PARP inhibitor combo shows early promise for patients with and without BRCA mutations

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Published: 1 May 2015
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Dr Timothy Yap - Royal Marsden Hospital, London, UK

Dr Yap talks to ecancertv at AACR 2015 about how a combination of two molecularly targeted drugs, olaparib and the investigational agent AZD5363, was safe and yielded responses in patients with a variety of cancer types.

Read the news story for more.

This phase I trial was essentially based on a few preclinical studies that were published, two were published from groups in Boston and one was published from a group in MD Anderson. Essentially what they showed was synergy between these two extremely interesting drugs, a PARP inhibitor and a PI3K AKT pathway inhibitor. That was seen in BRCA deficient cancers in mouse models but also in BRCA proficient cancers preclinically. What they actually hypothesised was you can actually give a patient who does have BRCA proficient cancers a PI3 kinase inhibitor and they can actually suppress the BRCA function, if you like, and therefore increase the susceptibility and sensitivity of such cancers to a PARP inhibitor.

And for PI3 kinase read AKT, they’re linked together?

Exactly. So it’s a PI3K pathway inhibition that we’re interested in and AKT is a key cog along that signalling pathway.

Now why did you go for cancers rather than one particular cancer?

I guess this is ultimately a phase I clinical trial and therefore speed is important. We did actually enrich our population with tumour types of interest and these included patients with BRCA mutant breast cancers, BRCA mutant ovarian cancers as well as castration resistant prostate cancers as well. We also wanted to enrol patients who had other interesting cancers such as pancreatic cancers as well as small cell lung cancers as well.

So you were hungry for new information with a very promising combination but you also had what you describe as a novel design of study. What was that novel design?

That’s right. It’s a novel intrapatient dose escalation trial design that we first described…


Intrapatient dose escalation that we first described in JCO a couple of years ago. With this trial design essentially we put on patients sequentially, one after the other, with a good period of time in between, so about a week at least in between each patient. Each patient if they’re tolerating the actual combination well they would then be permitted to go up to the next dose level. If they are still tolerating that well at the end of that cycle they will then go up to the third dose level which is the maximum dose level. There are several advantages to this approach. Number one, we can actually try and optimise and individualise drug doses according to how well the patient actually tolerates the drug. In a traditional phase I clinical trial the dose that a patient gets, no matter how low it is, is the dose that a patient stays on so that’s not optimal. With this trial design we actually are able to optimise the kind of dose that they get. In addition to that, because patients are actually going from one dose level to the next, it involves fewer patients on this phase I trial and also it’s quicker because patients seamlessly go from one dose level to the next dose level.

And, I imagine, it has quite a lot of patient appeal too?

It does because when we speak to patients about these experimental phase I trials we can actually tell them that you will get active doses of the drug if you are tolerating the drug well, the drug combination well. On this clinical trial we have actually seen early signals of activity, both in BRCA mutant cancers including breast, ovarian and prostate cancers, but we’ve also seen some activity in patients who do not have that BRCA mutation. That was seen, for example, in a patient with ovarian cancer who was resistant to platinum chemotherapy and when we tested both her germline DNA and also her tumour DNA we actually found that she did not have a BRCA mutation. So this was a BRCA wild-type patient who was responding to this combination. So this is all obviously very early data. We’re currently expanding at the optimal dose that we’ve found during dose escalation and we’re looking at two different groups of patients. The first group are the germline BRCA mutant cancer patients and we’re particularly interested in patients who have actually had PARP inhibitors in the past as a single agent to see if we can actually reverse this resistance to the PARP inhibitors and to see if they will actually respond. That’s our first cohort of patients; our second cohort of patients are patients who do not have this germline BRCA mutation and in these patients we want to see if we can still get responses with a PARP inhibitor and an AKT inhibitor in combination. So two take home messages, number one the combination of this PARP inhibitor, olaparib, and AKT inhibitor AZD5363 is safe, tolerable and we have seen some early signals of anti-cancer activity. The second take home message is that we were able to implement this intrapatient dose escalation trial design and were able to complete dose escalation in twenty patients in just 7½ months.