181P - Establishment of primary prostate cancer patient-derived organoids to assess PARP inhibitors antitumor activity beyond synthetic lethality

Background

PARPi are known to induce synthetic lethality (SL) in tumors with defects in the homologous recombination (HR) repair pathway, leading to their approval as targeted therapies for patients harboring mutations in HR related genes. However, several clinical studies have shown clinical benefits in HR proficient patients, suggesting an alternative route, independent of SL, contributing to PARPi antitumor activity. Understanding the molecular mechanisms underlying PARPi activity beyond SL may broaden the scope of their therapeutic application. Considering that patient derived organoids (PDO) can mimic the molecular and genetic heterogeneity of prostate cancer (PC), they represent an optimal model for studying the molecular features underlying drug response. However, establishing primary PC PDOs has shown little to no success, hindering translational research. Thus, we aim to optimize a protocol for generating PC PDOs and found a PC PDOs biobank with different molecular backgrounds to assess novel PARPi antitumor mechanisms.

Methods

58 patients who underwent a prostate biopsy were recruited. Biopsies from benign prostate and primary PC were used to optimize a protocol for establishing PDOs. Future experiments will identify potential biomarkers of response to PARPi, explore mutations, translocations, gene copy number alterations and neoantigens by WES, and identify expression signatures by RNAseq.

Results

We report a new method for generating benign and primary PC PDOs with success rates of 80% and 60% respectably, demonstrating that PC PDOs can grow efficiently for long time (>8 months). Recruitment is still ongoing to expand the PDOs biobank with diverse molecular and genetic backgrounds. Table: 181P

Conclusions

PC PDOs can be efficiently grown into self organizing structures that maintain the histologic, molecular, and genetic characteristics of the patient's tumor, and could serve as a tool for elucidating PARPi antitumor activity beyond SL.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

Instituto de Investigación Sanitaria HM Hospitales.

Funding

Open Innovation AstraZeneca.

Disclosure

All authors have declared no conflicts of interest.