castrationresistant

Castration-resistant refers to a form of prostate cancer that continues to progress despite castration levels of testosterone achieved with androgen deprivation therapy. The term is most commonly encountered as castration-resistant prostate cancer (CRPC), which can be metastatic or nonmetastatic. At progression, testosterone remains suppressed (typically below about 50 ng/dL) but tumor growth persists due to persistent androgen receptor signaling through mechanisms such as AR amplification, mutations, and AR splice variants, as well as increased intratumoral androgen synthesis.

Diagnosis is based on disease progression despite castrate testosterone levels, identified by biochemical progression (rising PSA), radiographic progression, or clinical progression. Management generally includes continuing androgen deprivation therapy to maintain castration levels, along with additional treatments that target the androgen receptor pathway, the cancer cells themselves, or bone health.

Therapies used in castration-resistant disease include androgen receptor pathway inhibitors (abiraterone, enzalutamide, apalutamide), chemotherapy (docetaxel, cabazitaxel), radiopharmaceuticals for PSMA-positive disease (such as 177Lu-PSMA-617), and PARP inhibitors for tumors with BRCA1/2 or related DNA repair mutations. Sipuleucel-T may be considered for asymptomatic or minimally symptomatic metastatic disease. Radium-223 is used for bone-dominant metastases, and bone-targeted agents address skeletal-related events.

Prognosis varies and has improved with newer therapies, but castration resistance generally indicates limited curative options. Ongoing research seeks biomarkers and combination strategies to tailor treatment and overcome resistance mechanisms.