What are you doing in this study and why are you doing it?
Both of these agents have had phase II studies; cediranib and olaparib have both had phase II studies that have shown that they have some activity in ovarian cancer. But what we had seen in pre-clinical studies and in the lab was that actually when you combine these agents, they look like they potentially had synergy. When we look at the toxicities of these agents, which are both oral, biologically available agents, those toxicities didn’t necessarily look like they really overlapped and so the thought was that we could potentially combine these agents without too much toxicity and see how that compared activity-wise against one of the agents alone.
One agent is a PARP inhibitor and the other is an anti-angiogenic. Why was that a good choice?
In the lab there’s this thought that PARP inhibitors and anti-angiogenics can have synergy. If you knock out PARP or you have a PARP inhibitor it decreases in vivo angiogenesis in mouse model studies. The other thing that has been shown is that PARP inhibition… cells are more sensitive to PARP inhibitors when they’re in a hypoxic setting. So that made it seem like a good combination to think about in a clinical trial.
So what did you do in the study?
In this study we combined cediranib and olaparib and we compared it to olaparib alone in women with recurrent platinum sensitive ovarian cancer. This was a phase II study where patients were randomised one to one between these two arms.
In this study what we found was that the median progression free survival was markedly increased by the combination of cediranib and olaparib versus olaparib alone with an increase from 9 months with olaparib alone to 17.7 months with the combination. That 8.7 month increase was highly statistically significant with a p-value of 0.005 and a hazard ratio of 0.42. We ended up having 47 patients with a known BRCA mutation and 43 patients who did not have a prior known BRCA mutation or whose BRCA status was unknown. When we looked at these in a post hoc analysis what we saw was that in women with a BRCA mutation there was a slight increase still in the activity of cediranib/olaparib that was not statistically significant, p-value of 0.16, but a trend. But in women without a BRCA mutation or whose BRCA status was unknown there was a marked increase in the activity of cediranib and olaparib compared to olaparib alone from 5.7 months on olaparib alone to 16.5 months on the combination and the p-value for this was 0.008.
What do you make of these figures?
We can’t draw conclusions from these figures by themselves because this is a post hoc subset analysis of a small randomised phase II study but certainly it’s very intriguing and interesting to explore whether or not this combination, adding cediranib to olaparib, can boost the effects more in women without a known BRCA mutation.
What message should cancer doctors take home from this?
What we take home from this is that this is an active combination in ovarian cancer with findings in the study that are certainly exciting and we should explore further. We need to validate these findings in a further study, in phase III studies, and it would be important to look at this combination as compared with standard of care chemotherapy to see how it compares against our typical platinum based chemotherapy regimens. If these findings are validated with two combination orally bio-available agents what’s very exciting about this is this could potentially offer an alternative to chemotherapy for women with ovarian cancer in this setting.
Do you think this is a big step forward? Does it look promising?
Absolutely. I think that if we can validate the findings of the study that this is truly a different approach to therapy for these patients as an alternative to chemotherapy and gives us a different way of attacking these cancers.