1840P - RNASEH2B loss and PARP inhibition (parpi) in metastatic castration resistant prostate cancer (mCRPC)

Background

mCRPC is molecularly heterogenous and PARPi is the only precision medicine for these diseases. PARPi improves outcomes in DNA repair defective (DRD; 20-30%) mCRPC but may also impact other mCRPC molecular subsets not currently encompassed in the FDA approved companion biomarker suite for PARPi. The RNASEH2B gene is located on chromosome 13, flanking RB1, with this locus being commonly lost in mCRPC at treatment resistance, associating with lineage plasticity and genomic instability. RNASEH2B may be co-deleted with RB1, with loss of the former but not the latter sensitising to PARPi. We have hypothesised that RNASEH2B loss in mCRPC is subclonal and that PARPi can clear these RNASEH2B deleted subclones.

Methods

Immunohistochemistry (IHC) for RNASEH2B and RB1, utilising validated assays, was performed on matched (same patient) hormone-sensitive (HSPC) and mCRPC patient biopsies, together with whole-exome sequencing (WES), targeted next-generation sequencing (NGS), and RNA sequencing. Low-pass whole genome sequencing (LP-WGS) was performed on a distinct mCRPC cohort for copy number analysis. RNASEH2B expression was correlated with clinical outcome, DRD and DNA damage signatures.

Results

Subclonal deletions on chromosome 13 encompassing RB1 and RNASEH2B are frequent in HSPC and mCRPC biopsies, although deep deletions are rare, and co-loss of RB1 and RNASEH2B protein is surprisingly uncommon. Heterogeneous and subclonal RNASEH2B protein loss was detected by IHC in mCRPC biopsies, with 54/124 (44%) samples having RNASEH2B loss in 50% cells, although complete RNASEH2B loss is uncommon (8.8%). Interestingly, RNASEH2B loss is not an independent prognostic variable, perhaps related to increasing PARPi and platinum use (50/125 (40%) patients in this study), but did not associate with established DRD or DDR signatures. Studies of the impact of PARPi on RNASEH2B subclone clearance in human mCRPC are ongoing.

Conclusions

RNASEH2B protein is frequently lost in mCRPC subclones, with RB1 loss being less common, and may be of critical importance as this discordant loss is most likely to sensitise to PARPi. This needs further exploration in clinical trials of PARPi.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Royal Marsden Hospital/Institute of Cancer Research.

Funding

Medical Research Council (UK).

Disclosure

C. Lord: Financial Interests, Institutional, Sponsor/Funding, Research funding, consultancy, SAB membership or honoraria payments: AstraZeneca, Merck, KGaA, Artios; Financial Interests, Institutional, Other, consultancy, SAB membership or honoraria payments: Syncona, Sun Pharma, Gerson Lehrman Group, Vertex, Tango, 3rd Rock, Ono Pharma, Abingworth, Tesselate, Dark Blue Therapeutics, Pontifax, Astex, Neophore, GSK; Financial Interests, Institutional, Stocks/Shares: Tango, Ovibio, Hysplex, Tesselate; Financial Interests, Personal and Institutional, Royalties: DNA repair inhibitors (various organisations) including PARP and ATR inhibitors. A. Sharp: Non-Financial Interests, Principal Investigator, Clinical trial in progress: AstraZeneca, Amgen, Exelixis, Nurix; Non-Financial Interests, Institutional, Product Samples, Access to IMP as a gift for research: AstraZeneca; Non-Financial Interests, Personal, Product Samples, Access to IMP as a gift for research: Cyclacel; Other, Other, Paid consultancy (to research): D.E Research, CHARM Therapeutics; Other, Other, Paid for teaching session: MSD. J.S. de Bono: Financial Interests, Personal, Advisory Board: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi Sankyo, Eisai, Genentech Roche, Genmab, GSK, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Financial Interests, Institutional, Advisory Board: Harpoon; Financial Interests, Institutional, Research Grant: Astellas, AstraZeneca, Bayer, Cellcentric, Daiichi Sankyo, Genentech Roche, Genmab, GSK, Harpoon, Janssen, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Vertex Pharmaceuticals, Sanofi Aventis, Sierra Oncology, Taiho, Crescendo Biologics; Non-Financial Interests, Principal Investigator: Amgen, Astellas, AstraZeneca, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, Daiichi Sankyo, Eisai, Genentech Roche, Genmab, GSK, Harpoon, Janssen, Menarini Silicon Biosystems, Merck Serono, Merck Sharp & Dohme, Orion Pharma, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, Terumo, Vertex Pharmaceuticals; Non-Financial Interests, Institutional, Product Samples: Daiichi Sankyo, Bayer, Pfizer, Merck Serono, AstraZeneca, Harpoon, Sierra Oncology, Genentech/Roche, Sanofi Aventis, GSK. All other authors have declared no conflicts of interest.