After years of treatment intensification, a new focus in metastatic hormone-sensitive prostate cancer is de-escalation. Trials like ADREAM are evaluating planned treatment interruptions for patients with excellent responses, aiming to provide 'treatment-free intervals' that improve quality of life without sacrificing efficacy.

Shifting the view of prostate cancer from "androgen-driven" to "androgen receptor-driven" provides a new framework. In curative settings, after the androgen receptor is targeted for a defined period, restoring testosterone is seen as logical to improve patient quality of life once the cancer is destroyed.

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.

The EMBARK trial showed that enzalutamide monotherapy was superior to standard ADT monotherapy for metastasis-free survival. This suggests potent AR antagonism may be a more effective strategy than simply depleting the testosterone ligand, challenging the long-held dogma of ADT being the fundamental building block for systemic prostate cancer therapy.

After years of successfully intensifying hormonal therapy, the focus in prostate cancer is shifting toward de-intensification. Researchers are exploring intermittent therapy for top responders and developing non-hormonal approaches like radioligands to spare patients the chronic, life-altering side effects of permanent castration.

Even when an ARPI is no longer effective as a standalone therapy, continuing it may be beneficial. By maintaining pressure on the androgen receptor pathway, the drug can upregulate downstream targets like PSMA, potentially enhancing the efficacy of subsequent PSMA-targeted therapies like radioligands or ADCs.

The oral GnRH antagonist Relagolix allows for much quicker testosterone recovery (1-2 months vs. 3-6 for leuprolide). While beneficial in curative-intent settings, this rapid recovery is a double-edged sword that could shorten the "off-therapy" period during intermittent treatment for metastatic disease.

For high-risk biochemically recurrent prostate cancer, intermittent androgen deprivation therapy (ADT) is the standard of care, not continuous therapy. This approach significantly improves quality of life, bone health, and metabolic health while effectively delaying progression to metastatic disease for years. Continuous therapy is vehemently discouraged in this setting.

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.