Abstract 651: Combination of the androgen receptor inhibitor darolutamide and the PI3K inhibitor copanlisib leads to improved anti-tumor efficacy and apoptosis in prostate cancer models
Authors: Sugawara Tatsuo , NGuyen Holly , Corey Eva , Nevedomskaya Ekaterina , Politz Oliver , Mumberg Dominik , Haendler Bernard 
Published: June 2022

Abstract
Prostate cancer is mainly driven by androgen receptor (AR) signaling so that drugs directly inhibiting this pathway such as GnRH ligands and AR inhibitors are now established as mainstay treatments. Unfortunately, treatment resistance often develops and combination therapies may represent potential strategies to prolong disease remission. The PI3K/Akt/mTOR signaling pathway plays an essential role in prostate cancer and is upregulated in about 30-50% of patients. Loss of the PI3K/Akt/mTOR pathway inhibitor PTEN is observed in up to 40% of late-stage prostate cancer patients. Compounds inhibiting PI3K or Akt have shown promising efficacy in preclinical prostate cancer models, and advanced clinical trials with these inhibitors are currently ongoing in metastatic castration-resistant prostate cancer, often in combination with AR inhibitors. Here we examined the impact of combining the AR inhibitor darolutamide with the pan class I PI3K inhibitor copanlisib on preclinical models in vitro and in vivo. We found that treating different androgen-dependent prostate cancer cell lines with darolutamide and copanlisib had a very strong synergistic inhibitory effect. Induction of apoptosis was observed in the PARP cleavage and caspase 3/7 activation assays after treatment with copanlisib and more so after treatment with copanlisib plus darolutamide. Expression analysis showed that darolutamide strongly down-regulated AR target genes such as KLK3, FKBP5 and TMPRSS2, but copanlisib had no additional impact. However, when examining genes involved in the apoptotic pathway we found that the down-regulation of pro-apoptotic genes that follows androgen treatment was strongly reversed by the combined darolutamide and copanlisib treatment. Finally, in vivo efficacy studies showed that the LuCaP 96 prostate cancer patient-derived (PDX) xenograft, which has a non-functional PTEN gene, strongly responded to darolutamide, but additional treatment with copanlisib did not increase anti-tumor efficacy. In the LuCaP 35 PDX model, which expresses PTEN at low level, darolutamide or copanlisib treatment alone showed only limited efficacy, while the combination exhibited tumor inhibitory effects. In conclusion, we found that combining darolutamide with copanlisib strongly inhibited the proliferation of prostate cancer models in vitro. This was linked to strong induction of cell apoptosis and prevention of pro-apoptotic gene down-regulation. Superior efficacy was also observed in the LuCaP 35 PDX xenograft model in vivo. Additional data are needed to explore the underlying molecular mechanisms. Together these results further support the exploration of the impact of combining AR and PI3K signaling inhibitors in late-stage prostate cancer patients.
Citation Format: Tatsuo Sugawara, Holly NGuyen, Eva Corey, Ekaterina Nevedomskaya, Oliver Politz, Dominik Mumberg, Bernard Haendler. Combination of the androgen receptor inhibitor darolutamide and the PI3K inhibitor copanlisib leads to improved anti-tumor efficacy and apoptosis in prostate cancer models [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 651.