Evolving Systemic Therapy for Prostate Cancer: Pivotal Clinical Trials, Biomarker-Driven Combinations, and Practical Sequencing in the ARSI–PARP–Radioligand Era

Systemic therapy for metastatic prostate cancer is increasingly defined by upfront intensification and biomarker-guided mechanism switching. This narrative review synthesizes pivotal randomized trials, guideline recommendations, and implementation-focused literature across metastatic castration-sensitive prostate cancer (mCSPC) and metastatic castration-resistant prostate cancer (mCRPC). Evidence was organized around decision points at mCSPC diagnosis and at mCRPC transition, while incorporating biological mechanisms of resistance, including AR-axis reactivation, AR splice variants, lineage plasticity, DNA repair–hormone signaling interactions, and PSMA expression heterogeneity. In mCSPC, androgen deprivation therapy plus docetaxel and/or androgen receptor signaling inhibitors (ARSIs) improves survival, with triplet regimens favored for selected chemotherapy-fit patients with aggressive de novo disease. In mCRPC, cross-resistance limits routine ARSI-to-ARSI switching, and randomized data support mechanism-distinct options, including taxanes, PARP-based therapy in homologous recombination repair (HRR)-altered disease, and PSMA-targeted radioligand therapy (RLT) in selected PSMA-positive patients. As RLT moves earlier, PSMA heterogeneity, renal function, bone marrow reserve, and emerging dosimetry-based optimization should inform practical implementation. Ongoing trials are evaluating earlier theranostics, alpha-emitting radioligands, and biomarker-enriched combinations. An implementation-first approach that intensifies treatment when appropriate, tests early and acts on HRR results, uses PSMA PET to guide RLT, and preserves hematologic reserve may maximize access to multiple life-prolonging mechanisms.