PARP inhibitors

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Published: 1 Nov 2010
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Prof Ruth Plummer - Newcastle University, UK
Prof Ruth Plummer speaks about the development of PARP inhibitors. Whilst none of these drugs have been licensed yet, BSI-201 has entering phase III clinical trials for metastatic triple negative breast cancer. Prof Plummer explains that the activity of PARP inhibitors, targeting a defect rather than the specific disease, indicates that they will be effective against a number of different cancers. Prof Plummer concludes by suggesting how these treatments will be made more effective by potentiating drug activity as opposed to the toxicity and discussing the challenges of developing radiosensitisers and explaining the potential of new radiosurgery technologies.

35th ESMO Congress, 8–12 October 2010, Milan

Interview with Professor Ruth Plummer (Newcastle University, UK)

PARP Inhibitors

Where are we with PARP now?

I think it’s become very exciting. As you know, up in Newcastle Hilary Calvert set up the programme to make a PARP inhibitor in 1990. I started working on that programme, developing an assay and wrote the clinical trial in the early 2000s and it was 2003 I wrote the first script for the first PARP inhibitor that was given to a cancer patient, which again we did the first three up in the North East as a Cancer Research UK sponsored study. But it’s really exciting now – there are nine compounds in the clinic and it’s a very exciting field.

The oncologists at ESMO won’t know where to start, will they? Have you got some advice for them? None of these drugs are yet available out of a clinical trial, or are they?

No, there isn’t a licensed compound yet.

For any of them? Right, that’s got to be very clear.

For any of them. The only one that’s entered phase III is the BiPar compound which is now with Sanofi-Aventis, has completed recruitment to a phase III breast cancer study.

What kind of breast cancer patients?

Triple negative breast cancer.

And tell us why?

They had data initially in cell lines with potentiation of chemotherapy in triple negative. Triple negative breast cancer biologically behaves in a similar way to the BRCA-mutated breast cancer in it’s got a double-strand break repair defect or a homologous recombination defect, or appears to have, for a number of those tumour types. So that’s where strategically BiPar and then Sanofi have gone, extremely successfully – Joyce O’Shaughnessy has just presented the updated data from their randomised phase II showing an overall survival benefit and very powerful hazard ratios for that.

And that was in triple negative women with metastatic breast cancer and with the BRCA1 mutation?

With metastatic breast cancer. Some of them had a BRCA1 mutation, but not all of them.

And did it matter?

I haven’t yet seen their stratification-- I’m not sure the stratified data is out there, but some of those patients had a BRCA1 mutation.

So you’ve got a very unique oversight, having been in the PARP development area from day one almost. Where do you see them finding their place in clinical management - in breast, ovary, prostate? It doesn’t need to be a particular tissue, does it? It’s the defect.

It’s the defect and I would hope that’s the way we’re going to go with most of the targeted therapies in that yes, it helps us understand the biology of cancer to know it was a breast cancer, it was an ovarian cancer, but we’re increasingly seeing it’s a c-KIT mutated cancer, it’s an EGFR mutated cancer, it’s a BRAF mutated, and we’ll be looking for HR defects when somebody works out how to do that signature and identify those tumours that are so uniquely vulnerable, like the BRCA mutated ones, you’ve then got the single agent PARP activity data which is clearly there. But the element I was talking about today, which is equally interesting, is if you protect DNA damage that you’ve caused by your DNA damaging agent, can you have a therapeutic index? Can you get a window in the tumour? And that has real implications for the scheduling because you’ve got an active agent where you’re doing combination toxicity in a different way when you’ve got an agent where you’re trying to potentiate not the toxicity but the activity of the drug you’re giving it with. So there are two forms of scheduling research we need to do.

And you’re doing that?

Yes, well I’m discussing with people, yes. There are ways of looking at it, it’s where you think you’re going to see your activity and how you’re aiming to use your PARP inhibitor and how you’re going to profile your patients. Because you may want to separate the chemotherapy and the PARP inhibitor if you’re just trying to use its single agent activity in combination with other active agents. Or if you’re chemo- or radiopotentiating you need them together when the damage is there.

When I was talking to Hilary Calvert earlier, a good friend, he was talking about radiosensitization as well and not to forget that. Is that also of interest to you?

Yes, I’ve designed a number of radiopotentiation studies that are being mulled over with various sponsors now. It’s a fascinating challenge on how you would do that because typically in radiotherapy you have to accept, despite being a medical oncologist, it’s the commonest ‘agent’ given to cancer patients, it’s probably one of the most active. So it’s quite difficult to improve its activity in clinical settings because you need to pick an inactive setting to improve on something because you wouldn’t want to take the dose down. But where it is active it’s also very long schedules and, I was saying in my talk, you’ve got the interesting concept of if we want to safely give it with a PARP inhibitor, not only do you need to look at different sites, because will the normal tissue toxicity in lung be different if you then give your local treatment to the bowel? Whereas at least when we’re testing drugs with a systemic therapy we can be reasonably confident we’ve tested all the combined toxicities all at once just by giving a drug. But with a local therapy combined with a systemic therapy you’ve got different elements to check but you can increase the dose of the chemotherapy, the PARP inhibitor, you might want to take down your radiotherapy fraction size, although I think they’d be reluctant to do that, but also you’ve got that horizontal dose escalation because of the length of the schedule. You could give it on alternate days with the radiotherapy, you could give it at the end, at the beginning and you’ve got to think about late tissue toxicity. So I think it’s something we need to do and I think it’s in some ways you could say that the clinical trial design is perhaps more interesting and more challenging.

And the radiation therapy is going in the opposite direction with only three fractions and a very much higher fraction dose with gamma knives and other sorts of knives. I was at the ESTRO meeting lately and they were talking about radio-surgery, they’re unbelievably accurate now with their targeting. And they’re trying, indeed, to get away from six weeks of post-operative radiation for breast cancer patients, getting it down to three weeks and then down to one week.

Yes, the gamma knife, it needs to be a small tumour, you’ve got to pick your patients, but with TomoTherapy and the IGRT and the IMRT where they’re really starting to paint the tumour, that in terms of combining with any of the novel agents, which there’s a real push to do that as we get these powerful drugs into the clinic, is going to make it easier because if you’re sparing normal tissue from the radiotherapy you’re going to spare toxicity. So I think the newer radiotherapy methods will make this sort of combination study easier.

Ruth, thank you very much indeed for giving us your time, that’s really interesting. That was a great PARP session today, congratulations.

It’s a pleasure. You know I’m always happy to talk about PARP.

Thank you very much indeed.