Hereditary Breast and Ovarian Cancers Meeting 2011, New York, USA

Olaparib extends PFS in women with high-grade serous ovarian cancer

Professor Hilary Calvert – University College London, UK

Today I’ll be talking about the use of PARP inhibitors. PARP stands for an enzyme that’s involved in DNA repair and it’s turned out that PARP inhibitors are extremely useful for treating BRCA-related breast and ovarian cancers. This is quite a recent discovery, the original pre-clinical paper was only published in 2005 and now there’s substantial clinical data showing that they’re very promising and there’s one randomised clinical trial in ovarian cancer showing a significant improvement in progression free survival. In this trial, patients who were treated with platinum-based chemotherapy for ovarian cancer, which is the standard, once they’d finished their chemotherapy they were randomised to be treated with a PARP inhibitor called Olaparib or to be given a placebo. The progression free survival was increased by I think it was about five months for the PARP inhibitor arm. The hazard ratio was about 0.4, which is an extremely big hazard ratio, much bigger than you normally see in oncology trials and, interestingly enough, the number of symptoms in the patients treated with the PARP inhibitor was less than it was in the control arm, probably due to the fact that the PARP inhibitor was suppressing cancer-related symptoms. So this is actually a really strongly positive trial and it’s really the first positive trial in ovarian cancer for about twenty years, since the trials of taxol. So just recently we’ve got some positive data with antiangiogenic agents in ovarian cancer and with PARP inhibitors but there’s been a twenty year hiatus when we haven’t really made any progress.

What’s next?

The PARP inhibitors are not licensed yet so we have to wait and see what kind of criteria the regulatory bodies want to license the PARP inhibitors. There are all sorts of possibilities for future clinical development in combination therapy and so on. Also something that I think will be discussed here, which is still very controversial, is whether you could use these drugs for prevention in known BRCA1 and BRCA2 carriers because, in theory, they could eliminate the transformed cell just at the time it transforms, before the cancer ever came about. The argument against it is that because they interfere with DNA repair, they are potentially oncogenic in their own right. So there might be a risk from long term treatment with the PARP inhibitors. So those are the two sides of the coin that will have to be examined before anybody decides whether to do a trial of that sort.

What about adverse effects?

There’s no data on adverse effects for the PARP inhibitors yet; the olaparib has some minor side effects which are probably unrelated to its mechanism of action. The other PARP inhibitors in trial really have nothing in the way of subjective or laboratory-based side effects that you can measure.

So do you think it has preventative potential or is it too early to say?

I think it might do but I wouldn’t like to commit just yet, but there’s a possibility there, yes.

Why should patients be interested in this?

Well a patient who has been diagnosed as a BRCA carrier knows that they’re in an increased risk of breast and ovarian and some other cancers and so they have a choice to make – do they undergo regular screening and hope that if a cancer occurs they can have it treated effectively before it becomes metastatic, or do they have prophylactic surgery, which is quite substantial surgery, such as a bilateral mastectomy or an oophorectomy or both? The data that we’ve seen at this meeting so far shows that patients are quite variable in their decision and some will decide one course, some will decide another and there may be cultural differences as well. Now if you did have a pill that was effective that didn’t have side effects, I think those dilemmas would go away and that would be a benefit for the patients. But so far, of course, it’s all theory, we don’t have any data to say that the pill would be effective for prophylaxis and we don’t have any data to say that it wouldn’t have side effects or long-term risks associated with it. So we have to wait and see here.

And the key point of your talk at the Hereditary Breast and Ovarian Cancers Meeting 2011?

The one point I’ll try and clarify in the talk is the data on PARP inhibitors over the last twelve months or so has been coming out very rapidly and there’s quite a lot of confusion about whether they work for breast cancer or ovarian cancer or both. There are a couple of trials in breast cancer that have presented negative results and so some people are feeling that they don’t work for breast cancer. I think this is a bit premature because there are also phase II trials that are positive for breast cancer and one of the negative trials, the trial conducted by Sanofi for a drug called iniparib, it’s turned out that iniparib probably isn’t a PARP inhibitor. So, although it’s a negative trial, it doesn’t show that the PARP inhibitors don’t work because it’s been done with a drug that is almost certainly not a PARP inhibitor.