This is a study on essentially germline determinates of castration-resistant prostate cancer and overall mortality in the STAMPEDE randomised phase III clinical trial that was based out of the UK that looked at basically standard of care, which is essentially androgen deprivation therapy or medical castration, versus standard of care plus the combination of enzalutamide and abiraterone.

It’s important to set this up, what was known prior to this study. There is extensive both mechanistic and clinical literature that about half of all men harbour a hyperactive form of an enzyme that enables their tumours to make androgens from non-testicular precursor steroids. It’s not just there in the germline but we have a number of different studies, including level 1 evidence, that shows that in the context of medical castration prostate cancer tumours actually become resistant more quickly and men have decreased overall survival, largely in low-volume metastatic disease when they have the hyperactive form of the enzyme. So that’s the background.

What was the study design and outcome?

The study design is to take a look at the STAMPEDE randomised phase II clinical trial which, for the men that were included in this part of the study, it’s nearly 600 men, again randomised to standard of care, which is essentially medical castration, versus standard of care plus abiraterone plus enzalutamide. We genotyped the men in this particular cohort for this gene HSD3B1 and categorised the men as those who either don’t get the hyperactive form of the enzyme versus those who inherit at least once copy of the hyperactive form of the enzyme that enables stimulation of androgen biosynthesis. Simply put, we basically looked at clinical outcomes for men who do versus don’t inherit the hyperactive enzyme and then looked at clinical outcome.

So essentially similar to prior studies, men who inherit the hyperactive form of the enzyme actually have decreased overall survival in the standard of care arm. The other takeaway is that adding abiraterone plus enzalutamide to standard of care is not enough to overcome the poor outcomes or poor overall survival in men who inherit the hyperactive form of the enzyme.

What is the clinical significance of these results?

So the clinical significance is that there’s a very common germline genetic driver of poor outcomes in prostate cancer. There’s a very clear interaction between inheritance of this genetic factor and outcomes in various clinical studies of hormonal therapy. It’s not entirely clear what needs to be done to overcome this mechanism of resistance. Perhaps direct pharmacologic targeting of the enzyme is one proposed future mechanism for developmental therapeutics.