Olaparib maintenance therapy for ovarian cancer and updates from ICON7

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Published: 22 Jun 2011
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Prof Jonathan Ledermann - UCL Cancer Institute, London, UK

Prof Jonathan Ledermann talks about his randomised phase II clinical trial which demonstrated that the oral PARP inhibitor drug olaparib, given after chemotherapy, improved progression-free survival in women with high-grade serous ovarian cancer, the most common type of recurrent ovarian cancer. This is the first randomised trial to demonstrate a benefit for maintenance therapy for recurrent ovarian cancer, and the first randomised trial of a PARP inhibitor in ovarian cancer. Prof Ledermann discusses what further PARP inhibitors are currently in development, the potential for combining PARP inhibitors with platinum based compounds.

Interim survival data from a randomised Phase III ICON7 trial suggests that adding bevacizumab to standard carboplatin and paclitaxel chemotherapy for treatment of newly diagnosed ovarian cancer patients may offer benefit over treatment with chemotherapy alone, particularly for patients with more aggressive disease. Prof Ledermann concludes by explaining the relationship with the Sarah Cannon Research Institute that will allow clinical trials to be offered to private health care patients.

ASCO 2011 Annual Meeting, June 3-7 2011, Chicago

Olaparib maintenance therapy for ovarian cancer and updates from ICON7

Professor Jonathan Ledermann – UCL Cancer Institute, London, UK

 

You’ve had a busy year at ASCO, you are not finished yet. The first big thing which has really been hitting the waves has been olaparib, tell us about that.

Well this was a study with olaparib which is a PARP inhibitor in ovarian cancer and we know that in addition to women who’ve got BRCA gene mutations, who are particularly sensitive to PARP inhibitors because they have deficiency in homologous recombination repair of DNA damage, there is a much bigger group of women who do not have germline mutations of the BRCA gene who also seem to have a deficiency in homologous recombination.

Is that what you call BRCAness, John?

It’s sometimes called BRCAness, that’s right.

It’s a bit clumsy, that.

It’s a little clumsy. I think we would prefer to use the term deficiency in  homologous recombination or HRD for short, and that may affect as much as 50% of women with particularly serous, high grade serous, ovarian cancer which is the most common type, or sub-type, of ovarian cancer. So to test this out we did a randomised phase II study using a design, a maintenance design, where patients went through chemotherapy, platinum based chemotherapy, because we also feel that this HRD phenotype is most prevalent in women who’ve got platinum sensitive tumours. So at the end of their chemotherapy they were randomised either to olaparib or placebo and they took this as maintenance until disease progression. And what we showed in this study was that there was a highly significant improvement in the progression free survival of patients on olaparib, a 65% reduction in the risk of recurrence in favour of olaparib. So that was really quite remarkable I think. We haven’t yet got the survival data because fortunately the women are surviving and it will take probably another year or so until we get survival data. But we hope that this will also show a survival difference.

That’s really exciting and of course there are other PARP inhibitors coming along down the line, I heard that there are nine altogether, some of them with names and some of them with just numbers.

That’s right. It is a sort of crowded area but I think the companies are going to have to make their decisions about which ones to go for. At the moment the Astra Zeneca compound, olaparib, is out in front. And also in the US the Abbot compound, veliparib, is also undergoing extensive trials in ovarian cancer.

And PARP with platinum compounds, that’s an interesting thing too. I heard Plumber talking about this.

That’s right, I think that there are certainly theoretical reasons to suggest that there would be an additive or synergistic effect, but there is also increased toxicity. So there are some rather complicated detailed studies going on at the moment looking at the interaction of PARP inhibitors, particularly with platinum, to see whether the effect of platinum and strand breakage and the inability to repair those strand breaks is potentiated using drugs like olaparib and chemotherapy. And it’s really only when those studies have been completed can one make a decision as to whether to back a trial that would incorporate chemotherapy and a PARP inhibitor, or whether it would be better to use a PARP inhibitor purely as a maintenance, as we have done in this recurrent disease setting.

So, on the topic of maintenance, your other big story? You reported last year with the ICON study that maintenance bevacizumab, and actually bevacizumab up front added to carboplatin and paclitaxel, was indeed improving progression free survival and now we’ve got overall survival confirmation. And what intrigued me, apart from being a phenomenal result and the first of its kind in my time in ovarian cancer, is that for the first time bulky disease doesn’t seem to be a big issue and people who are rather poor on prognosis are actually getting benefit and this is also a good piece of news.

Yes. The ICON7 data still are not sufficiently mature for a full analysis of survival. Having said that, there have been more events since last year and, as part of filing for the regulators, the regulators have asked for an interim survival analysis which is what was shown yesterday. There does seem to be some persistence of the survival difference that we saw last year at ESMO with increased numbers of events, and so I think this is looking more promising than it did last autumn, which is encouraging. And what is also beginning to become a little more clear with the ICON7 sub-group analysis is that it seems to be particularly the women who’ve got bulky residual disease after surgery, and who have a worse prognosis, that may benefit more from a drug such as bevacizumab. The problem with bevacizumab at the moment, and the antiangiogenics, is we don’t have a biomarker for response but at least I think if we can find the sub-group where the drug may be more effective, and that may turn out to be those with bulky disease, then at least that guides us as to which patients might benefit more from this drug. 

I think it’s a fascinating area, and I can see that you were spoilt with riches for a little while now, and I can see a lot of maintenance trials looming. Somebody was criticising both the bevacizumab trials for stopping bevacizumab at 12 months when the biological data clearly said that the minute you take away the antiangiogenic suppression then the thing goes on, and so I think that’s a very interesting area. Now you’re doing masses of trials and I have been hearing quite a bit about the changes in London, in the HCA, and the notion that the private patients might be eligible and might be interested in clinical trials, and the SCRI group, the Sarah Cannon Research Institute, are partnering the team, including yourself I gather?

That’s right.

This was great news because in the past if you went into private sector the last thing you would get would be a clinical trial, which was bad news.

That’s right.

So this is really quite an interesting development.

That’s right. It’s come about from several different angles. I think strategically in the private sector HCA, one of the big insurers and runs private hospitals, very much felt that their patients, the patients being treated in the private sector, should have access to clinical trials, particularly the early phase clinical trials. And then the relationship with Sarah Cannon Research Institute developed. Sarah Cannon Research Institute has needed, when it’s operated in the US, to be linked to an academic partner for all sorts of reasons so we were very pleased that Sarah Cannon approached us and we started the discussions with them. We are geographically, of course, very close to their place in central London, but it’s actually really the academic collaboration that’s going to be the real strength. We will be able to help them with some of the translational research with their own studies and then as part of the affiliation, of course, many of their trials are investigator initiated trials and we will therefore have greater access to drugs that particularly become available in the US that then could be trialled in Europe or in London. And so we are very much looking forward to this collaboration. The other thing is it is not only the private patients who benefit here because, of the relationship we have with them, it’s not only with UCL but with UCL hospitals, the NHS hospital, and we will be able to open some of the Sarah Cannon sponsored studies, not only in the private sector, but also in the Health Service, so that National Health Service patients will be able to get access to these drugs too.

That seems to be a really good solution to a chronic problem that has been hanging around London for a long time and it is really quite frustrating because the UK has got such a good record in discovering and developing drugs, but actually getting access to them has been a problem and this seems to be very innovative. Jonathan, thank you so much for those three snippets, we will see you in Milan at ESGO in December.

I will look forward to that, thank you.