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.

Lutetium faces criticism for its fixed 6-cycle regimen, which may be suboptimal as the PSMA target diminishes with ADT. However, this critique is rarely applied to other drugs like PARP inhibitors, which are given until progression. This highlights a double standard and the tension between using a fixed regimen for regulatory approval versus finding the optimal dose in practice.

The term "hormone resistance" was misleading. Researchers discovered that even in a castrate state, prostate cancer tumors produce their own testosterone locally. This maintained androgen receptor signaling, proving the disease was still "androgen addicted" and opening the door for new targeted therapies.

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 Orphan Drug Act successfully incentivized R&D for rare diseases. A similar policy framework is needed for common, age-related diseases. Despite their massive potential markets, these indications suffer from extremely high failure rates and costs. A new incentive structure could de-risk development and align commercial goals with the enormous societal need for longevity.

Beyond tackling fatal diseases to increase lifespan, a new wave of biotech innovation focuses on "health span"—the period of life lived in high quality. This includes developing treatments for conditions often dismissed as aging, such as frailty, vision loss, and hearing decline, aiming to improve wellbeing in later decades.

Even when an ARPI is no longer effective as a standalone therapy, continuing it may be beneficial. By maintaining pressure on the androgen receptor pathway, the drug can upregulate downstream targets like PSMA, potentially enhancing the efficacy of subsequent PSMA-targeted therapies like radioligands or ADCs.

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.

Three 2025 trials (AMPLITUDE, PSMA-addition, CAPItello) introduced personalized therapy for metastatic hormone-sensitive prostate cancer. However, significant benefits were confined to narrow subgroups, like BRCA-mutated patients. This suggests future success depends on even more stringent patient selection, not broader application of targeted agents.