Nutrient Guidance for Patients on ADT

The European Association of Urology just published a short paper summarizing dietary recommendations for men on ADT. As  a context for this paper the authors note that,  “dietary interventions for mitigating ADT side effects are promising, but few interventions have focused on diet alone and they offer limited evidence of benefit.”

The authors thus acknowledge that there has not been much research on diet specific for men on ADT. They also write, “longer-term studies that incorporate longitudinal compliance measures and collect progression outcomes or intermediate biomarkers of prognosis are needed in cancer patients, and specifically in patients treated with ADT.” That's a fancy way of saying that we need more research on compliance.

The authors flag a study that is underway and looks at whether a digital platform can help support patients who try to make lifestyle changes while receiving ADT. Their study recognizes that the challenge is not so much about getting relevant nutritional information to patients, but in getting patients to comply with the recommendations.

The paper has two interesting tables.

The first one lists recommendations for preventing heart disease and for reducing cancer death overall, including prostate cancer death. It is noteworthy that the data are not specific to men on ADT, but are nevertheless in line with the recommendations in the ADT book on a heart healthy diet for men on ADT.

The second table lays out a few of the questions that patients might ask about diet when starting on ADT. And it offers some answers to those questions. These include recommendations relevant to avoiding osteoporosis and weight gain. The table also informs patients that evidence for benefit from supplements is negligible, except perhaps for vitamin D and calcium (plus vitamin B12, if one is on a vegan diet.)

What is interesting is a discrepancy between Table 1 and Table 2. In terms of alcohol consumption for heart health, Table 1 recommends limiting one’s alcohol consumption to one or two drinks per day…and avoiding it completely, if one wants to reduce the risk of dying from cancer in general. The table also suggests limiting alcohol consumption to five or less drinks per week, to reduce the risk of lethal prostate cancer.

Table 2 has a more lenient and perhaps more realistic recommendation, which is prefaced with: those who aren't drinking, obviously shouldn't start. However, for those that do like to drink, recommendations are to limit one’s intake to one or two drinks per day.

Despite these inconsistencies, the authors do a good job laying out what we know and need to know in order to arrive at helping men on ADT maintain the best nutritional status.  At the moment, there is no easily managed diet for overcoming most of the detrimental metabolic side effects ADT.

Reference:

Kenfield, S., Van Blarigan, E., Graff, R., Borno, H., Macaire, G., & Chan, J. (2023). Nutrition Guidance for Patients on Androgen Deprivation Therapy. European Urology Focus, S2405-4569(23)00060-3.

https://doi.org/10.1016/j.euf.2023.02.009

ADT and the Kidneys

Listed among the rare side effects of ADT is acute kidney injury (AKI). One does not hear much about that though, presumable because it is rare. But what is behind that risk? Is it rare–like some rare allergic reactions, which some people never experience, but for others are life threatening?

There is now a review by a urologist in Japan on how ADT might lead to impaired kidney function. This paper helps demystify the risk of AKI.

AKI is an extreme form of renal impairment and, as the author points out, some level of renal impairment can occur with dyslipidemia. So, what is dyslipidemia? Dyslipidemia is an unhealthy level of the triglycerides and high- and low-density cholesterol in one's blood. Dyslipidemia is associated with diabetes and is part of the type of metabolic syndrome that has been associated with ADT, and the elevated risk of diabetes for men on ADT.

We often talk about how ADT, if not properly managed, can increase the risk of diabetes. In the same way that a poor lipid profile puts men at risk of diabetes, it can increase the risk of renal impairment. This doesn't get discussed often because it typically goes unnoticed…unless it is severe and presents itself as AKI and, in the extreme, as kidney failure.

For the same reason that we need a good lifestyle to avoid the risk of diabetes when on ADT, the same precautions can help avoid renal impairment. Another way to view this is that patients on ADT should maintain a lifestyle that avoids dyslipidemia, not only because of the risk of cardiovascular disease and diabetes, but also because it helps preserve good kidney function.

The author ends with simple recommendation about language and we think it is a good one. There he states: “With regard to lipid dysfunction due to ADT, the term ‘renal impairment’ should be used instead of ‘AKI’”.

Reference:

Masuda, H. (2023). Renal Impairment: A Major Adverse Event in Prostate Cancer Patients Treated With Androgen Deprivation Therapy. Anticancer Research, 43(1), 305-309.

Are Too Many Old Men With Prostate Cancer Going on ADT?

According to a group of urologists in Italy, the answer is “yes”.

Residing in Europe, the authors reached that conclusion based on the formal guidelines for the use of ADT set out by the European Association of Urology. Those guidelines are clear that with no sign of systemic disease, and with a low PSA and a long PSA doubling time, there is no benefit in putting elderly patients on ADT. These guidelines also state that it is inappropriate to put such men on ADT, if they have not yet received, but could safely receive, treatment for localized disease.

Following those guidelines, the researchers found that out of 427 elderly patients, who were treated with ADT, 66 (15.5%) started on ADT when they shouldn't have. These were all elderly men. Many were identified as “old old”; i.e., over 75 years old.

The paper rigorously reviews the serious cardiovascular side effects that can come from ADT, such as a heart attack and osteoporosis, as well the most bothersome ones, such as fatigue and hot flashes. Given the potentially dangerous side effects of ADT in the elderly population, a case can be made to avoid ADT when there is little sign that the patients will benefit from the treatment.

Although the paper does not go into this, one might imagine that these men are not good candidates for a radical prostatectomy, but that would not rule out external beam radiation, which could be an alternative to starting them prematurely or unnecessarily on ADT. The authors also point out that excessive use of ADT has a large financial cost on the health care system.

There is no reason to suppose that excess use of ADT is a problem specific to Italy. We have personally seen men with a very low and slow climbing PSA well over 75 anxious to start ADT. Given their climbing PSA, they fear that they must start ADT as soon as possible…regardless of other factors that could influence their overall survival. It would be interesting to survey such patients and find out why they are more worried about prostate cancer than having a heart attack, a stroke, or falling down and breaking a hip from osteoporosis. Although this is only a speculative guess, we suspect that the word “cancer” is interpreted as more threatening to the men then many of  of the health risks associated with the side effects of ADT.

This paper is a great review of the side effects of ADT, but it also raises the question of why a large percentage of men are started on this treatment when they don't benefit from it. Are the clinicians recommending it excessively or are the patients demanding it excessively? To be clear, although we see great benefit in the appropriate use of ADT for extending the lives of men with advanced prostate cancer, we know of no great benefit for older men to start on it without clear evidence that the benefits out rank the risks.

Reference:

Oderda M, Bertetto O, Barbera G, Calleris G, Falcone M, Filippini C, Marquis A, Marra G, Montefusco G, Peretti F, Gontero P. Appropriateness and complications of androgen deprivation therapy for prostate cancer: Can we do better? A retrospective observational analysis from a referral center. Urologia. 2023 Jan 26:3915603221149502. doi: 10.1177/03915603221149502 Epub ahead of print. PMID: 36703243.

Does ADT Increase the Risk of Alzheimer’s Disease?

Approximate 200 papers in the medical literature over the last six years have commented on a possible association of long-term ADT with dementia for prostate cancer (PCa) patients. We have reviewed some of those papers in previous blog entries. Yet the papers keep coming out and some have seemingly contradictory conclusions. Here are two examples:

“Cumulative ADT exposure was associated with dementia.” [Lonergan et al. 2022] 

“Androgen deprivation therapy was associated with a significantly decreased risk of AD for men with prostate cancer.” [Du & Song, 2023; note “AD” stands for Alzheimer’s disease]

The first paper sounds bad, but the second one sounds surprisingly good. So, what is going on here?

The Du & Song study was a retrospective look at data from the SEER database linked to a Medicare database in the USA. It included information on 350,000 men diagnosed with PCa, who were all over the age of 65. Some had been on ADT and some also had an AD diagnosed. A separate epidemiological study by Lehrer & Rheinstein (2023) using data form the UK’s Biobank reached a similar conclusion. Both studies suggested that ADT does not cause Alzheimer’s disease and may even be associated with lower risk of that disease. Both studies depended on large registry files with formal neurological diagnoses, plus drug prescription data to define the study populations.

The conclusion that ADT doesn’t cause AD may seem somewhat problematic considering that many studies suggest that long term ADT may lead to some cognitive impairment. To make sense of these papers one needs to realize that Alzheimer’s disease is a specific form of cognitive impairment. Both the Du & Song and Lehrer & Rheinstein papers distinguish Alzheimer’s disease from a variety of other forms of dementia. AD is one form of dementia, but there are others.

A patient who says, after starting on ADT that he is more likely to misplace his car keys or glasses may never be diagnosed with any form of dementia, as that sort of daily cognitive challenge is common with aging. Occasional “senior moments” are not classified as clinically significant dementia. They are just common with aging and are not likely to be recorded in databases like the SEER, which relies on rigorous criteria for neurological diagnoses.

Age turns out to be a key factor here. As we get older, we are all likely to show some signs of cognitive impairment. That is a sad reality of aging, but in and of itself is not a definitive sign of AD. Notably the PCa patients on ADT were on average older than the patients not on ADT. However, if ADT helps men live longer, then they are more likely to experience some decline in cognitive function over time.

Conversely, if AD shortens one’s life expectancy, then it will be less likely to be linked to long term use of ADT. The complicating variable here is that ADT use and the emergence of AD are both more common with old age, but not necessarily causally linked to each other.

So, does ADT cause cognitive impairment? A variety of studies, but not all of them, would say “yes”, as there is some statistical association at the population level between cognitive performance and the long-term use of ADT. But that does not mean that all men on ADT will experience cognitive impairment and it may not show up at all, if they are relatively young and otherwise healthy.

Does ADT specifically increase the chances of getting AD? The data on that suggests the answer is “no”. That is particularly true if they are relatively young and otherwise healthy.

References:

Du, X.L., Song, L. A (2023) Large Retrospective Cohort Study on the Risk of Alzheimer’s Disease and Related Dementias in Association with Vascular Diseases and Cancer Therapy in Men with Prostate Cancer. J Prev Alzheimers Dis. https://doi.org/10.14283/jpad.2023.8

Lehrer S, Rheinstein PH. (2023) Androgen Deprivation Therapy Unrelated to Alzheimer's Disease in the UK Biobank Cohort. Anticancer Res. 2023 43(1):437-440. doi: 10.21873/anticanres.16179. PMID: 36585167. 

Lonergan PE, Washington SL 3rd, Cowan JE, Zhao S, Broering JM, Cooperberg MR, Carroll PR.  (2022) Androgen Deprivation Therapy and the Risk of Dementia after Treatment for Prostate Cancer. J Urol.  207(4):832-840. doi: 10.1097/JU.0000000000002335

Does ADT increase the risk of getting COIVD? – Nope.

It is nice when the title of a medical paper is in the form of a complete sentence and tells the main story of the paper. A new study out of Sweden managed to do just that.

The paper is titled “Androgen deprivation therapy in men with prostate cancer is not associated with COVID-2019 infection.” Covid 2019 in Sweden is what most people in North America now simply call COVID; the disease caused by the SARS-CoV-2 virus.

Early on during the COVID pandemic, there was a lot of discussion about whether prostate cancer (PCa) might increase (or decrease) the risk of getting the infection. There was similar concern about whether treatments for PCa influenced the risk of getting the infection or the severity of it once acquired. 

This new paper involved a comparison of 224 PCa patients treated with ADT, 431 PCa patients who had not been treated with ADT, and 240 men diagnosed with just benign prostatic hypertrophy.

The authors found no association between ADT use in prostate cancer patients and subsequent risk of SARS-CoV-2 infection, nor of the severity of the disease for men who caught it. The authors did, however, find that obesity and having type 1 diabetes increased the risk of getting COVID.

This appears to us to be a relatively clean study, but the sample size was not large enough to know whether men who are on ADT and subsequently get diabetes were also at increased risk of severe COVID. That has, though, been reported in other studies.

The take-home messages here is that one should not worry about being at increased risk of getting COVID, if one is on ADT. However, they should be concerned if they’re not taking precaution, while on ADT, to avoid excessive weight gains that get them into the obese range on put them at risk of becoming diabetic.

Reference:

Davidsson, S, Messing Eriksson, A, Udumyan, R, et al. Androgen deprivation therapy in men with prostate cancer is not associated with COVID-2019 infection. Prostate. 2023; 1- 8. doi:10.1002/pros.24485

It is Not Necessarily Metabolic Syndrome that You Should be Worried About…

Most of us on ADT have experienced some weight gain and loss of muscle mass. Those are two conspicuous features of what is called metabolic syndrome (MetS). MetS is defined by a suite of features that include not just those two conspicuous features, but also a shift in blood markers related to lipids, cholesterol, and the risk of diabetes. One doesn’t need to have all of the features of MetS to be considered at risk of developing MetS. As PCa patients, we are warned that ADT carries a risk of MetS and that one should maintain a healthy lifestyle (exercise and diet) to minimize the risk.

Against that background, there’s a new paper out that does a meta-analysis of previous studies on ADT and comes up with a surprising result. There the author reports that “ADT was not associated with the development of MetS”.

One needs to remind themselves that it is not MetS per se that is the issue, but rather it is indicative of elevated risk for certain serious cardiovascular diseases such as hypertension and diabetes. In that regard, the paper concluded that men have a 25% increased risk of developing diabetes and a 30% increased risk of developing hypertension while on ADT. That’s serious stuff.

How could this paper find that the patients on ADT are less likely to develop MetS, yet still are at increased risk of hypertension and diabetes? It seems like a contradiction.

When one digs into the paper, a few factors show up that can account for this.

For example, the authors note that for some studies included in their analysis, it wasn’t clear what form of ADT the patients were on. Secondly, the studies were done from around the world. One needs to remind themselves that MetS is not one thing, but a suite of things…and one doesn’t have to present with all of them to be classified as having MetS. So, for example, for one population, weight gain may be the most common sign of MetS and in another , a shift in triglycerides may be more prominent. The authors didn’t document that specifically, but the studies included in the meta-analysis were from around the world and the authors acknowledged the high variability in their data, which may account for why they found less evidence of MetS.

Of course, that isn’t what really matters. It’s the long-term risks of the serious stuff like hypertension and diabetes that we need to be concerned about. In this regard, the authors are firm on their recommendations and we endorse them. Men starting on ADT need to be assessed for cardiac function and diabetic risk.

In addition, along with getting regular PSA tests, men should also get their haemoglobin A1c checked as a blood marker for diabetes, a cardiac assessment, and track their blood markers for MetS (triglycerides and cholesterol).

It isn’t the MetS that you need to worry about. It’s the cardiovascular and metabolic risks that need to be monitored, on any form of ADT.

Reference:

Swaby J, Aggarwal A, Batra A, Jain A, Seth L, Stabellini N, Bittencourt MS, Leong D, Klaassen Z, Barata P, Sayegh N, Agarwal N, Terris M, Guha A. Association of Androgen Deprivation Therapy with Metabolic Disease in Prostate Cancer Patients: An Updated Meta-Analysis. Clin Genitourin Cancer. 2022 Dec 26:S1558-7673(22)00264-6. doi: 10.1016/j.clgc.2022.12.006. Epub ahead of print. PMID: 36621463.

On Using 2nd Generation Anti-androgens as Monotherapy to Delay More Aggressive Treatments for Patients on Active Surveillance

The main reason we have this blog series is to report on new findings about ADT, in particular, ways to manage or avoid the more adverse effects caused by the main drugs used for ADT. Those are LHRH agonists and antagonists. Occasionally though, there are other drugs worth reporting on, particularly when their timely use can delay the need for patients to go on the more challenging LHRH drugs.

Here is a report on two such papers on a new context: using second generation anti-androgens as monotherapy.

The drugs of interest are the androgen receptor targeting agents, enzalutamide (Xtandi) and apalutamide (Erleada). These drugs are usually prescribed to patients with advancing disease and administered in combination with the LHRH drugs. However, there have now been two reports on patients administering these drugs who were diagnosed with low to intermediate grade disease, and elected to go on active surveillance, delaying more aggressive treatments.

Patients on active surveillance get their PSA regularly monitored and go for regular biopsies. If the biopsies indicate disease progression, then they go for more definitive treatments, such as a prostatectomy or radiotherapy.

In the most recent paper, 22 men who were on active surveillance, went on apalutamide for three months. They all had biopsies before starting the drug treatment. After three months, they had a follow-up biopsy and 57% of the men’s biopsies came back clean; i.e., no sign of disease! The men were biopsied again after a year and 33% had negative biopsies. At two years out, approximately 20% still had clean biopsies.  

Although this was a one arm (i.e., no control group) and unblinded study, it suggests that early use of the new anti-androgens can delay patients–who have low grade disease–from having to go for more aggressive treatments. A major problem though with this study is the small sample size.

The second paper involved a similar, active surveillance patient population but with a larger sample size, 114 men. Those men were on another commonly used anti-androgen, enzalutamide, and stayed on it for a year. The results were pretty much the same in demonstrating that early use of a second generation anti-androgens can slow disease progression as indicated by biopsy results.

Both studies suggested that monotherapy with second-generation anti-androgen drugs is less burdensome in terms of side effects then the LHRH drugs. That is not to say they don't have side effects. Fatigue was the most commonly reported side effect for the men in both studies. Otherwise the men appeared to have a better quality of life than men on the LHRH drugs.

We expect that these two papers will be followed up with a similar study using yet another second generation anti-androgens, namely darolutamide (Nubeqa). If that yields the same result, this could lead to a paradigm shift in how we think about sequencing ADT agents. In the past, patients needing systemic therapy started on an LHRH drug and, if that was not fully effective in arresting the cancer, a second-generation anti-androgens would be added in. However, it might be better for patients’ quality of life to start earlier with the anti-androgen alone. Then, if there is sign of disease progression, add in an LHRH drug.

Both papers have received a fair bit of criticism for a variety of reasons. Going on either drug is admittedly a form of active treatment and thus patients are no longer really on just surveillance. We also don't know whether a short-term improvement in biopsy results for patients diagnosed with low to intermediate grade disease will translate into any overall survival advantage. We need much larger and longer term studies to find out.

Furthermore, the drugs are expensive.

That said, a lot of patients, who start on active surveillance, get anxious when they see a rise in their PSA. Many find this stressful to live with and, although their cancer may never become symptomatic, give up on active surveillance and go for definitive invasive treatments. If short term use of an anti-androgen can slow down disease progression by a year or two, it should make men more likely to stay with active surveillance. We see that as a win.

References—

Schweizer MT, True L, Gulati R, Zhao Y, Ellis W, Schade G, Montgomery B, Goyal S, Nega K, Hakansson AK, Liu Y, Davicioni E, Pienta K, Nelson PS, Lin D, Wright J. Pathological Effects of Apalutamide in Lower-risk Prostate Cancer: Results From a Phase II Clinical Trial. J Urol. 2023; 209(2):354-363. doi: 10.1097/JU.0000000000003038. Epub 2023 Feb 1.

Shore ND, Renzulli J, Fleshner NE, Hollowell CMP, Vourganti S, Silberstein J, Siddiqui R, Hairston J, Elsouda D, Russell D, Cooperberg MR, Tomlins SA. Enzalutamide Monotherapy vs Active Surveillance in Patients With Low-risk or Intermediate-risk Localized Prostate Cancer: The ENACT Randomized Clinical Trial. JAMA Oncol. 2022; 8(8):1128-1136. doi: 10.1001/jamaoncol.2022.1641. Erratum in: JAMA Oncol. 2022 Aug 1;8(8):1225

A new paper on ways to improve the quality of life of patients on ADT is fabulous, but… also frustrating

A new paper written by a group of medical oncologist in Italy has the intriguing title “How to improve the quality of life of patients with prostate cancer treated with hormone therapy?“

How could we not love a paper on that topic?!

Well, we do love the paper because it has a remarkably valuable summary of the literature on the side effects of not just classic ADT agents, but also those agents when used in combination with abiraterone (Zytiga) or second generation anti-androgens; i.e., enzalutamide (Xtandi) apalutamide, (Erleada) and darolutamide (Nubequ). The paper includes a large and quite comprehensive table listing the well-documented ADT side effects, how they present, and management strategies.

In addition, there’s another table that outlines the side effects sorted by each drug. For patients who want to dig deeper, the text summarizes research from over 100 peer-reviewed studies that include information on the side effects of these drugs. In this table, one can find out what the odds are of getting osteoporosis, hot flashes, and major cardiac events, from prolonged use of ADT.

The paper is particularly timely since there is growing evidence that using these drugs in various combinations has survival benefit. It also points out that many combinations intensify common ADT side effects. This means in the future, patients will more often be prescribed a combination of ADT drugs and therefore will have more intense side effects for a longer amount of time. That makes managing the side effects in a timely fashion—before the side effects become intractable—even more important.

It is on the management side of the side effects that the paper frustrates us. The authors perspective is strictly on the patient. The psychosocial side effects of the drugs are not mentioned. The authors acknowledge that the drugs can influence patients’ intimate relationship(s), yet nothing is said about how to manage negative impacts on patients’ partners or their partnerships in general.

As an overall management strategy, the authors promote using ADT intermittently or delay starting patients on ADT. However, that isn’t really managing drug side effects. Rather, it is simply avoiding using the drugs.

The management strategies that are offered are not as extensive as they could be. For example, although it is an off-label use, there is now published data that transdermal estradiol can reduce the risk of osteoporosis. But this isn’t mentioned in the article.

It is particular frustrating that what the researchers label as “management” in the table of “adverse events associated with hormone therapies” is not management, but really just monitoring the risk. That is what’s offered for both cognitive effects and renal toxicity. Monitoring is not the same as mitigating, once the side effects emerge.

For sexual dysfunction, the first management strategy offered is “appropriate pre-treatment counselling”. Sadly, research to show what is “appropriate” (i.e., what is effective) in the way of pre-treatment counselling for sexual function is not well established.

And so, here we have it–a great review of the problems, but not necessarily an advance on ways to improve patients’ quality of life on ADT!

Turco, F., Di Prima, L., Pisano, C., Poletto, S., De Filippis, M., Crespi, V., ... & Buttigliero, C. (2023). How to improve the quality of life of atients with Prpostate cancer treated with hormone therapy? Research and Reports in Urology, 9-26.

Where Might One Go for Info on ADT that is Not Too Technical, but Nevertheless Accurate and Up to Date?

We often get asked about how one can find reliable information about prostate cancer on the internet that is not too technical. The following are some guidelines we’ve used over the years.

When it comes to websites, generally we trust those whose addresses end with “.EDU“ and “.GOV“ over those that end with “.COM”. [Yup, our own website ends in “.COM”, so we must work extra hard to maintain our own credibility.] There are a couple of pages discussing additional tips on how to distinguish the more reliable from less reliable sites at the beginning of the Resource chapter in the ADT book. But, what if you want to go deeper than that and keep up to date on an on-going basis?

Here is what we do—

To get access to original and peer-reviewed medical literature we use PubMed. It is the search engine for the US Library of Medicine and accessible at: https://pubmed.ncbi.nlm.nih.gov/

We also use Google Scholar, and you can too. See: https://scholar.google.com/

Additionally, we subscribe to Google Alerts, which searches Google Scholar daily for us on the words “androgen deprivation therapy.” That pulls up the newest medical papers mentioning ADT. Google Alerts is a free service linked to Google and Google Scholar. Check it out at: https://www.google.com/alerts

PubMed and Google Scholar typically pull up pretty technical stuff. The average patient might ask: “Is there one particular site that you feel is reliable, up-to-date, and still accessible to patients with no medical background?” That brings us to that National Comprehensive Cancer Network. The NCCN posts on its website recent updates regarding guidelines for cancer treatments. The NCCN has pages devoted to both early stage and advanced prostate cancer. The NCCN has a large panel of medical experts advising them. To their credit, they have free and accessible information, specifically written for patients.

As an introduction to the NCCN, check out these links:

https://en.wikipedia.org/wiki/National_Comprehensive_Cancer_Network

https://www.nccn.org/patientresources/patient-resources 

https://www.nccn.org/patientresources/patient-resources/guidelines-for-patients/guidelines-for-patients-details?patientGuidelineId=50

Androgen annihilation? Hormonal intensification? Triple therapies? ARTAs/ARSIs?—What’s this all about?

Hormone therapy for prostate cancer (PCa) started to change in a big way a decade or so ago when abiraterone (=Zytiga) came on the market. That change accelerated when second generation anti-androgens—i.e., enzalutamide (=Xtandi), apalutamide (=Erleada), and darolutamide (=Nubeqa)—also became available to treat PCa. Those four drugs, plus similar compounds in development, are collectively known as androgen-receptor targeted agents (ARTAs) or androgen-receptor signaling inhibitors (ARSI) [and by a few other names as well].

In the last few years there has been a wave of PCa clinical trials involving not just standard ADT, but ADT in combination with various ARTAs. These combinations of treatments are known as hormonal intensification. Adding an ARTA to ADT as a double therapy has been shown to improve survival in certain populations of PCa patients. Those include men with metastatic disease, which can’t be controlled by standard ADT alone; i.e., men with metastatic, castrate resistant PCa (often abbreviated mCRPC).

If that combination doesn’t control the cancer, these men typically progress to chemotherapy. Often their PSA is rising rapidly after localized treatment, such as a radical prostatectomy or brachytherapy. Imaging may confirm metastatic spread of their disease. ADT plus chemotherapy is also an established form of double therapy, which has been shown to provide some disease control for men with a high disease burden (i.e., who are symptomatic). But recent trials have shown that for some of these patients adding an ARTA helps even more. The combination of these three treatments is one form of triple therapy.

In addition, there are yet newer drugs, such as PARP inhibitors and radioligand PSMA agents, under investigation in combination with the treatments mentioned above. As such, we envision even more treatment protocols becoming available as hormonal intensification, and these are likely to include triple, or perhaps even quadruple therapies.

That gets to the key question here: What should a patient on ADT, experiencing a rise of PSA indicative of biochemical progression, make of the many new treatment options arising from all these trials? Is more treatment indeed better treatment?

While we think this research is encouraging, there are a handful of issues that patients who are experiencing a rising PSA after localized treatments, should be aware of.

Here are a few:

1. Because abiraterone blocks testosterone production, not just from the testes but from the adrenal glands, treatment with abiraterone is sometimes called “androgen annihilation.” That label emphasizes its dramatic capability to suppress testosterone production.

   Unfortunately, abiraterone suppresses not only testosterone production from the adrenal glands, but also glucocorticoid production. The predominant glucocorticoid is cortisol; a steroid produced by the adrenal glands with a vast array of functions in the body. These functions include processing sugars, controlling inflammation, and regulating the salt concentrations in the body that influence fluid balance and the risk of cardiovascular disease. As such, if one is taking abiraterone, they need to take it along with a synthetic steroid, such as prednisone, to correct for the loss of cortisol caused by abiraterone. Every patient on abiraterone needs that steroid replacement, plus regular blood tests to assure that the dosages of the two drugs are precisely right for them. In general, the health of patients on ARTAs combined with standard ADT needs to be monitored even more rigorously than those on ADT alone. This is particularly true when prednisone or similar drugs are added in for they are associated with their own additional side effects.

2. Not all the trials that found a benefit for double and triple therapies have had the same outcome. One might assume that the endpoint for any trial for advanced cancer patients would be overall survival (OS). However, clinical trials that use this outcome as their end point, usually need to run a decade or so to get enough data to know, for sure if the new treatment is truly better than the old treatment.

   Thus, researchers often use surrogate outcomes that can capture useful data earlier. These include evidence of disease progression (i.e., progression free survivor; PFS) or signs of progression on radiographic scans (i.e., radiographic progression-free survival, rPFS). In some trials, new treatments have shown better PFS, yet in the long run haven’t shown an advantage in OS. Patients need to be aware of what the outcomes are for any trial they might enter, or the rationale for any double or triple therapy protocol they might elect to go on to treat their cancer. A drug combination may slow disease progression, which can be reassuring in the short-term. However, that doesn’t necessarily translate to prolonged life or better quality of life in the long term.

3. Increasingly oncologists are recommending double and triple therapies for patients, with rising PSA after localized PCa treatment. A potential and not uncommon drawback, when patients go on hormonal intensification treatments, is they are at risk of more intense side effects. This is an unavoidable reality of cancer treatments that involve multiple drugs; i.e., the more effective the combination, the more diverse and/or intense the side effects are likely to be.

   The side effects that are most likely to be intensified with double and triple therapies vary with the ARTA used. Whatever the side effects, hormonal intensification does not make managing ADT side effects any easier.

4. There is increased use of PSMA diagnostic PET scans that can find metastases long before they become symptomatic. As more patients get PSMA PET scans, more will be considered candidates for double and triple therapies. With research increasingly suggesting that many PCa patients will benefit from combining ARTAs with ADT, we can expect more PCa patients to be offered hormonal intensification…and be on those treatments for a longer time. Again, earlier attention to managing ADT side effects will become that much more important.

5. With all new drug combinations that get approved for clinical use, there is a chance that some rare, but serious side effects will come to light only after the treatments is used by many more patients than in the trials. This is an inevitable trade off in making promising cancer treatments available as soon as their benefits are documented.

   What we learn about novel treatments after the clinical trials are over is called “real world data.” And real world data are starting to come in for double and triple PCa treatments. Real world studies, for example, show that patients on ADT combined with some ARTAs versus others, are slightly more likely to fall and fracture a bone. Therefore, maintaining bone strength is increasingly important.

If a person has any signs of conditions that may be exacerbated by ADT—for example, heart disease, problems with memory, osteoporosis, or diabetes—alone or by the drugs combined with it, those specific risks needs to be taken into consideration when considering hormonal intensification. It is not yet possible to say, for example, that a combination of A+B+C is better than just A+B or A+C for every patient.

This gets into the realm of personalized medicine. The overall health of each patient has to be individually assessed and monitored for any patients considering any double or triple PCa therapies.

The bottom line—

If you are likely to be offered a hormonal therapy that combines ADT with other agents, such as ARTAs, this may indeed offer some benefits such as slowing down disease progression. However, only time will tell if this will impact overall survival.

To better manage the probable increase in side effect burden accompanying hormonal intensification, it is increasingly important to pre-emptively take up a lifestyle that keeps you as fit as possible in advance of going on the therapy. With hormonal intensification, it becomes more important than ever patients do what they can to manage ADT side effects as early as possible. We have been campaigning for years for patients on ADT to do everything they can to maintain good health—particularly cardiovascular health—when starting ADT. With more patients starting on double and triple therapy with ADT, ARTAs, and chemotherapy, management of side effects is more critical than ever.

References:

Note—this is a sample. The literature from just the last year examining double and triple therapies is enormous. As such, we will not attempt now (or in the future) to review each individual trial involving ADT and ARTAs.

De Giorgi U, Hussain H, Shore N et al. Consistent survival benefit of enzalutamide plus androgen deprivation therapy in men with nonmetastatic castration-resistant prostate cancer: PROSPER subgroup analysis by age and region. Eur. J. Cancer 159, 237–246 (2021). 

Hussain A, Jiang S, Varghese D, Appukkuttan S, Kebede N, Gnanasakthy K, Macahilig C, Waldeck R, Corman S. Real-world burden of adverse events for apalutamide- or enzalutamide-treated non-metastatic castration-resistant prostate cancer patients in the United States. BMC Cancer. 2022 Mar 22;22(1):304. doi: 10.1186/s12885-022-09364-z. PMID: 35317768; PMCID: PMC8939229.

Roy S, Sayyid R, Saad F, Sun Y, Lajkosz K, Ong M, Klaassen Z, Malone S, Spratt DE, Wallis CJD, Morgan SC. Addition of Docetaxel to Androgen Receptor Axis-targeted Therapy and Androgen Deprivation Therapy in Metastatic Hormone-sensitive Prostate Cancer: A Network Meta-analysis. Eur Urol Oncol. 2022 Oct;5(5):494-502. doi: 10.1016/j.euo.2022.06.003.

Kostos L, Murphy DG, Azad AA. Double or Triple Trouble in Metastatic Hormone-sensitive Prostate Cancer? Eur Urol Oncol. 2022 Oct;5(5):503-504. doi: 10.1016/j.euo.2022.07.001.

Jazayeri, S. B., Cooley, L. F., Srivastava, A., & Shore, N. (2022). Hormonal Intensification Should Start at the Low-risk Stage in Metastatic Prostate Cancer. European urology open science, 45, 38–40. https://doi.org/10.1016/j.euros.2022.05.015

Wang, E. C., Lee, W. R., & Armstrong, A. J. (2022). Second generation anti-androgens and androgen deprivation therapy with radiation therapy in the definitive management of high-risk prostate cancer. Prostate cancer and prostatic diseases, 10.1038/s41391-022-00598-3. Advance online publication. https://doi.org/10.1038/s41391-022-00598-3

Loguidice, C. T. (2022) Novel AR-Targeted Therapies for Metastatic Hormone-Sensitive Prostate Cancer: Which One to Choose. https://www.onclive.com/view/novel-ar-targeted-therapies-for-metastatic-hormone-sensitive-prostate-cancer-which-one-to-choose