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.

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.

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 rapid advancement of ARPIs wasn't just a scientific breakthrough. It was a rare convergence of FDA interest in new endpoints, a deeper biological understanding of castration resistance, and intense industry and academic collaboration that created a uniquely fertile ground for innovation.

The field is moving away from distressing terms like 'castration-sensitive/resistant' toward a more precise, patient-friendly nomenclature. The new terms—APM-Naive (APMN), APM-Sensitive (APMS), and APM-Resistant (APMR)—better reflect a patient's treatment history within the modern therapeutic landscape.

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.

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.