Niraparib Is Active Against Prostate Xenograft Models That Are Wild Type Or Defective For Dna Damage Repair Genes

Patients with metastatic prostate cancer may respond well to first- and second-generation androgen receptor (AR)-targeted therapies, but all will eventually experience disease progression, indicating a need for alternative therapies. A subset of these patients bears prostate tumors harboring mutations that cause DNA repair defects (DRD). Alterations in DRD genes, such as breast cancer (BRCA)2, render tumors sensitive to drugs that inhibit poly (ADP-ribose) [PAR] polymerase-1 (PARP1), thereby inducing synthetic lethality. Clinical study results of PARP inhibitors tested in late stage prostate cancer have confirmed this hypothesis. However, not all tumors with mutations in DRD genes respond to PARP inhibition, and it is possible that some patients with DRDwt prostate tumors could benefit from treatment. To better understand the basis for response to PARP inhibition, nonclinical studies evaluated the efficacy of niraparib in genetically-profiled prostate xenograft models and advanced prostate cancer patient-derived xenograft (PDX) models. The models tested included BRCA2 biallelic mutant, ataxia-telangiectasia mutated (ATM) biallelic mutant, BRCA2 monoallelic mutant and DRDwt tumor models. The two BRCA2 biallelic mutant PDX models showed variable responses to niraparib, with significant tumor growth inhibition (TGI) seen in the LuCaP 174.1 PDX, but more modest TGI observed in LuCaP 96CR. This result is similar to the clinical experience, in which many, but not all, patients with biallelic BRCA2 mutant tumors respond to PARP inhibition. BRCA2 monoallelic mutant models did not respond to PARP inhibition, suggesting that a reduction in functional BRCA2 was insufficient to result in PARP inhibitor sensitivity. In contrast, two ATM biallelic mutant models responded to niraparib treatment with significant TGI and survival benefit. Finally, DRDwt models showed distinct patterns of response to niraparib, in that several models showed significant TGI/prolonged survival, while the majority of DRDwt models did not respond. IHC studies indicate that niraparib treatment in responsive tumor models is associated with increased levels of caspase-3, histone γ-H2AX phosphorylation (indicating increased DNA double-stranded breaks), and reduced cell proliferation. Taken together, these studies support the hypothesis that niraparib can provide clinical benefit to prostate cancer patients whose tumors are DRDmutant. Further research is warranted to understand the efficacy of niraparib in DRDwt prostate tumors. Citation Format: Linda A. Snyder, Krista Menard, Georges Habineza Ndikuyeze, Holly M. Nguyen, Anna Hughes, Lorraine Angelillo, Gerald Chu, Jenny Driscoll, Rebecca Hawkins, Eva Corey. Niraparib is active against prostate xenograft models that are wild type or defective for DNA damage repair genes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4127.