Prostate Cancer Treatment and Research
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Abstract
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): most patients are now ARPI-pre-exposed, whereas the pivotal trials of PARP inhibitors (PARPi), prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) and antibody–drug conjugates (ADCs) enrolled fewer than 5% such patients. The optimal sequence of available agents is undefined. Methods: We performed a narrative review of phase II and III trials reporting radiographic progression-free survival (rPFS) or overall survival (OS) in mCRPC, including the mature 2025 OS datasets (TALAPRO-2, PROpel, PSMAfore, BRCAAway) and 2025–2026 congress presentations, searching PubMed, EMBASE and ClinicalTrials.gov to June 2026. All clinical statements are graded against a five-level evidence hierarchy, and data that have not been peer reviewed are labelled explicitly. Results: No prospective sequencing trial has been reported. CARD (cabazitaxel versus a second ARPI after docetaxel and prior ARPI; OS HR 0.64) remains the strongest sequencing-specific dataset. PARPi benefit concentrates in BRCA2-altered disease (TALAPRO-2 BRCA1/2 OS HR 0.50; BRCAAway combination versus abiraterone OS HR 0.39), whereas CDK12 biallelic loss shows no PARPi activity. RLT improved rPFS against an ARPI switch (PSMAfore HR 0.41) but OS was confounded by 60% crossover; against taxanes, RLT improved PSA response and tolerability without an OS advantage, and raw OS in PLUDO/PR.21 favoured docetaxel first (HR 1.64, 95% CI 1.14–2.35). Conclusions: We propose a four-track, hypothesis-generating framework stratified by homologous recombination repair status and PSMA-PET expression, and define the prospective trials required.
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@article{Sharaf2026Treatment,
title = {Treatment Sequencing in ARPI-Pre-Exposed Metastatic Castration-Resistant Prostate Cancer: Radioligand Therapy, PARP Inhibitors, and Antibody–Drug Conjugates},
author = {Baha Sharaf and Mohammed Al-Rwashdeh and Osama El Khatib and Akram Al-Ibraheem and Ala Abu Fara and Ameen Ismail and Hadeel Alkasrawi and Mohamed Abdalla and Sharif Jehad},
journal = {Preprints.org},
year = {2026},
doi = {10.20944/preprints202609.0219.v1},
url = {https://doi.org/10.20944/preprints202609.0219.v1}
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