Metastatic Prostate Cancer — Castration-Sensitive to Castration-Resistant

Sequencing for metastatic prostate cancer: intensify androgen-deprivation therapy up front with an androgen-receptor pathway inhibitor (with docetaxel added for high-volume disease), then at castration resistance branch on molecular and PSMA imaging findings — a PARP inhibitor for HRR/BRCA alterations, lutetium-177 PSMA radioligand therapy for PSMA-positive disease, or taxane chemotherapy otherwise.

Metastatic castration-sensitive disease — volume and chemotherapy fitness?

• High-volume, chemotherapy-fit → ADT + darolutamide + docetaxel (triplet therapy)
• Low-volume or chemotherapy-unfit → ADT + androgen-receptor pathway inhibitor (abiraterone, enzalutamide, or apalutamide)

1L: ADT + androgen-receptor pathway inhibitor (abiraterone, enzalutamide, or apalutamide)

Doublet intensification is standard for essentially all mCSPC; ADT alone is inadequate. Abiraterone requires prednisone and LFT/potassium monitoring; enzalutamide and apalutamide carry fatigue, falls, and rash risks.

Evidence: LATITUDE · TITAN · ARCHES · STAMPEDE

• Castration resistance → At castration resistance: molecular (HRR) and PSMA-PET findings?

1L: ADT + darolutamide + docetaxel (triplet therapy)

Preferred for high-volume, chemotherapy-fit patients: triplet (ADT + darolutamide + docetaxel) improves overall survival over ADT + docetaxel. Abiraterone + docetaxel + ADT (PEACE-1) is an alternative triplet.

• Castration resistance → At castration resistance: molecular (HRR) and PSMA-PET findings?

At castration resistance: molecular (HRR) and PSMA-PET findings?

• HRR / BRCA mutation → PARP inhibitor (olaparib)
• PSMA-positive → Lutetium-177 PSMA radioligand therapy
• Biomarker-negative → Taxane chemotherapy or androgen-receptor pathway inhibitor switch (docetaxel; cabazitaxel later)

2L: PARP inhibitor (olaparib)

BRCA1/2 or other homologous-recombination-repair gene alteration after progression on an androgen-receptor pathway inhibitor. Monitor for anemia and fatigue; talazoparib + enzalutamide is a combination alternative.

Evidence: PROfound

2L: Lutetium-177 PSMA radioligand therapy

PSMA-PET-positive mCRPC after an androgen-receptor pathway inhibitor and a taxane. Monitor for xerostomia, cytopenias, and renal function; radiation safety precautions apply.

Evidence: VISION

2L: Taxane chemotherapy or androgen-receptor pathway inhibitor switch (docetaxel; cabazitaxel later)

For biomarker-negative disease or after targeted options: docetaxel, then cabazitaxel at further progression. Switching between abiraterone and enzalutamide gives limited benefit due to cross-resistance.