Treatment Sequencing in ARPI-Pre-Exposed Metastatic Castration-Resistant Prostate Cancer: Radioligand Therapy, PARP Inhibitors, and Antibody–Drug Conjugates
TL;DR
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 to propose a hypothesis-generating four-track framework for discussion between clinicians and patients.
Abstract
Simple Summary Men whose prostate cancer stops responding to hormone-blocking treatment now have several further options, including targeted tablets for those with inherited or tumour DNA-repair faults, a radioactive drug that seeks out a protein on prostate cancer cells, and chemotherapy. No trial has compared these options head to head in the order they should be given. Almost all patients now receive a potent hormone-blocking drug earlier in their illness, which means the evidence guiding these later choices was generated in patients who differ from those seen today. This review sets out what the trials do and do not show and proposes a provisional framework for discussion between clinicians and patients. It is not a treatment guideline. Abstract 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.