PD04-02 USING GENOMIC AND TRANSCRIPTOMIC PROPERTIES TO DETERMINE ANDROGEN RESPONSE IN DUCTAL PROSTATE CANCERS AND DETERMINE EFFICACY OF POLY(ADP-RIBOSE) POLYMERASE INHIBITORS WITH ANDROGEN SIGNALLING INHIBITORS THERAPY IN VITRO

You have accessJournal of UrologyCME1 Apr 2023PD04-02 USING GENOMIC AND TRANSCRIPTOMIC PROPERTIES TO DETERMINE ANDROGEN RESPONSE IN DUCTAL PROSTATE CANCERS AND DETERMINE EFFICACY OF POLY(ADP-RIBOSE) POLYMERASE INHIBITORS WITH ANDROGEN SIGNALLING INHIBITORS THERAPY IN VITRO Weranja Ranasinghe, Melbourne, Australia Patricia Troncoso, Mitchell Lawrence, Nicholas Choo, Birunthi Niranjan, Melissa Papargiris, Hong Wang, Andrew Ryan, Peter Shepherd, Bradley Broom, Ganiraju Manyam, Renea Taylor, Timothy Thompson, Nora Navone, Gail Risbridger, and Brian Chapin Weranja RanasingheWeranja Ranasinghe More articles by this author , Melbourne, Australia Patricia TroncosoMelbourne, Australia Patricia Troncoso More articles by this author , Mitchell LawrenceMitchell Lawrence More articles by this author , Nicholas ChooNicholas Choo More articles by this author , Birunthi NiranjanBirunthi Niranjan More articles by this author , Melissa PapargirisMelissa Papargiris More articles by this author , Hong WangHong Wang More articles by this author , Andrew RyanAndrew Ryan More articles by this author , Peter ShepherdPeter Shepherd More articles by this author , Bradley BroomBradley Broom More articles by this author , Ganiraju ManyamGaniraju Manyam More articles by this author , Renea TaylorRenea Taylor More articles by this author , Timothy ThompsonTimothy Thompson More articles by this author , Nora NavoneNora Navone More articles by this author , Gail RisbridgerGail Risbridger More articles by this author , and Brian ChapinBrian Chapin More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003228.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The histologic variant prostatic ductal adenocarcinoma (DAC) has an aggressive biology with predisposition to metastasize early to visceral organs at low PSA levels. In contrast to acinar adenocarcinoma of the prostate (PAC), DACs have no effective systemic therapies, responding poorly to androgen deprivation therapy and chemotherapy. Poly(ADP-ribose) polymerase inhibitors (PARPi) may synergize with androgen signaling inhibitors (ARSI) inducing a “BRCAness” phenotype in castrate resistant prostate cancer (CRPC). A recent clinical trial demonstrated the efficacy of this combination therapy in CRPC, regardless of HR status. We aimed to characterize the genomic and transcriptomic properties of DAC to determine the androgen response and assess efficacy of PARPi+ARSI therapy in vivo. METHODS: 20 DAC and 10 PAC tumors, matched for stage, grade and volume, were micro-dissected from radical prostatectomy samples. Whole exome sequencing, RNA sequencing and Hallmark pathway analyses were performed. Validated BRCA2 heterozygous mutant (201.1A-Cx) and HR-proficient (287R) patient-derived DAC organoid models were treated with PARPi, enzalutamide and the combination of PARPi+enzalutamide. RESULTS: DACs had higher rates of mutations compared to matched PAC tumors (Figure 1). Unsupervised hierarchical clustering of RNA expression identified a distinct DAC cluster, with downregulation of AR pathways and enrichment of HR pathways, compared to PAC. Niraparib+Enzalutamide significantly reduced organoid viability of BRCA2 heterozygous mutant (201.1A-Cx) and HR proficient (287R) cells compared to control, Niraparib or Enzalutamide alone. Moreover, PARPi and ARSI were synergistic in these DAC models. Similarly, Talazoparib + Enzalutamide reduced the viability of the HR proficient 287R organoid compared to control, Talazoparib or Enzalutamide (65% vs 100% vs 91% vs 78%, p<0.01). CONCLUSIONS: In contrast to PACs, primary DACs have a unique genomic and transcriptomic landscape with high rates of mutations associated with intrinsic androgen resistance. PARPi+ARSI were more effective at decreasing DAC organoid viability than either treatment alone, regardless of the HR status. Source of Funding: N/A © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e142 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Weranja Ranasinghe More articles by this author Melbourne, Australia Patricia Troncoso More articles by this author Mitchell Lawrence More articles by this author Nicholas Choo More articles by this author Birunthi Niranjan More articles by this author Melissa Papargiris More articles by this author Hong Wang More articles by this author Andrew Ryan More articles by this author Peter Shepherd More articles by this author Bradley Broom More articles by this author Ganiraju Manyam More articles by this author Renea Taylor More articles by this author Timothy Thompson More articles by this author Nora Navone More articles by this author Gail Risbridger More articles by this author Brian Chapin More articles by this author Expand All Advertisement PDF downloadLoading ...