek Narayan, MD, provides a high-level overview of how oncologists use and think about androgen deprivation therapy (ADT) in prostate cancer. Additionally, he discusses how oncologists can try to balance both oncologic and toxicity concerns.
Related Links: Twitter @PennMDForum Dr. Narayan’s physician profile
So I was asked to talk about how, from an oncology perspective we might choose energon suppression or energy deprivation therapies for men with prostate cancer. So I know that this audience is certainly familiar with the potential cardiovascular toxicities that can occur with energy and deprivation. But I was going to try in 15 minutes or less to sort of give a high level overview of how as oncologist we use and think about it in prostate cancer and how we might balance or try to balance both. Uncle logic and toxicity concerns. So as background, we've known since the 1940s that prostate cancer is fundamentally an androgen driven disease. And this was largely led by the seminal work of Huggins and Hodges, who in 1941 published this paper where they were able to illustrate that following surgical or key ectomy, men with advanced prostate cancer had pretty rapid and robust declines in these markers of bone turnover. So these facilities markers in the peripheral blood and of course prostate cancer has a proclivity for metastases to the bone. And this therapeutic effect was actually reversed by the exogenous administration of testosterone or insurgents. And so this work showing that prostate cancer was fundamentally an energy and driven disease, ultimately led to the Nobel Prize for this group in the 1960s. And so even today, surgical or more often medical castration is the fundamental therapy and thankfully induced, pretty significant and robust disease regressions and the vast majority of men. So from a physiologic level, we know that androgens and the body come from one of two sources either the hypothalamus pituitary gonna tell axis, which gives about 90 of our physiologic androgens and men. And there's also about minority of production from extra genital sources. And so one example of this would be the adrenal pathway. But regardless of where this energy comes from, we know that it can circle, circulate into the tissues and be converted into die hydro testosterone. And these energies bind androgen receptor which can trans locate to the cell nucleus and essentially facilitate the transcription of a number of our target genes and these are implicated in the growth and survival of prostate cancer. And so from a therapeutic standpoint, we use an urgent deprivation therapy effectively for men with prostate cancer. And the goal is to really suppress these circulating androgens to as low levels as we can achieve. And this is most commonly done through the use of GN Rh agonists which can seek to block the pulse it'll release between the high pathologist and the pituitary of LH Rh. And we can also potentially use generate antagonists which more directly block this signaling between the hypothalamus and pituitary. But regardless of the approach that we use, the goal again, is to achieve castrate levels of testosterone, which is defined as less than 50 nanograms per mil leader. But oftentimes these agents are able to effectively suppress this even less than 20 uh huh. But we know that this profound suppression of androgens in male physiology can certainly have toxicity concerns. And primarily this can be metabolic changes and this is a figure just illustrating some of this and how it has overlap with what I know cardiologists are quite familiar with with the classic metabolic syndrome. So this can be issues like changes in fat deposition or predominant subcutaneous fat deposition, Sarka, Penick, obesity with decreasing lean body mass and lean muscle mass and display academia and hypertension with some potential agents and similar to the classic metabolic syndrome in numerous observational studies and prostate cancer. This is the exposure and deprivation therapy has been associated with major adverse cardiovascular events such as ischemic heart disease and my etcetera. So from an uncle logic standpoint, we primarily at a high level use 18 1 of two treatment settings. The first is a curative intent population. And this is often in conjunction with radiation therapy for men with clinically localized prostate cancer. And here we either use 80 for what's called a short course of about 4-6 months of energy and suppression or what we sometimes term a long course which can be anywhere from a year and a half to three years of energy deprivation therapy. And the primary decision factors that we think about really relate to the use of a TT and the duration of Aditi. So a short course versus a longer course. And here, I would say the primary factor that influences this decision is really NCC and risk grouping. So how we risk stratify the prostate cancer itself. And there's guideline based evidence level one randomized trial evidence for informing this decision for intermediate risk or higher risk prostate cancer patients. And so this is really sort of a level one basis for how we make this determination about the use in duration of a TT for these curative intent patients. But of course there's a number of other sort of individualist factors are ways that we can personalize this. And this relates to the underlying comorbidities of the patient and certainly metabolic and history of cardiovascular disease and patient preferences in their tolerance of potential toxicities. And then the second major treatment setting that we use a TTS in non curative intent settings. And this would be patients with metastatic prostate cancer either as a de novo presentation or who those those in whom disease may recur following curative intent therapy. And here the typical standard is lifelong and continuous androgen deprivation therapy. So throughout the disease course and so rather than a use and duration, the primary decision factor here with regards to add it is more I think in terms of intensity of treatments, how profoundly do we want to attenuate androgen signaling. And here I think the primary decision factor more relates to disease burden and the symptoms that they may have. And again, there's a high level evidence to support that as an influential factor. But again, especially in a palliative, intense setting, the patient level factors underlying comorbidities and again, the toxicity tolerance and personal preferences certainly play a role. Up until recently, we haven't really had a huge distinction in terms of specific drug choice. So more or less energy deprivation therapy mechanisms were felt to be equivalent in this in either of these two settings. But I think recently, based on some data, which I'll show in a moment that may be changing. And this is the hero study which was actually presented and published last year, which was a phase three randomized trial that sought to evaluate the standard generate agonist therapy loop relied versus a novel oral generate antagonist therapy. And they randomized patients who are all planned to receive 80 for various treatment settings. And I won't go into the uncle logic details of this study, but I just wanted to focus on the cardiovascular endpoints because there has always been over the last several years, some interest in potential treatment related differences from a toxicity standpoint between generates antagonist vs. Agonist therapies. And so that was changes in cardiovascular outcomes was a key secondary endpoint of the study. And when we look at the baseline patient characteristics for this study, over 90 of both treatment arms had some level of cardiovascular risk factor. And this is actually, I think quite common for clinical trials and prostate cancer because we're dealing with an elderly male population on average. And so I'll just point out that in both treatment, arms around 13 or 14 of patients had a prior history of a major adverse cardiovascular event. And again, I think this is pretty typical for a prostate cancer clinical trial population. And again, the key secondary endpoint was looking at the incidents of major adverse cardiovascular events between these two treatments. And they found that in the overall study population there was a lower rate of adverse cardiovascular events, 2.9 with the antagonist therapy, versus 6.2 with the agonist therapy. And this was appeared to be more profound in those patients who again, that 15 or so who had an underlying history of a major adverse cardiovascular event where There was this interaction and a much more profound benefit in favor of the antagonist therapy at 3.6 incidents versus 17.8 incidents. And so this shows the cumulative incidents curves where it corresponded to about 54 reduction, relative risk reduction with the antagonist therapy. And interestingly these curves separated relatively early following treatment initiation. And so this study generated a lot of press. It was actually published in the New England Journal of Medicine last year. And recently this drug has now really galex has been FDA approved just has a few weeks ago. And so I think for the first time this may be sort of giving an opportunity to think about different specific prostate cancer treatments and how we might select treatments based on underlying comorbidities and specifically cardiovascular comorbidities. I think we talked about the fundamental role of energy and suppression and the treatment of prostate cancer. But I think a second key concept that I wanted to describe is this concept of hormone resistant versus castration resistant prostate cancer. Because I think this reflects our improved and evolving understanding of the biology of prostate cancer and the role that energy and suppression plays. Because historically we used to for example have men with metastatic prostate cancer. We would give them fundamental treatment with androgen deprivation therapy such as a GN Rh agonist and at some point in their disease course they would invariably become resistant to that therapy. And we return that hormone resistance and go on to other treatments that don't necessarily target the androgen axis such as chemotherapy. But in the last decade or so we've had a much improved understanding of the biology and the nature of energon signaling and prostate cancer, where we know that if we give those same patients energy deprivation therapy, there's actually multiple mechanisms where prostate cancers adapt and maintain psychogenic androgen signaling even despite castrate levels of testosterone. And so this can happen through up regulation of the androgen receptor or splice variants are activating mutations and the androgen receptor, which then leads to sustained psychogenic androgen signaling despite castrate levels of testosterone. And so I think the more informative term here is really castration resistant prostate cancer and not necessarily androgen resistant prostate cancer. And this has led to a whole new class of agents really. Over the last decade, which we've collectively termed second generation androgen signaling inhibitors, but can seek to surmount some of these resistance mechanisms to standard. And so I just make this point that androgen signaling really retains critical importance throughout the disease course for the majority of men with prostate cancer, not just in the initial treatment. And so, you know, many of these drugs you're familiar with or have certainly seen patients who have been on these agents because they're quite commonly used in the treatment of prostate cancer, primarily in the advanced treatment settings. But they do have some unique considerations, especially as it relates to potential cardiovascular concerns. And so one of the older agents that is still commonly used today is a drug called abiraterone, And what this drug is is it's a selective 17 alpha inhibitor. So essentially acts to try to inhibit the extra genital production of circulating androgens. And so it inhibits the adrenal androgen bio synthetic pathway. And that pathway is depicted here. And what drugs like abiraterone do is they block these downstream enzymatic steps in the production of adrenal androgens and it can very effectively do that. But one of the consequences of this inhibition is that it can also inhibit the production of normal cortisol levels. And as a result there's a loss of negative feedback or I guess I should say there's positive feedback on this pituitary adrenal axis where there can then be up regulation of ACDC signaling. But because of the block downstream, this signaling gets shunted towards Aldo Stallone production. And so when you use drugs like abiraterone, some of the toxicities can be those of mineral according to access. And so there is risk of hypertension typically miA and fluid retention. And in fact in the clinical trials of drugs like abiraterone, the rates of grade three hypertension. So severe hypertension, we're up to a third of patients exposed to the drug and as a result, we per FDA label always administer abiraterone along with predniSONE at a dose of 5 to 10 mg daily. And the role here of the predniSONE is primarily to try to block this positive feedback loop and reduce the production of th and the potential effects of mineral cortical access. And so when we think about specific patients where we want to use drugs like abiraterone, we have to be mindful of the risk for toxicities and mineral accord. A quick access to those who are already have baseline uncontrolled hypertension might be prone to electrolyte imbalances or have issues with fluid retention or who may have strong contraindications to long term predniSONE use. But the second big category of agents that would fall under this novel energon receptor signaling category would be a variety of our receptor antagonists. And so you've probably heard of drugs like Ngilu to mind, a polluted mind or Daryl Liew to Mind, which I think would all fall into this category. And these are essentially potent ways of inhibiting the er receptor and its trans location to the cell nucleus. And they are also associated with a number of potential side effects. And I'll just point out here that in particular, they can also, even though they don't have the same mineral according to excess in the prospective trials that have evaluated this, they have also been associated with grade three hypertension in a quarter to a third of patients and because of their very potent androgen receptor signaling inhibition, it does cause significant sarko pina and changes in weight and have been associated with some functional consequences of that. So, decreased exercise tolerance and actually a risk of falls and because of document and bone density fracture risk as well. From an oncological standpoint, we actually think of these agents pretty equivalent equivalently. So this is just one example of study of a study that tried to compare uncle logic endpoints between drugs like abiraterone and Saluda meid and ultimately, there's not felt to be a significant difference in their therapeutic efficacy and prostate cancer. And so I just point that out because it gives us an opportunity, since we have multiple agents to sort of think more about the toxicity aspects and individualist based on certain patient profiles. And I'll just close by by sharing this slide, which just shows the treatment landscape as as it currently exists in advanced prostate cancer. And I just show it because I guess a couple points to take away. So first of all, there's a lot of overlap. So you can see drugs like ends, luda meid have FDA approvals and can be used in a variety of different treatment settings across the natural history of prostate cancer. Same with abiraterone, same with apple in mind. And and and so there's a lot of variability in practice about how we might use these drugs, at least from the oncological standpoint. But I think the second point and perhaps more important is that it just emphasis is that these various ways of potently attenuating androgen signaling really used throughout the disease course. So all the way from even men with clinically localized earlier stages of prostate cancer to those who have treatment refractory towards end stage prostate cancer, we have the ability to potentially use these agents. And and this natural history of prostate cancer often plays out over many, many years. And so it just hopefully emphasizes the point that energy attenuation happens throughout the disease course. And we're able to thankfully really prolong survival for prostate cancer patients with these drugs. But it really also emphasizes the importance of thinking about the long term consequences of this from a physiologic perspective and really starting to think about toxicity management and survivorship from the beginning. Um I think often times when we are seeing a new patient with metastatic prostate cancer. Obviously the patient worry is about the diagnosis, the uncle logic diagnosis and the fact that they may need to start treatment. But we do try to also emphasised that this is a long natural history and we do need to think about toxicity mitigation from the beginning.
