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.

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.

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.

Targeting GSPT1 is highly effective because its degradation disrupts the production of a specific subset of proteins critical to cancer. This simultaneously reduces levels of key drivers like MYC, androgen receptor (AR), and Cyclin D1, creating a powerful multi-target effect from a single drug.

Contrary to common belief, HER2 can be expressed or amplified in prostate cancer, particularly in subtypes with neuroendocrine features. This creates a rare but actionable target, with reported complete responses to HER2-directed therapies like TDXD, highlighting the need for broader genomic testing.

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.

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.

A unique three-arm trial allowing crossover between single-agent PARP inhibitors, AR inhibitors, and a combination showed superior outcomes for the upfront combination. This suggests that "saving" a therapy for later is a suboptimal strategy for this biomarker-selected patient population.