Initial treatments for advancing prostate cancer focus on reducing the levels of circulating male hormones (androgens) in the body which the tumour requires for growth. Over time however, the cancer cells are able to circumvent such treatments and can develop into the castration resistant form of the disease (CRPC). This is lethal with overall survival typically less than 14 months.
The development of CRPC is characterised by presence of functional but altered ARs, which mediate the effects of male hormones. Current therapies are ineffective in reducing the activity of these altered receptors. Inobrodib works in a different way and lowers the levels and the function of ARs in prostate cancer cells, and importantly, of AR-splice variants that arise as disease progresses. It is these variants that are thought to drive resistance to current therapeutic agents, such as Xtandi, Zytiga and Erleada. Inobrodib also affects other key oncogenes including MYC.
In an in vivo cancer xenograft model that is driven by AR-splice variants (22Rv1), inobrodib can cause complete tumour stasis at a well-tolerated dose. Anti-tumour effects are dose dependent.
Intriguingly, tumour stasis is maintained for a significant period after dosing cessation (and when drug has completely cleared from the system). This suggests some kind of reprogramming of tumours with inobrodib. It also means that there is significant scope for different dosing schedules of inobrodib, as the first-in-class drug is used in patients.
As well as direct effects on AR and AR-SV protein levels, inobrodib affects downstream biomarkers of AR-inhibition and prostate cancer. In pre-clinical efficacy models, plasma PSA is profoundly reduced by dosing with CellCentric’s drug, corresponding with tumour growth inhibition. Other downstream genes are also affected including TMPRSS2 and KLK3 in tumours.
As the use of second-generation anti-hormonal drugs continues to increase, the numbers of patients that become resistant to them also continues to grow. This is now a recognised and significant population of high unmet need. inobrodib is ideally positioned for these patients, either as a monotherapy or in combination with existing agents.