IGCS 2012

State of PARP inhibitors and anti-angiogenics

Professor Stan Kaye – Royal Marsden Hospital, London, UK



Professor Kaye, you’re one of the key people here, you’re delivering two big talks here in Vancouver. Let me ask you about the first one because you address the issue of what we know, don’t know and need to know about PARP inhibitors. We’re talking, of course, in the context of ovarian cancer, can you start off by spelling that out to me? What do we know, first of all?

What we know is that they work. It’s an amazing story, actually. It was about seven years ago that the laboratory work showed that in cells that are derived essentially from BRCA-related ovarian cancer, so that’s the ovarian cancer that relates to familial disease, we know it relates to mutations of the BRCA1 and BRCA2 gene, those cells have got a specific DNA repair defect called homologous recombination deficiency. The laboratory folk showed that if you expose those cells to this drug called a poly (ADP-ribose) polymerase inhibitor, PARP inhibitor, they melt away. I guess they never thought that it would work as well.

Now that’s a significant minority but even more patients with ovarian cancer can respond to this drug, not just the ones with that mutation.

It turns out that’s the case. So we now know it’s about 18% actually have the mutation of the high grade serous ovarian cancer, which is the commonest. But from other work it looks like up to half of patients with that disease, so these are patients who don’t have to have a mutation, can also respond to a PARP inhibitor.

So if you have advanced ovarian cancer, what happens if you take a PARP inhibitor and do you do it as a single agent or in combination?

Well it is in both but my prejudice is the single agent work. It’s a very well tolerated oral treatment given continuously. If you have a BRCA mutation you’ve got at least a 50% chance of a responding tumour shrinking away for at least eight months, sometimes longer. If you don’t have a BRCA mutation you can still respond to a reasonably high level of expectation, the difference, though, probably relates to platinum sensitivity, you know the story of platinum sensitive or platinum resistant. In other words, if the patient has had platinum before, how long ago was it? The further away it was the more likely they are to respond to a PARP inhibitor. But that does differ, I think, between the BRCA mutation patients and the broader group.

This is moving on to what we don’t know about PARP inhibition because there are some questions hanging over this. What don’t we know and what would we like to know?

What we need to know more about is what happens next after somebody has had a PARP inhibitor. One of the hypotheses is that if you had a PARP inhibitor and you’re going to have more treatment, which women will generally have, does that impact on the potential for further treatment to have a benefit? It looks to me as if there may be a difference there between the BRCA gene mutation patients and the others but we don’t know that yet. We really need to know that because we’re looking at long-term treatment.

For the busy cancer doctor what are the data so far? Can you apply this use of PARP inhibition?

Yes. There is a randomised trial that has shown a definite benefit as a maintenance treatment, and this has now been published, actually published in The New England Journal of Medicine recently, a positive trial showing that women who have had ovarian cancer that has responded, placebo controlled, PARP inhibitor delays recurrence. The question is whether in any subset of those it can demonstrate a survival benefit as well. That hasn’t been shown yet. I think we’re heading towards a situation, I hope within the next couple of years, that a PARP inhibitor will be registered for the treatment of ovarian cancer. That’s really what I think should happen and my prediction would be that it will be in those that have a germline BRCA mutation.

So if your best hopes are fulfilled, what sort of impact? You talked about eight months of extension of remission of the disease.

I think that my expectation in those patients is that we would see a prolongation of survival. It won’t replace chemotherapy, women with this disease get five, six, seven, eight sometimes chances of treatment and my hope is that it will add another line of treatment and add survival as a result of that in the patients with a germline BRCA mutation. I should just add one thing which is that although up until now germline BRCA mutation testing has been restricted to those that have a family history of ovarian cancer, I think it should be much broader. My hope would be that any woman walking into a clinic with high grade serous ovarian cancer should have testing for germline BRCA testing, irrespective of family history and we’re getting close to that.

Is there any downside of implementing that sort of strategy?

Not really. I think that there is the question about the family, if you know that you have a germline BRCA mutation then family members, children, daughters, would be at increased risk themselves of ovarian cancer and that has to be done in the context of genetic counselling. But I think that the upsides far outweigh the downsides.

Another promising modality at the moment is anti-angiogenesis therapy. Again this is a topic you are addressing at this conference in Vancouver, looking at future directions, what’s happening?

What’s happening there is happening even more quickly. Bevacizumab is the lead compound. The whole idea that you can treat cancer by affecting the blood supply is not a new idea. I feel frustrated, actually, because this is a modality that has been tested in colon and breast and lung cancer with slightly modest results and that approach has been sometimes criticized. Ovarian cancer, for me, is a different ball game, it’s very much driven by the growth pathways, the VEGF pathways, that will be inhibited by a drug like bevacizumab. So I’m delighted that we now have randomised trials that show that bevacizumab should be part of the treatment for ovarian cancer.

And the data so far in terms of progression and survival?

Yes, there are different trials at different stages including studies that have shown a survival benefit, definite progression free survival benefit. The problem with some of those studies is that if bevacizumab is freely available when patients relapse, it makes it hard to show an overall survival benefit and it is widely used. But I think that the situation is going to evolve quite quickly so what I’m going to try to crystal ball gaze is to get to the point where, because I think this is a new and important modality for treating ovarian cancer, how bevacizumab, which is the lead compound, will fit in a situation where there are several others that target the pathway in a slightly different way are coming along very quickly. We may have a time when women will need to move from one type of anti-angiogenic therapy to another. It’s really interesting.

Talking of bevacizumab though, it did have a problem with breast cancer, didn’t it?

Exactly, exactly, and the difference is that breast cancer isn’t a disease that’s driven quite so much by the VEGF pathway so the results were rather modest. It’s ovarian cancer and renal cancer are the two cancers where that pathway is critical to the growth of the cancer in a way that isn’t the same in breast cancer.

Are there other anti-angiogenic agents which could be considered in ovarian cancer?

Yes, there are several. There are probably about five or six different small molecules, tablets to take every day that inhibit lower down on the pathway, the VEGF pathway. Randomised trials will be available, results next year, and then there are other antagonists of another signal called the angiopoietin axis and there are randomised trials of that too. So putting this all together is going to be lots of fun.

And what’s your summary, then, of what busy cancer doctors should take home from these findings so far?

Well I think that bevacizumab is the lead compound.

And in the PARP inhibitors too.

Sure, well actually it raises the question about which of these we’re going to take forward. We’ve got, I think, two genuine advances in the treatment of the disease. Interestingly, there might be some merit in combining them together at the right time. The busy cancer doctor is going to say ‘How are we going to pay for all of this?’ That’s going to be the real problem because these are not cheap treatments and I think that we’re going to need to get into serious discussions about prices, patient selection, who might benefit most. But I think that we can’t ignore the fact that in ovarian cancer specifically we’ve got two definite ways forward that are not chemotherapy that will make a difference.

Stan, thank you very much for joining us on ecancer.tv.

OK, thank you.