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.
Cancers. 2026 Jun 17*** epublish ***
Takatoshi Somoto, Takanobu Utsumi, Rino Ikeda, Tatsuharu Sugimoto, Naoki Ishitsuka, Yodai Kadono, Takahide Noro, Yuta Suzuki, Shota Iijima, Yuka Sugizaki, Ryo Oka, Takumi Endo, Naoto Kamiya, Hiroyoshi Suzuki
Department of Urology, Toho University Sakura Medical Center, Sakura 285-8741, Japan., Department of Urology, Toho University Graduate School of Medicine, Ota-ku, Tokyo 143-8540, Japan.