Abstract 1236: Biomarkers of response to abiraterone and the polo-like kinase 1 (PLK1) inhibitor onvansertib in metastatic castration resistant prostate cancer (mCRPC) patients (2022)

Abstract Background: Abiraterone (abi), a widely-used standard of care for castration-sensitive and castration-resistant prostate cancers, inhibits the androgen receptor signaling pathway. While abi slows disease progression, extended treatment universally results in acquired resistance. PLK1 is a serine/threonine protein kinase, master regulator of the cell cycle. PLK1 is upregulated in prostate cancer following androgen-deprivation therapy and PLK1 inhibition synergizes with abi in CRPC models, providing a potential means to reverse or delay abi resistance. Onvansertib is an oral highly selective PLK1 inhibitor that showed synergistic anti-tumor activity with abi in in-vitro and in-vivo CRPC models. A phase 2 clinical trial (NCT03414034) is ongoing to assess the efficacy of onvansertib in combination with abi in mCRPC patients with early abi resistance. Genomic and transcriptomic analyses were performed to identify response biomarkers for the onvansertib/abi combination. Methods: Cell-free DNA isolated from patient plasma was analyzed by targeted sequencing using Guardant OMNI® (500-gene panel). RNA expression profiling was performed using archival tissues by Veracyte (formerly Decipher Biosciences). Genomic and transcriptomic profiles of patients who progressed within 12 weeks of treatment (“PD” patients) were compared to patients who had radiographic stable disease at 12 weeks (“SD” patients). Results: Genomic profiles were successfully obtained from 19 PD patients and 31 SD patients. On average, PD patients had more somatic alterations than SD patients (14 vs 7, p=0.017). SD was positively correlated with the presence of alterations affecting signaling pathways such as MTOR, NF1, PTEN and EGFR, and negatively correlated with gene alterations involved in cell migration and invasion such as APC, KDR, PREX2, NF2 and AKT3. Eight (26%) of the 31 SD patients had alterations either in MTOR (n=5) or PTEN (n=3), that were predicted to have functional impacts on the protein, while only 1 PD patient (5%) had an alteration in either of those 2 genes. Moreover, transcriptomic analyses performed on tissue from 8 patients revealed that SD patients (n=5) exhibited a gene expression signature of “PTEN loss” that was absent in PD patients (n=3) (p=0.016). Conclusions: Taken together, these data suggest that alterations in PTEN and MTOR, two key genes of the PI3K signaling pathway, are potential biomarkers for sensitivity to onvansertib/abi combination in mCRPC patients with early abi-resistance. Preclinical studies are underway to assess the activity of onvansertib/abi in combination with PI3K-pathway inhibitors. Citation Format: Maya Ridinger, Errin Samuelsz, Peter J. Croucher, Mark Erlander, Katherine Ruffner, David J. Einstein. Biomarkers of response to abiraterone and the polo-like kinase 1 (PLK1) inhibitor onvansertib in metastatic castration resistant prostate cancer (mCRPC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1236.