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BackTable / Urology / Article
ADT Side Effects: Balancing Efficacy & Complications
Reilly Fogarty • Updated May 12, 2025 • 31 hits
Managing androgen deprivation therapy (ADT) increasingly demands the balancing of treatment efficacy and a host of complex side effect profiles from targeted hormonal suppressant drugs. Guiding patients to a protocol that they can both tolerate and that will effectively treat their disease requires clinical judgement shaped by patient context, ever-evolving evidence, and long-term risk considerations. As new pharmaceutical agents enter routine practice, survivorship becomes more central to care and treatment protocols must evolve to minimize side effects and maximize patient quality of life.
Learn how these novel drugs can be used in combination to minimize ADT side effects and complications with medical oncologist Dr. Rana McKay. This article features excerpts from the BackTable Urology Podcast – you can listen to the full episode below.
The BackTable Urology Brief
• ADT duration and intensity can be individualized, particularly in higher-risk patients who struggle with tolerating medication side effects.
•Use of first-generation anti-androgens like bicalutamide is declining due, in part, to side effect profile. ARSi therapies (e.g. abiraterone, enzalutamide) provide similar therapeutic benefits with more manageable adverse effect profiles.
•Side effects like testosterone flare, sexual dysfunction, vasomotor symptoms, bone health and metabolic changes are frequent sources of patient complaints. Patients benefit from early counseling and actionable strategies to address these and other potential treatment complications.
•Although the theoretical cardiovascular risks of GnRH agonists have not yet been supported by clinical trials, cardiovascular risk assessment should be a part of ADT and can be coordinated with other care teams. Cardioprotection associated with GnRH antagonists remains plausible but similarly unproven.
Table of Contents
(1) Managing the Side Effects of Androgen Deprivation Therapy
(2) ADT Cardiovascular Risk
Managing the Side Effects of Androgen Deprivation Therapy
Androgen deprivation therapy is a careful balancing act of hormonal suppression, drug effect and side effect management. Side effects like gynecomastia, body dysmorphia, anemia, fatigue and depression are relatively common and can have a serious effect on the patient’s quality of life. Counseling before treatment and careful drug selection to minimize these risks is necessary for any successful ADT protocol. Longer term side effects like osteoporosis may also necessitate baseline DEXA scanning and extended surveillance, something often overlooked by patients and missed in pretreatment counseling.
Testosterone flare – an initial increase in testosterone associated with GnRH agonist medications – is chief among the complications of ADT and has been linked to significant exacerbations of pain, neurological sequelae and risk of mortality. GnRH antagonists like degarelix or relugolix can be used to prevent these flares in some urgent situations, while older first-generation anti-androgens like bicalutamide may be used to prevent flare in non-metastatic disease without an ARSi.
[Dr. Aditya Bagrodia]
While I think we like to get those durations of ADT in for the intermediate-risk patients and for the higher-risk patients – it's a little bit of a conversation, right? If they're completely miserable and life is not worth living, then it's not like we're going to strap you down and get you two years in. It might be, “all right, you're higher risk, let's really try to get a year in and we can worst trade after that”. You mentioned there's injections, there's Degarelix or Relugolix, there's good old-fashioned ADT, anti-androgens, do those have much of a role anymore?
[Dr. Rana McKay]
Very good question. I think there's probably a lot more hand-waving around the testosterone flare when people first start on an agonist than anything else. I think when it's absolutely necessary is in individuals who have symptoms, urinary symptoms that you're worried about obstruction, metastatic disease, pain, cord compression, that's where it's absolutely critical to ensure that you guard against the testosterone flare that can happen. Certainly an antagonist avoids that completely.
I think it has gotten complicated because of the ARSi's and the fact that we use ARSi's a lot in multiple settings and are you going to put somebody on Lupron or bicalutamide, then Lupron wait for their ABI script to come in and then switch them from the bicalutamide to like -- what are you actually doing with the bicalutamide and are you actually impacting their survival in any way by giving them the two or four weeks of bicalutamide?
I think, not to say that there's been a movement away, but I think we are seeing less utilization of the first-generation anti-androgens in the clinic because of the fact that we have these next-generation agents and many individuals are getting such agents. I don't feel so strongly that somebody must absolutely get bicalutamide to suppress the T-flare. I think in the localized context where I'm not using an ARSi, then I will absolutely do that. When I am using an ARSi, I think it just gets very complicated for the patients to also have to worry about getting their first-generation anti-androgen while we're getting their ABI on board or ENZA on board. We may just tell them to start their ABI or ENZA first and then come in later for the injection. At the end of the day, do I think that that impacts overall survival? No.
[Dr. Aditya Bagrodia]
I would tend to agree. I think in those extreme contexts, cord compression, saddle paraesthesia, and so forth, it's pretty easy to use a GnRH antagonist and just be done with it and get castrate on the order of hours. I think that's also a context where bilateral orchiectomy still remains in the toolkit. All right. Side effects, my usual, and it's always a little bit tricky, especially when you're talking to people with a new diagnosis of prostate cancer and they're a candidate for surgery or radiation and you're talking about hormones.
I almost feel a little bit bad because when you run through the litany of stuff, it sounds so awful that people are just like, "There's no way I'm going to do that. There's going to be loss of muscle mass, increase in fat mass, or maybe some cognitive impact, some cardiovascular risk, some osteoporosis, weight gain, loss of libido, rectal dysfunction, fatigue." Do you run through this?
[Dr. Rana McKay]
I do. I do run through the side effects because I think at the end of the day, patients want to know, and I hate it when somebody comes back in the clinic and they're like, "Nobody ever told me this was going to happen." I really want patients to be informed about the side effects that they may experience and the different things that may happen. We certainly can't go through every little possible thing that could certainly happen, but I think it's key to go through the key ones that you're worried about when starting ADT and I think it's important because then you can help with prevention, so that's going to be key.
I think the first thing is going through the fatigue side effects. Many patients want to know, am I going to be able to continue working? Am I going to be able to continue exercising? Level setting is important around there. The vasomotor symptoms I think are really important to describe. The other thing that I think is really important is the sexual side effects and not just with regards to libido, but the body dysmorphism that can happen from going on ADT. I think patients want to know and not be like, "What is happening to me?"
The testicular atrophy that could potentially happen, hair loss, changes in even smell, the different kinds of things that can happen when patients are on treatment. I think it's important to go through that. The other thing is bone health. Some patients may need a baseline DEXA scan certainly if they're going to be on treatment for a prolonged period of time. Optimization around bone health, muscular loss, irritable mood, sleep, metabolic changes is critically important.
Actually even thinking about doing a cardiovascular risk assessment or making sure somebody is doing that, whether it be their internist, cardiologist, or you yourself as their oncologic care provider is important.
I think it's key to go through that. I think this is also an opportunity where our nursing team can be leveraged, our APP team can be leveraged. They're really fantastic and go through the detailed summaries of the different things that patients may experience.
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ADT Cardiovascular Risk
Cardiovascular concerns in ADT stem primarily from the use of GnRH agonists, which are theorized to have some association with diabetes, coronary heart disease, and MI. The data on this remains inconclusive, with the recent PRONOUNCE study on cardiovascular risk in ADT patients using GnRH agonists versus GnRH antagonists ending early due to lack of cardiovascular events in both trial groups.
In the face of still-evolving data many clinicians have begun to favor GnRH antagonists for patients with significant cardiac history, but it should be noted that the cardioprotection of this approach remains theoretical. Dr. McKay advocates for strong cardiovascular risk assessments and actionable strategies in this space while the research develops, noting vitamin D and calcium supplementation, heart-healthy lifestyle guidance, and engagement with sexual health specialists.
[Dr. Aditya Bagrodia]
[on patient counseling] Maybe I subconsciously downplay some of the adverse effects that I don't want it to come across as biased, which is silly. I think it's an opportunity to empower the patients that while these things are being done to them, you can get vitamin D and calcium for bone health, get the DEXA scan, weight-bearing exercises, heart-healthy diet, sleep hygiene, supplements, maybe even potentially.
That you don't have to be a passive victim in this, that there are things that you can do, plugging in with sexual health counseling, a men's health team. Maybe for me, in the events that I still do, vitamin D, calcium, baseline dexa run through it. By all means, if they've got cardiovascular risk factors, that's where I'm going to probably engage a team. You mentioned there's some controversy around it. What do you think? GnRH antagonists, do they have some cardioprotection? Do they not? Hard to say.
[Dr. Rana McKay]
Yes. I think the big take-home message is that you can't just put somebody on their ADT and check out, because what we saw from the PRONOUNCE study, which was actually designed to look at cardiovascular risk in people that were getting an agonist versus an antagonist. In the context of the trial, they had a very robust upfront cardiovascular risk assessment. Patients on both arms were getting seen by cardiology or getting ongoing cardio prevention.
At the end of the day, the study had to close down because the event rate was so low in both arms and wasn't any different in either arm. I think the key take-home is, prevention is key and staying on top of it is key. I think, certainly if I have somebody before me who's got an extensive cardiac history and they really need to be on ADT, they've got high-risk disease and you're treating them with a curative intent and they need to start treatment, yes, in that context, I'm going to go ahead and prescribe an antagonist, every day over an agonist just to do everything that I possibly can to mitigate their cardiovascular risk, like whether it be a thrombotic event or arrhythmia or something.
I think at the end of the day, I think there's probably a little bit more hype than true data. I think the data that is out there has some flaws in it, but I think that it doesn't necessarily put the person in any worse off situation from an efficacy standpoint or a side-effects standpoint and may potentially mitigate some CV tox.
Podcast Contributors
Dr. Rana McKay
Dr. Rana McKay is a medical oncologist and associate professor at UC San Diego Health in California.
Dr. Aditya Bagrodia
Dr. Aditya Bagrodia is an associate professor of urology and genitourinary oncology team leader at UC San Diego Health in California and adjunct professor of urology at UT Southwestern.
Cite This Podcast
BackTable, LLC (Producer). (2025, January 21). Ep. 210 – Personalizing ADT Across the Prostate Cancer Spectrum [Audio podcast]. Retrieved from https://www.backtable.com
Disclaimer: The Materials available on BackTable.com are for informational and educational purposes only and are not a substitute for the professional judgment of a healthcare professional in diagnosing and treating patients. The opinions expressed by participants of the BackTable Podcast belong solely to the participants, and do not necessarily reflect the views of BackTable.
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