130P - Transcriptomic analysis of patients with metastatic hormone-sensitive prostate cancer to identify genomic signatures involved in the transition from androgen-dependent to androgen-independent phenotype

Background

Prostate cancer, initially hormone-sensitive, often progresses to an androgen-independent phenotype, posing treatment challenges. This study uses transcriptomic analysis to compare gene expression in metastatic hormone-sensitive and androgen-independent prostate cancer, aiming to identify genomic signatures driving this progression.

Methods

Total RNA was extracted from Formalin-Fixed Paraffin-Embedded (FFPE) tissue samples of 24 patients with mHSPC treated with ADT plus ARPI using the Maxwell® RSC RNA FFPE Kit and NanoString® Tumor Signaling 360 Panel was performed.

Results

To identify gene signatures specifically associated with response to ADT + ARPI, we investigated differentially expressed genes between non-responder (NR) and responder (R) patients. Interestingly, NR exhibited a marked increase in genes involved in cell-cycle progression and DNA replication, promoting unchecked cellular proliferation. Additionally, there was a strong up-regulation of genes associated with androgen receptor signaling, a key driver of prostate cancer growth and progression. Further affecting response to therapy, NR hyper-expressed ligands known to activate metastasis-promoting receptors. Thus, the concurrent increase in metastasis-promoting ligands and the dysregulation of cell-cycle progression suggest a multifaceted mechanism of resistance to hormonal therapy in NR patients. This proposes that combining hormonal therapy with chemotherapy, which can target rapidly dividing cells, could potentially overcome this resistance and improve treatment efficacy.

Conclusions

The study identified key genomic signatures and pathways involved in the transition from androgen-dependent to androgen-independent mHSPC. These findings provide insights into the molecular mechanisms driving resistance to androgen receptor-targeted therapies and highlight potential biomarkers for early detection of therapy resistance. The identified signatures may serve as therapeutic targets for developing novel treatment strategies aimed at delaying or preventing the onset of castration resistance in prostate cancer patients.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

S. Scagliarini, S. Rossetti: Financial Interests, Personal, Invited Speaker: Ipsen, AstraZeneca. V. Conteduca: Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly, Novartis. R. Bianco: Financial Interests, Personal, Invited Speaker: AstraZeneca, Eli Lilly, Novartis, AIRC. L. Formisano: Financial Interests, Personal, Invited Speaker: Ipsen, Eli Lilly, AstraZeneca, Novartis. All other authors have declared no conflicts of interest.