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

What Prostate Cancer Patients Treated with ADT Recall About It Is Worse Than We Thought

Buried within a retrospective study about what prostate cancer patients in Australia recall about their cancer treatments are some disturbing data on hormone (aka androgen deprivation) therapy. The study ran from 2009 to 2019. The data of particular interest are from 221 respondents, who were asked about their treatment history and provided enough information that their recollections could be compared with their actual medical records.

The men were on average 76 years old and had been treated on average six years earlier (range 0 to 18 years). Their recall of their treatment history was overall pretty good, ranging from a high of 96% (for chemo) to a low 66% (for ADT). Notably, this low recall accuracy for ADT means that a third of the respondents could not recall correctly whether they had or had not been on ADT. In fact, over a quarter asserted that they had not had ADT when their medical records showed they had. The patients who recalled accurately being on ADT were overall: 1) younger, 2) had been on ADT more recently, and 3) had been treated solely by ADT.

The author suggested that overall poor recall about ADT may be because the patients viewed ADT as a minor “passive treatment” and they did not consider it (or were not informed about it) being a major part of the effort to control their cancer.

The authors conclude their paper saying because “recall is indicative of patient understanding [of treatment and side effect management], our results suggest that there is an opportunity for further improvement particularly in the areas of hormonal treatment….“ We couldn’t agree more. The ability of patients and those around them to maintain a good quality of life when the patients are on ADT is predicated on the fact that the patients know they on that treatment! It is hard to help patients recognize and adapt to ADT, if they do not even know they are getting that treatment.

It’s hard to imagine anything more discouraging about the concept of informed consent, when there are patients on certain treatments, who do not even know they are getting that treatment. Hopefully the situation, in terms of educating patients about treatment options, side effects, and outcomes, has improved in Australia and elsewhere since the time when the men in this study where getting their cancer treatments.

To read the full paper, see: https://www.sciencedirect.com/science/article/pii/S2405632422000427

Reference:

Brown, A., Tan, A., Anable, L., Callander, E., Lourenco, R. D. A., & Pain, T. (2022). Perceptions and Recall of Treatment for Prostate Cancer: A Survey of Two Populations. Technical Innovations & Patient Support in Radiation Oncology.

Yet another obscure side effect of ADT? Not really.

In order to help PCa patients manage adverse effects of ADT, we need to know all the ways that ADT affects the body. As such, we try to track all the literature suggesting ADT side effects no matter how obscure those side effects might be.

A new paper out of Turkey looked at the effect of ADT on various aspects of the eyes of 57 patients. This included high resolution CAT scans, which allowed the researchers to assess details, such as: the size of small muscles that move our eyes to redirect our gaze, the fat around the eyes, and the thickness of the optic nerve. The researchers found that 12 months or more of ADT caused a decrease in the size of the muscles that move the eye and an increase in the fat around and behind the eye. This extra fat pushed the eye forward slightly stretching and thinning the optic nerve.

At first glance, this sounds scary. Thus, it is important to point out the authors found no evidence of clinical changes in vision. They noted that these changes were “remarkably lower” than what would be considered clinically significant.

The change in fat was approximately 12% over baseline. Researchers pointed out this was in the range of what is commonly reported as overall weight gain for men on ADT for a year or more. The change in muscle mass was similarly consistent with what is average for men on ADT long term. Typically, though, when we think about changes in fat and muscle with prolonged use of ADT, we think about weight gain around the abdomen and weaker legs from loss of muscle mass in the extremities

It is not surprising that the same changes happen on a much smaller scale for the tiny muscles and fat around the eyes. Indeed, these results are what we would have predicted from what we know about ADT’s effects on the body in general. It is good to note that although the sample size was not large, there is no indication that these changes around the eye affect vision in any significant way

Reference:

Sonmez H, K, Sonmez G, Doğan S, Horozoglu F, Demirtas A, Evereklioglu C (2022) Effects of Androgen Deprivation Therapy on the Extraocular Muscles, Retrobulbar Orbital Fat and the Optic Nerve in Patients with Prostate Cancer. Ophthalmic Res. doi: 10.1159/000527387

A Few Comments on the Surgical Option for ADT

The original form of androgen deprivation therapy, which won Charles Huggins, MD, the Nobel prize, was surgical castration. Although that may seem like excessive treatment compared to the injectable LHRH agonist and antagonist drugs now used for ADT, it remains as effective for PCa control and less expensive in the long term. In poverty-stricken parts of the world, surgical castration is still offered to patients who cannot afford the more expensive LHRH agonist and antagonist drugs.

But what about in a country like Turkey?

In a new study, researchers asked 217 urologists and 170 medical oncologists in Turkey, if they offered surgical castration as an ADT option to their advanced PCa patients. Only 7.5% offered this option. Surgeons were statistically more likely to offer it than medical oncologist, but that is hardly surprising since surgical castration is a surgical procedure performed by surgeons.

We have two comments on this study.

In the discussionof their findings, the authors take it as a given that patients consider surgical castration detrimental to their body image. This may be true, but the literature documenting this is very limited. There is remarkably little data on patient preference for different forms of ADT, where the patients were confirmed to be fully informed of the costs and benefits of all the treatment options. One would suppose that patient choice would be influenced by their knowledge about the effectiveness of the treatment against the side effects that might occur.

A common argument against surgical compared to pharmacological castration is that surgery is not reversable. However, this argument is not particularly relevant for older, patients with a advanced disease and do not desire to father children. Patients in that class, who start on ADT, are likely to stay on treatment for the rest of their life.

A couple of studies have found that PCa patients, who elected surgical castration for ADT, were significantly less anxious overall than patients on injectable depot LHRH medications. Now, with so many different ways to suppress testosterone’s influence on PCa cells, it might be worth exploring how much patient comfort or discomfort—with any form of treatment—is influenced by their knowledge of treatment options.

If less than 10% of physicians present all the options to their patients, it would not be surprising that patients may not be making well-informed decisions about their treatments. Are few advanced PCa patients in Turkey (or elsewhere) considering surgical castration for ADT because they feel it will negatively impact their self-image or because they are not being told about that option by their physicians?

This is more than an academic discussion. There are increasingly data showing that the effectiveness in cancer control for patients on the standard ADT drugs can be enhanced with the newer androgen receptor targeting agents (ARTAs). But ARTAs are not cheap drugs. When patient’s financial status is limited, ADT via surgical castration remains a credible option. It certainly should remain an option offered to patients, who might benefit from both standard ADT plus an ARTA, but can’t afford both.

To read the full paper, see: https://www.turkishjournalofurology.com/Content/files/sayilar/206/287-293.pdf

Reference:

Semiz, H. S., Kisa, E., Yildirim, E. C., Atag, E., Arayici, M. E., Muezzinoglu, T., & Karaoglu, A. (2022). What Is Your Choice for Androgen Deprivation Therapy in Metastatic Prostate Carcinoma: Surgical or Medical?. Turk J Urol, 48(4), 287-293.

Do men need to stay on ADT when they have advanced PCa and have started taking one of the newer antigen receptor targeting agents?

In a short theoretical paper, a group of Italian researchers question the rationale for advanced PCa patients staying on standard ADT when they start on an antigen receptor targeting agent (i.e.,the ARTAs; abiraterone, enzalutamide, apalutamide and darolutamide). Their argument is built around the idea that, if bipolar androgen therapy (BAT) helps control PCa by cycling between testosterone and androgen suppression, then it may be similarly advantageous to come off of standard ADT agents, when one is on an ARTA agent.

This is an interesting idea, but it is well ahead of the clinical research. The ARTAs were initially introduced to treat the most advanced PCa and now, justified by data from a series of on-going clinical trials, they are being introduced earlier in the treatment progression. We simply do not have enough data on the long-term efficacy of ARTA monotherapy to know whether they will work better alone, specifically in terms of both long-term survival and patient quality of life. Presumably, the patient quality of life will be better. However, we don’t know about survival. That’s because it takes many years to collect long term survival data and most of drugs have not been around long enough to answer that question.

It also needs to be recognized that BAT is still quite experimental and about 1/3 of the patients in trails so far found that the protocol accelerated their disease.

What this says to us is not only do we need more long-term data on ARTAs when used in combination with other therapies, but we also need more long-term data on the efficacy of ARTAs used alone as either continuous or intermittent therapy.

To read the full paper, see: https://doi.org/10.1007/s12020-022-03166-w

Reference:

Caramella, I., Dalla Volta, A., Bergamini, M., Cosentini, D., Valcamonico, F., & Berruti, A. (2022). Maintenance of androgen deprivation therapy or testosterone supplementation in the management of castration-resistant prostate cancer: That is the question. Endocrine, https://doi.org/10.1007/s12020-022-03166-w