What was the previous background to the study you presented at ESMO 2022?
In 2018 was the initial progression free survival analysis and that’s what led to the EMA and FDA approvals of the drug for this. In that study they showed a 70% reduction in the risk of progression or death in the maintenance olaparib arm versus the placebo arm. At that time the median progression free survival wasn’t reached yet in the olaparib arm. An updated survival analysis was done at five years after last patient randomised and in that one we found that the median progression free survival was 56 months compared to just 13 in the control arm, so a big difference – that reduction in progression and death was still seen. So that hazard ratio was of the same calibre as it was in the first report.
What was the methodology behind the study you presented at ESMO 2022?
This study basically grew out of the knowledge we gained about early phase trials with PARP inhibitors, that this PARP inhibitor class of drugs work especially well in women with advanced ovarian cancer who had a BRCA mutation. So through that we began to see the development of phase II, phase III trials, later lines of chemotherapy. SOLO1 really was how do we get this into the frontline where we think we can make our greatest impact? So, that really was the genesis of this trial was to take that class of drugs known to be efficacious in a subset of women with ovarian cancer and provide that to them in a randomised trial.
This one we do a descriptive analysis of overall survival. So in this particular instance we picked a seven year descriptive time point to do this assessment. The trial has overall survival as a secondary endpoint but it’s requiring a certain number of events or data maturity and that’s set at 60%. We’re at nowhere near that yet. So in this presentation we looked at the seven year time point which is a clinically meaningful time point in ovarian cancer survival. It’s a point in time where people have done analyses and shown that the incidence of death for women who have ovarian cancer relative to the incidence of death for just the general population is very close; so a lot of your risk of death has already gone by. So in this trial we looked at that particular time point and that was really the genesis of what we spoke about.
We found a literally clinically meaningful benefit. The median overall survival for the maintenance olaparib arm hasn’t been reached yet. Overall survival median for the placebo arm was 75 months so the hazard ratio was 0.55, so a 45% reduction in the risk of death at seven years out. So really compelling data for us.
When we talk about statistical significance, from a statistical perspective we did something called an alpha-spend. It’s a way to take a look at data without ultimately compromising your final endpoint. The p-value had to be extremely rigorous in order to pass muster so our p-value, although profound at 0.0004, was not technically statistically significant. But if you look at the clinical meaning, 67% of women were alive seven years after diagnosis in the study who were on the maintenance olaparib arm versus 45% in the placebo arm. So, to us, really meaningful and compelling data.
What is the take home message for doctors on the treatment of ovarian cancer?
Really it’s just another message that PARP inhibition, and specifically in this case olaparib, in the setting of women with advanced ovarian cancer and a BRCA1 or 2 mutation has a clinically meaningful impact on their survival, true survival. It just drives home the fact that today in 2022 when we practice ovarian cancer medicine we need to know the germline status of our patients, we need to know is there a somatic mutation in their tumour. Because finding this integral or predictive biomarker is incredibly important for that population and you have a drug targeted to that that can enhance their survival.