Exploiting Heterogeneity in Hormone Therapy Response to Reveal Early Determinants of Drug Resistance in Advanced PCa

Exploiting Heterogeneity in Hormone Therapy Response to Reveal Early Determinants of Drug Resistance in Advanced PCa

The goal of this observational study is to study intra-patient tumor and TME heterogeneity after initiation of hormonal therapy (ADT +- ARSI), while the patient is responding to treatment, to understand the drivers of hormonal therapy resistance and identify potential novel therapeutic targets in metastatic prostate cancer patients. The main question it aims to answer if intra-tumor adaptive mechanisms including expression of immune checkpoint proteins and changes in the tumor immune infiltrate are related to the induction of a senescent phenotype in response to hormonal therapy.

Participants will asked to provide an FFPE and/or fresh biopsy sample from the primary tumor or a metastatic site at baseline (before starting hormonal therapy) and during the course of hormonal therapy. Additionally, a maximum of 2 blood tubes (10ml) will be collected each time.

Inclusion Criteria Group A:

• Patients with histological diagnosis of advanced prostate cancer (defined as the presence of metastatic disease, including both metastatic hormone naïve prostate cancer patients and metastatic castration resistant prostate cancer patients);
• Patients who started ADT or ADT plus AR inhibitor therapy (Enzalutamide, Darolutamide or Apalutamide or Abiraterone) in a standard therapy.
• Have accessible metastatic and/or primitive disease to perform a biopsy safely during hormonal therapy (ADT or ADT plus AR inhibitor therapy) and before hormonal therapy (alternatively, as a basal biopsy could be used archival FFPE or frozen tumor material left over from surgical procedures or previous biopsies, if available)
• Written acceptance of informed consent to be included in the present study.
• Aged 18 or over.

Inclusion Criteria Group B:

• Patients due for prostate biopsy to confirm the diagnosis of a prostate adenocarcinoma at high risk of metastatic disease. High risk is defined as follows:
• PSA >=20ng/dL with or without imaging suggestive of metastatic prostate cancer OR
• PSA >=10 ng/mL and <= 20 ng/mL AND >=33% risk to have a high grade disease on prostate biopsy according to the MSKCC nomogram "Risk of high grade cancer of prostate biopsy" (https://www.mskcc.org/nomograms/prostate/biopsy\_risk\_dynamic).
• Written acceptance of informed consent to be included in the present study.
• Aged 18 or over