Today we presented the results of a phase II randomised controlled trial of olaparib and abiraterone versus abiraterone and placebo.
We have 142 patients in this trial and one of the unusual features of this study is that we’ve recruited patients independent of homologous recombinant repair mutation status.
We have randomised them on a one-to-one basis with a primary endpoint of radiological metastasis free survival with a variety of secondary endpoints including HRR mutation status.
One of the key features is that although we recruited without having the HRR mutation status we did actually measure that in tissue, in whole blood for a germline or in plasma for circulating DNA.
We classified patients according to whether they were definitely HRR mutated, in other words they had a positive either in tissue or germline or circulating DNA, or they were wild-type in which case they were negative in germline or circulating DNA, or the tissue was unclassifiable.
In those where the tissue was unclassifiable they were partially classified.
What we found was that in terms of radiological progression free survival there was a significant difference in patients receiving the combination treatment, olaparib and abiraterone, by comparison with those receiving abiraterone and placebo.
That difference had a delta of 5.6 months. Of considerable interest is that the effect when we looked at HRR mutation status, in other words HRR mutated, HRR wild-type or partially classified, the effect was independent of any of those three types and that we did see an effect notwithstanding the HRR mutation positivity or negativity.
There were side effects and we found that the combination treatment of olaparib and abiraterone had an increased side effect profile. In particular, anaemia at grade 3 was present in about 20% of the patients.
We did see an excess of cardiovascular events: we had seven in the combination and only one in the placebo group.
So our conclusions overall are that the combination of abiraterone and olaparib in patients who are metastatic castrate resistant who previously had treatment with docetaxel and failed do get an improvement in radiological progression free survival that is significant.
And that is independent of HRR status.
This is the first study that has shown this combination to be effective without HRR mutation status.
There is a trade-off and that’s the side effect profile and there is a planned large scale randomised phase III trial which is going to take place to validate these findings.
If I could just quickly ask for any advice for any clinicians working there for patients who do have cardiac comorbidities, if they should consider participating in these larger trials or if that immune profile and the adverse events are something that might discount them?
Regarding the cardiac comorbidity issue, in the randomised phase III trial there will be a much more stringent entry criteria which will look at cardiac function in ejection fraction MUGA scanning and a variety of other cardiac related morbidity measures.
They will be excluded from the randomised phase III and we hope that this will help to mitigate the effects of the excess cardiac morbidity which we have seen in the phase II trial.