Treatment Sequencing in ARPI-Pre-Exposed Metastatic Castration-Resistant Prostate Cancer: Radioligand Therapy, PARP Inhibitors, and Antibody-Drug Conjugates.
- 1Department of Internal Medicine, King Hussein Cancer Center (KHCC), Amman 11941, Jordan.
- 2Department of Nuclear Medicine, King Hussein Cancer Center (KHCC), Amman 11941, Jordan.
- 3Faculty of Medicine, Yarmouk University, Irbid 21163, Jordan.
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.
Related
- Prognostic Value of Baseline High-Uptake PSMA Tumor Volume Fraction in Metastatic Castration-Resistant Prostate Cancer Patients Treated with [177Lu]Lu-PSMA Radioligand Therapy
- Real‐World Overall Survival With Abiraterone Acetate and Enzalutamide in Patients With Chemotherapy‐Naïve Metastatic Castration‐Resistant Prostate Cancer From the Flatiron Electronic Health Records Database
- Immune biomarkers of response and resistance to ipilimumab and nivolumab in metastatic castration-resistant prostate cancer
- Niraparib in patients with metastatic castration-resistant prostate cancer and DNA repair gene defects (GALAHAD): a multicentre, open-label, phase 2 trial
- Global clinical trial activity in metastatic castration-resistant prostate cancer from January 2020 to March 2026: a landscape analysis
BibTeX
@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 Mohammad 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 = {Cancers},
year = {2026},
month = sep,
doi = {10.3390/cancers18193119},
url = {https://europepmc.org/article/MED/42882814},
note = {CC BY},
}
RIS
TY - JOUR
TI - Treatment Sequencing in ARPI-Pre-Exposed Metastatic Castration-Resistant Prostate Cancer: Radioligand Therapy, PARP Inhibitors, and Antibody-Drug Conjugates.
AU - Baha Sharaf
AU - Mohammad Al-Rwashdeh
AU - Osama El Khatib
AU - Akram Al-Ibraheem
AU - Ala Abu Fara
AU - Ameen Ismail
AU - Hadeel Alkasrawi
AU - Mohamed Abdalla
AU - Sharif Jehad
PY - 2026
DA - 2026/09/25
JO - Cancers
DO - 10.3390/cancers18193119
UR - https://europepmc.org/article/MED/42882814
AB - 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.
SN - 2072-6694
ER -