Injectable testosterone suppresses natural production, causing infertility. New protocols use shorter-half-life oral/topical testosterone combined with enclomiphene (which blocks estrogen feedback) to increase T-levels while maintaining the body's own production, making it a viable option for younger men concerned about fertility.

A meta-analysis of six trials (Poseidon) found no overall survival benefit from adding long-course (24 months) hormone therapy to post-operative radiotherapy. It suggests that a shorter course of 4-6 months is adequate for most men, marking a significant shift towards treatment de-escalation to reduce long-term toxicity without compromising efficacy in this specific setting.

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.

The development of SERDs for adjuvant therapy was stalled for two decades not by efficacy concerns, but by logistics. Fulvestrant, the first SERD, required monthly intramuscular injections, a pragmatically unfeasible strategy for a 5-year adjuvant trial, a problem only solved with the advent of oral SERDs.

The EMBARK study demonstrates that an intermittent approach to androgen deprivation therapy (ADT), especially with combination ADT and enzalutamide, can provide patients with low-volume metastatic disease a median of 1.5 years off therapy, improving quality of life without compromising outcomes.

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.

Counterintuitively, administering super-physiologic levels of testosterone can induce responses in certain castration-resistant prostate cancers. This strategy, called Bipolar Androgen Therapy, exploits the tumor's overexpressed receptors, turning a growth signal into a therapeutic vulnerability, though it remains a risky approach.

The IMbark trial demonstrated that an ARPI (enzalutamide), either alone or with ADT, outperformed ADT monotherapy in high-risk patients. This pivotal finding raises the question of whether giving ADT alone in any setting, such as with radiation for localized disease, is now an outdated and inferior approach.