Ovarian cancer research

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Published: 20 Jul 2010
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Professor Stan Kaye - Institute of Cancer Research, London, UK

Prof Kaye talks about the future of ovarian cancer research. One area that is expected to be very important is research targeting the VEGF protein. A key presentation at ASCO 2010 has shown that a maintenance treatment of avastin, a targeted therapy that blocks VEGF, increases overall survival in ovarian cancer patients. The second area discussed is research into PARP inhibitors. After some spectacular initial results in women with BRCA mutations, a trial presented at ASCO 2010 has shown that olaparib is also effective at treating women with the more common high grade serous ovarian cancer.

ASCO 2010 Annual Meeting, 4—8 June 2010, Chicago

Interview with Professor Stan Kaye (Institute of Cancer Research, London
Ovarian Cancer Research) 

Thank you very much for giving us some precious time at ASCO here in Chicago, it’s a very exciting meeting and you’re going to tell me a little bit about it, particularly related to ovarian cancer and how it’s going to impact on the Institute of Cancer Research which you run in London. Tell us about the ovarian cancer stuff.

Well what’s going to happen in the next five years in ovarian cancer is a question I often get asked because we’re getting involved in targeted treatments in our unit and obviously getting to understand what’s happening in targeted treatments. I think there are probably two big bags that are going to really change the treatment: one is VEGF targeted treatment, the whole Avastin story which is about to take off and we’re going to hear at ASCO in about an hour, actually, the results of the first major first line randomised trial that demonstrates that Avastin, given as a maintenance treatment, not with chemotherapy, prolongs time to progression; it has an odds ratio of 0.7.

Not yet overall survival?

Yes.

Wow, that is news.

And the reason that Avastin hasn’t made it in ovarian cancer before is a commercial thing, not a scientific thing. The data in other diseases has been a bit equivocal. But what’s interesting is that it does not, as I see it, add to chemotherapy. So the first time that it’s been separated the effect is a maintenance effect. Now this is going to put the cat among the pigeons because it’s going to be very expensive and there are going to be lots of issues about who should get it and other alternatives. Actually last year at ASCO we had this really interesting issue about weekly Taxol, and weekly Taxol has an anti-angiogenic effect, and that prolonged overall survival too. So that, in terms of the way that targeted treatment is going in ovarian cancer, there’s no doubt in my mind that VEGF targeted treatment is going to make a major impact.

After a remission induction with standard Carboplatin?

Yes. We’ve been working with actually one of the small molecule anti-angiogenics called Cediranib from Astra Zeneca – very good indeed, we’ve seen lots of single agent activity. So I think with the solid tumours, with the exception of renal cancer, VEGF targeted treatment in ovarian cancer is very likely to make an impact. The problem is that there’s no way of picking out who is going to benefit at the moment, there is no marker.

But the second area that’s really going to take off is a PARP inhibitor story, which is basically based on the fact that ovarian cancers, some people say is a disease of DNA repair deficiency. So if cells are deficient in homologous recombination, one of the methods of endogenous DNA repair, that is exquisitely sensitive to this PARP inhibitor which in 2005, four or five years ago, in the lab turned out to be spectacular. We started to work with it and it’s our third or fourth ASCO now that we’ve presented our data on the PARP inhibitor and we couldn’t believe the first data because tumours shrank with this drug that had no toxicity. Patients said to us, ‘This is nothing like chemotherapy,’ and we couldn’t quite believe it. So in fact we were delighted that an international trial showed the same thing – roughly a 50% response rate in women with either sensitive or resistant ovarian cancer, but recurrence of ovarian cancer. Now the big news at this ASCO, because that was done initially in women with familial ovarian cancer…

BRC1 or 2 mutated. Well mostly 1.

Exactly, which is a relatively small proportion. But what was known from the lab was that that defect in ovarian cancer that is present in this germ-line BRCA is also present in a much bigger proportion of ovarian cancer in women who are never known to have familial – no family history, no germ-line BRCA mutation, that had this same defect in the cells. In fact, the calculation was that in the commonest ovarian cancer, which is high-grade serous, up to 50% would respond. So we were really keen to know was that the case, and yesterday at the presentation from Vancouver the same drug that we worked on, Olaparib, which is the Astra Zeneca drug, was tested in about fifty-odd women with high-grade serous ovarian cancer, BRCA negative, and the response rate looked to us to be actually quite close to the response you might have expected had they been germ-line, possibly a bit less.

50%?

No. If you put together the resist and the marker response rate it was about 40% but the response duration was still what we got – about seven months.

And this is ovarian cancer resistant or previously treated with a platinum or combination

Previously treated. I actually asked them the question what exactly was the breakdown for sensitive and resistant platinum and they didn’t have the answer, but they were all previously treated. So they’re all women who hadn’t exhausted all conventional treatments but, for sure, this was, for them, a significant step forward.

Do you think the platinum’s adding to that DNA damage?

It could be. Well actually, one of the questions is whether you should give platinum with a PARP inhibitor. The problem there is that when you do that you get enhanced toxicity so there is a big momentum to try to develop combination strategies. Hilary Calvert, who actually was one of the godfathers of the PARP inhibitor story in Newcastle some eight or nine years ago…

Well we got into that, I remember, because of Temozolomide resistance and the PARP was one of the pathways that he picked up.

Exactly. But I think that the problem is that when you combine a PARP inhibitor with chemotherapy you usually have to drop the doses and that’s been a problem with most of them.

But now maybe sequential is the way to go.

Yes. But I think the themes that we’ve got in ovarian cancer, that we have in every cancer now, is the theme of personalised medicine – can we pick the patients who we’re going to have to spend the money on? Because these drugs can be hell of expensive. And the beauty of the PARP inhibitor story is that there has to be a biomarker because, unless the cancers have got that defect, you wouldn’t expect there to be an effect. So this morning from Boston there was a really neat presentation looking at a gene profile, some genomic profiling of sixty or seventy ovarian cancer samples, matched with another set of patients who are being treated with platinum. That asked the question is there a BRCA like profile? Can you do a test that will say these are now germ-line negative but that this predicts platinum and PARP inhibitor response? And they’ve got a profile that looks very promising. So I think we’re probably only about a year away from having a biomarker driven PARP inhibitor programme and there are six companies after it at least, probably more.

Well we’ll see you in ASCO 2011. Thanks very much indeed, Stan.