{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T21:48:17Z","timestamp":1793915297197,"version":"4.8.0"},"reference-count":66,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T00:00:00Z","timestamp":1781654400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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\u2013hormone 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.<\/jats:p>","DOI":"10.3390\/cancers18121966","type":"journal-article","created":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T05:56:31Z","timestamp":1781675791000},"page":"1966","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Evolving Systemic Therapy for Prostate Cancer: Pivotal Clinical Trials, Biomarker-Driven Combinations, and Practical Sequencing in the ARSI\u2013PARP\u2013Radioligand Era"],"prefix":"10.3390","volume":"18","author":[{"given":"Takatoshi","family":"Somoto","sequence":"first","affiliation":[{"name":"Department of Urology, Toho University Sakura Medical Center, Sakura 285-8741, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9423-7361","authenticated-orcid":false,"given":"Takanobu","family":"Utsumi","sequence":"additional","affiliation":[{"name":"Department of Urology, Toho University Sakura Medical Center, Sakura 285-8741, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rino","family":"Ikeda","sequence":"additional","affiliation":[{"name":"Department of Urology, Toho University Sakura Medical Center, Sakura 285-8741, Japan"},{"name":"Department of Urology, Toho University Graduate School of Medicine, Ota-ku, Tokyo 143-8540, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatsuharu","family":"Sugimoto","sequence":"additional","affiliation":[{"name":"Department of Urology, Toho University Graduate School of Medicine, Ota-ku, Tokyo 143-8540, Japan"},{"name":"Department of Urology, Seirei Sakura Citizen Hospital, Sakura 285-8765, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Naoki","family":"Ishitsuka","sequence":"additional","affiliation":[{"name":"Department of Urology, Toho University Sakura Medical Center, Sakura 285-8741, Japan"},{"name":"Department of Urology, Toho University Graduate School of Medicine, Ota-ku, Tokyo 143-8540, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yodai","family":"Kadono","sequence":"additional","affiliation":[{"name":"Department of Urology, Toho University Graduate School of Medicine, Ota-ku, Tokyo 143-8540, Japan"},{"name":"Department of Urology, Mihama Hospital, Mihama-ku, Chiba 261-0013, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7869-2742","authenticated-orcid":false,"given":"Takahide","family":"Noro","sequence":"additional","affiliation":[{"name":"Department of Urology, Toho University Sakura Medical Center, Sakura 285-8741, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuta","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Urology, Toho University Sakura Medical Center, Sakura 285-8741, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shota","family":"Iijima","sequence":"additional","affiliation":[{"name":"Department of Urology, Toho University Sakura Medical Center, Sakura 285-8741, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuka","family":"Sugizaki","sequence":"additional","affiliation":[{"name":"Department of Urology, Toho University Sakura Medical Center, Sakura 285-8741, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ryo","family":"Oka","sequence":"additional","affiliation":[{"name":"Department of Urology, Toho University Sakura Medical Center, Sakura 285-8741, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takumi","family":"Endo","sequence":"additional","affiliation":[{"name":"Department of Urology, Toho University Sakura Medical Center, Sakura 285-8741, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4183-2490","authenticated-orcid":false,"given":"Naoto","family":"Kamiya","sequence":"additional","affiliation":[{"name":"Department of Urology, Toho University Sakura Medical Center, Sakura 285-8741, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5838-114X","authenticated-orcid":false,"given":"Hiroyoshi","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Urology, Toho University Sakura Medical Center, Sakura 285-8741, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,17]]},"reference":[{"key":"ref_1","unstructured":"European Association of Urology (2025). 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