Treatment Sequencing in ARPI-Pre-Exposed Metastatic Castration-Resistant Prostate Cancer: Radioligand Therapy, PARP Inhibitors, and Antibody–Drug Conjugates

Background/Objectives: Androgen receptor pathway inhibitor (ARPI) intensification in metastatic hormone-sensitive prostate cancer has changed the population reaching metastatic castration-resistant prostate cancer (mCRPC), and the optimal sequence of subsequent therapies is uncertain. Methods: The study presents a narrative review of phase II/III trials reporting radiographic progression-free survival (rPFS) or overall survival (OS) in mCRPC, including congress data, to June 2026, graded on a five-level evidence hierarchy. Results: No prospective sequencing trial has been reported. CARD (cabazitaxel versus an ARPI switch after docetaxel; OS HR 0.64) remains the clearest sequencing dataset. Alpha-controlled OS benefit for PARP inhibitors is established in the PROfound cohort A (HR 0.69) and in the TALAPRO-2 all-comer population (HR 0.80); larger BRCA-specific estimates are exploratory, and BRCA OS in TRITON3 was not improved (HR 0.91). 177Lu-PSMA-617 improved rPFS versus an ARPI switch in PSMAfore, but intention-to-treat OS did not differ (HR 0.91) amid 60% crossover; no taxane-controlled trial has shown an OS advantage, and in preliminary PLUDO data, OS favoured docetaxel first (HR 1.64), a difference potentially confounded by asymmetric crossover. Conclusions: We propose a hypothesis-generating four-track framework stratified by homologous recombination repair status and PSMA-PET expression; treatment choice remains individualised.