ADT monotherapy is an obsolete strategy for metastatic prostate cancer. For patients too frail for standard ADT+ARPI combination therapy, enzalutamide monotherapy is a superior alternative. It offers effective treatment that can be quickly stopped to reverse side effects if tolerance issues arise, unlike injectable ADT.

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.

Blocking the androgen receptor with enzalutamide can increase PSMA expression. In patients on enzalutamide alone, this predicts a poor outcome. However, for patients receiving combination therapy, this increased expression creates a better target for lutetium-PSMA, effectively mitigating the negative prognosis and improving survival.

The enzalutamide arms saw discontinuation rates of 20-25% due to adverse events. This high rate reflects a different risk calculation for patients who feel healthy and are asymptomatic. Unlike in advanced disease where patients tolerate more toxicity, this population has a very low threshold for side effects, making early intervention a significant trade-off.

The EMBARC study's "intermittent" arm is misleading. It tested only one treatment-free period, limited to extreme responders who achieved an undetectable PSA. Therapy was then resumed continuously until progression, making it more akin to a trial for metastatic hormone-sensitive disease with a single break, not a model for real-world, multi-cycle intermittent therapy.

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.

The sharp early decline on progression-free survival (PFS) curves for oral SERD monotherapy trials indicates that 40-50% of patients have resistance mechanisms beyond just an ESR1 mutation. This highlights the need for better patient selection for monotherapy versus combination approaches to overcome this multifaceted resistance.

Despite some positive clinical trial data for AKT inhibitors in prostate cancer, expert opinion suggests this class of drugs is unlikely to see the light of day in routine clinical practice. Skepticism remains about their overall impact, with a feeling that they do not represent a new, meaningful chapter for treatment.

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.