Introduction:

Advanced castration-resistant prostate cancer (CRPC) contributes to majority of prostate cancer-related deaths. Although CRPC responds initially to androgen receptor (AR) antagonists and androgen-synthesizing enzyme inhibitors, the cancer develops resistance due to multiple mechanisms, such as AR amplification, AR ligand-binding domain (LBD) mutations, and AR splice variants (AR-SVs). Since all approved and many AR antagonists currently in clinical development target the LBD, they are rendered ineffective in many CRPC patients harboring the mutations and variants. The Dual Action Androgen Receptor Inhibitors (DAARIs) ONCT-534 and ONCT-505 are small molecule AR antagonists that interact with the LBD but also bind to the N-terminal domain (NTD) of the AR leading to signaling antagonism and AR and AR-SV protein degradation.

Methods:

DAARIs were evaluated in AR- and AR-SV-positive cell-line and patient-derived xenografts. DAARIs were also tested in patient-derived organoids.

Results:

In preclinical studies, ONCT-534 and ONCT-505 exhibited strong anti-tumor activity in enzalutamide-resistant AR and AR-SV-positive 22RV1 and LuCaP 86.2 tumor xenografts in castrated and intact animals with tumor growth inhibition ranging from 50% to complete regression. ONCT-534 and ONCT-505 were further evaluated in CRPC patient-derived organoids (PDOs) that are resistant to various AR antagonists. Lastly, the DAARIs were also compared to the PROTAC ARV-110 in a xenograft model.

Conclusion:

The results from our preclinical studies suggest that DAARIs possess excellent preclinical efficacy and drug-like properties thus, supporting continued preclinical and eventual clinical development. DAARIs might have the potential to become a new treatment paradigm for patients suffering from advanced AR and AR-SV-positive CRPCs that are refractory to existing standard of care therapies.

Funding: Funding for this work was provided by grants from National Cancer Institute (NCI: 1R01 CA229164), Oncternal Therapeutics Inc., San Diego, CA, and Muirhead endowment.