Unlike traditional ADT, enzalutamide monotherapy can better preserve sexual activity. However, it leads to compensatory increases in testosterone and estrogen, resulting in gynecomastia, a side effect many men find distressing. This trade-off is a key discussion point.

Contrary to concerns about compliance with daily oral medication, real-world retrospective studies show patients demonstrate higher persistence and adherence to oral relugolix compared to traditional injectable GnRH agonists and antagonists for prostate cancer, challenging clinical biases.

Transdermal estradiol is gaining renewed attention as an ADT option. Recent trials show it is non-inferior to standard LHRH analogs, offering a different side effect profile. This allows clinicians to trade side effects like hot flashes for gynecomastia, enabling more personalized treatment decisions.

With multiple FDA-approved oral SERDs available, clinical decision-making is heavily influenced by their distinct side effect profiles. Elacestrant predominantly causes nausea, while iminoralestrant causes diarrhea. This distinction is a primary factor in tailoring treatment to individual patients.

The HERO trial demonstrated that the ADT antagonist relugolix has a 54% lower risk of major adverse cardiovascular events compared to the agonist leuprolide. This makes antagonists a safer choice for prostate cancer patients with pre-existing cardiovascular disease.

A drug-drug interaction study found that apalutamide induces an enzyme (CYP3A4) that lowers relagolix concentrations, leading to suboptimal hormonal suppression. To maintain efficacy when used in combination, the standard dose of the oral GnRH antagonist relagolix must be doubled.

Clinical trials combining potent ARPIs like abiraterone and enzalutamide have consistently failed. Once the androgen receptor pathway is maximally suppressed by one agent, adding another with a similar mechanism provides no further clinical advantage, much like hammering a nail that is already flush with the wood.

A significant, immediate use for adjuvant oral SERDs like gerodestrant will be for patients who cannot tolerate the arthralgias and other side effects of standard aromatase inhibitors (AIs). This addresses a large and challenging clinical problem, positioning SERDs as a key alternative for maintaining long-term adherence to endocrine therapy.

When using intermittent androgen deprivation, GnRH antagonists like relugolix are preferred over LHRH agonists like leuprolide. Antagonists allow for a much faster recovery of testosterone during off-treatment periods, which is a significant quality-of-life benefit for patients. With agonists, testosterone recovery can sometimes take years.