Advanced prostate cancer has been associated with fatigue, cognitive decline, and dementia. It is often unclear whether these effects result from the disease itself or are side effects of treatment; however, many patients who receive ADT do not have extensive metastatic disease, so it seems likely that these effects are due to the therapies we use rather than the disease, in many cases. In fact, most androgen axis–targeted therapies have been shown to cause fatigue. In the past, urologists and radiation therapists would focus on the short-term effects, such as hot flashes and loss of libido. Those side effects are common early on, but, for many men (especially those on therapy for many months or even longer), there are other important issues in other areas that must be addressed, such as centripetal weight gain, loss of muscle mass, fatigue, bone mineral density changes, and, in some patients, cognitive issues. LHRH agonists are commonly used as ADT to achieve castrate levels of testosterone; however, they cause an initial testosterone surge that may result in flare symptoms. Recent data from the HERO trial suggest that GnRH antagonists such as relugolix may be more effective than LHRH antagonists, with a more rapid onset and no flare.

One important principle here is to give hormonal therapy only to patients who need it and/or who may benefit from it. Additionally, as practitioners, we should be having conversations each step of the way with our patients about how they are responding to therapy. Younger patients may be particularly affected by the side effects of ADT. For instance, for high-risk patients receiving radiation therapy, the plan might be intermediate-term hormonal therapy for 18 to 24 months, but I let these patients know that we will reassess their responses to treatment along the way. If we have a patient who is miserable on hormonal therapy, we may consider giving them a break from therapy or taking measures to mitigate their side effects.

The relationship between ADT and dementia, depression, and fatigue is currently a hot topic among patients and clinicians, although it is not as clear as some believe. Concerns have been raised about the potential for ADT to increase the risk of adverse cardiovascular events that include stroke, possibly by exacerbating cardiovascular risk factors. Available data on the second-generation antiandrogens are limited, but a recent review by Ryan et al suggested that abiraterone was associated with a low central nervous system (CNS) adverse-event profile when compared with enzalutamide, while the rate of cognitive issues among those taking darolutamide appeared to be comparable to that of placebo (ie, ADT alone). I have great interest in darolutamide and the extent to which we will see a reduction in CNS side effects, owing to its lower potential for blood-brain barrier penetration. However, since there have been no head-to-head randomized studies of these agents, further investigation is needed. Ongoing clinical trials seek to define the CNS tolerability of newer androgen receptor pathway–targeted therapy options more clearly.

Recently, an “ADT-free” option has been evaluated and shown to be equally effective. Apalutamide combined with abiraterone acetate has demonstrated strong activity in advanced castrate-sensitive prostate cancer, so this may be something to watch for in the future as well.