For an older patient population, the ultimate goal in prostate cancer treatment might not be a traditional cure, but rather turning it into a quiescent, chronic disease manageable with well-tolerated therapy, similar to HIV. This reframes success as long-term control until a patient dies of other causes.

Unlike bladder cancer, prostate cancer has highly effective androgen-pathway inhibitors (ARPIs) that extend survival. This success has pushed chemotherapy and, by extension, ADC development to later treatment lines as clinicians prioritize other novel mechanisms of action first.

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.

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.

Early neoadjuvant trials in the 1990s failed to show clinical benefit because they included many low-risk patients and used less potent hormonal therapies. The PROTEUS trial's success was built on learning from this history by strictly enrolling high-risk patients and using a powerful androgen receptor pathway inhibitor (ARPI).

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 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 Referring to it as 'intensification' is outdated and misrepresents its role as the new standard.

Registrational clinical trials for prostate cancer drugs enroll patients who are substantially younger (median age 67-69) and healthier than the typical real-world patient (median age 73-74). This gap means trial data on efficacy and safety doesn't perfectly apply to the majority of patients seen in clinic.