A new analysis from the PROMPT study has highlighted the value of molecular tumour testing in metastatic castration-resistant prostate cancer (mCRPC). Researchers performed next-generation sequencing on 340 tissue samples from 307 men, 51% of which were newly biopsied, to identify druggable genetic alterations that could guide precision therapy. Valid results were produced in 84% of cases (76% new, 92% archived), and all underwent expert review by a molecular tumour board for genotype-matched treatment (GMT) recommendations.
Pathway Alterations and Clinical Insights
Druggable targets were found in 39% of patients, most commonly affecting the PI3K-AKT (26%) and Homologous Recombination (HR; 21%) pathways. Metastatic mCRPC (P < 0.01)tissue yielded a higher rate of GMT recommendations than primary prostate tissue (P = 0.03). The presence of HR-associated genes was linked to a shorter interval from ADT to castration resistance (odds ratio 3.77, 95%CI 1.62–10.32, P < 0.01), whereas PI3K-AKT alterations correlated with longer progression times to CRPC (OR 0.47, 95%CI 0.25–0.87, P = 0.017) and metachronous metastases (OR 0.48, 95%CI 0.26–0.89, P = 0.021).
Universal Molecular Testing Recommended
No combination of clinical or pathological characteristics reliably identified which patients harboured druggable genotypes. The study concluded that molecular tumour testing should preferably be performed on metastatic tissue, where detection rates of actionable mutations are highest. Reflex molecular characterisation is advocated as standard practice for all mCRPC patients, ensuring that opportunities for personalised, targeted therapy are maximised.
This research supports the routine use of molecular tumour boards and genomic profiling to improve the precision and impact of oncology care for men with advanced prostate cancer. Broader implementation of comprehensive genomic testing may also accelerate clinical trial enrolment, refine therapeutic sequencing, and promote equitable access to targeted treatments. As precision oncology continues to evolve, integrating genomic insights into everyday clinical workflows will be key to achieving better outcomes and advancing personalised cancer care.
Reference
Kloots ISH et al. Molecular reflex testing in patients with early metastatic castration-resistant prostate cancer within the PROMPT-study. British Journal of Cancer. 2025; https://doi.org/10.1038/s41416-025-03243-7.
