For high-risk, PTEN-deficient metastatic prostate cancer, a proposed strategy to maximize benefit while minimizing toxicity is sequential intensification. Clinicians can administer a triplet of ADT, an ARPI, and docetaxel first, and only after the chemotherapy course is complete, add the AKT inhibitor capivasertib to avoid severe, overlapping toxicities.

In metastatic hormone-sensitive prostate cancer, patient outcomes vary dramatically. Triplet therapy is the default only for the highest-risk group: patients with de novo, high-volume disease, whose median survival on ADT alone is just three years. For all other patients, including those with low-volume or metachronous disease, doublet therapy is the standard.

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 PRESTO trial evaluated adding apalutamide (APA) and abiraterone (Abby) to a standard LHRH analog. The triplet combination arm demonstrated increased toxicity without any additional efficacy gains compared to the doublet arm (LHRH + APA). This finding reinforces that more intensive combination therapy is not always better and can be detrimental in this 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.

Intensive treatments like ADT plus an ARPI can suppress a patient's PSA so effectively that it becomes an unreliable marker of disease status. Patients may show radiographic progression on scans even while their PSA remains low and they feel clinically well. This discordance necessitates periodic imaging to avoid missing actual disease progression.

The standard of care for metastatic castration-sensitive prostate cancer has evolved. ADT plus an ARPI is now the baseline treatment for nearly every patient. Referring to it as 'intensification' is outdated and misrepresents its role as the new standard.

For a newly diagnosed metastatic prostate cancer patient, an effective strategy is to initiate ADT alone while immediately ordering NGS testing. Waiting a few weeks for the genetic results before adding an ARPI allows for a more informed treatment choice, such as selecting a PARP inhibitor combination for a patient with a BRCA2 mutation.

A VA study using real-world data confirms that androgen receptor pathway inhibitors (ARPIs) combined with ADT significantly improve survival in elderly (>75), frail, and high-comorbidity prostate cancer patients. This evidence directly addresses clinician hesitancy to treat these vulnerable populations with standard-of-care combination therapy.