The story with fulvestrant, if I can ask you about Dr Robertson’s very interesting presentation, because it seems historically fulvestrant was not adopted, even though it was actually quite efficacious. Can you spell out some of the background to this and what he told us this morning?
Sure. I helped to develop fulvestrant in my own lab back in the ‘90s and in our hands, in both cell cultures and in animal models, fulvestrant was the best endocrine therapy that we had, better than Tamoxifen, better than depriving the cells of oestrogen. Then studies were started, first comparing a 125mg dose with a 250mg dose; 125mg dose was ineffective, totally, but 250mg was effective and that was the dose that was chosen. But because it was only twice the 125mg I was always sceptical, as were many other people, that it still wasn’t the highest dose that we could give or the optimal dose that we should be giving. So eventually studies were done looking at 500mg which is clearly better. But the problem that happened was that fulvestrant at the 250mg dose was compared to other endocrine therapies. So you’re taking a dose of fulvestrant that’s not the optimal dose and comparing it with aromatase inhibitors and Tamoxifen and since it wasn’t any better than those in those studies it was laid aside and used for advanced breast cancer, not in the adjuvant situation.
Was that because it was injected rather than an oral preparation?
Sure, because it was a little bit more difficult to give a monthly injection. The injection most patients tolerated extremely well, that’s not the issue, but it’s just inconvenient to come in every month and get an injection. So Tamoxifen and the aromatase inhibitors remained as the standard of therapy for this group of women. Now fulvestrant has been reserved to a second or third line therapy in women with metastatic disease; you could certainly argue that at the 500mg dose we now wish there had been an adjuvant trial. It may have turned out to be the best endocrine therapy we have.
Could you summarise what in fact we heard about the use of the 500mg dose today in terms of efficacy?
Well, it shows a statistically significant improvement in progression free survival and overall survival, something you hardly ever see in metastatic breast cancer, much less in oestrogen receptor positive metastatic breast cancer. So this is 500mg of fulvestrant compared to an aromatase inhibitor, arimidex, which is one of the drugs that’s considered the best drugs we have for endocrine therapy of breast cancer.
It seems a big difference too, so it is now looking better than anything else.
Yes, I would say so.
So what do you think doctors might make of this now?
It’s really difficult to extrapolate from metastatic breast cancer to treatment in the adjuvant situation where you’re treating for a long period of time, thousands of women, intramuscular injections every month without having data. That would be a very difficult jump. I think what it tells us is that we’d like to have a study done for the adjuvant therapy of breast cancer using fulvestrant or another selective oestrogen receptor down-regulator, if one comes along, that would be easier to give. There are a number of those that are in research, it’s going to be a while before we know. I would like to see fulvestrant go forward personally because I think it’s going to be hard to beat it. But this approach of getting rid of the oestrogen receptor, rather than just blocking it, makes a lot of sense as a good therapy, perhaps the best we have for ER positive breast cancer.
In the light of what we were hearing at the recent ASCO where there are publically funded studies getting good results, do you think there’s a case for putting fulvestrant forward as a publically funded large study to see?
I would like to see that. With the patent life expectancy, which is rather short now for fulvestrant, I can’t imagine the company spending millions and millions of dollars to do another large phase III adjuvant trial with ten years of follow-up. But the differences were sizable enough that this could make a major difference in the adjuvant therapy where typically results are better, the differences are more evident in the adjuvant studies than they are in metastatic disease. So this could be a really big drug in the adjuvant setting. Whether that kind of study will ever be done, I don’t know.
Does it give you a clinical challenge about whether actually to go ahead and use it?
I wouldn’t use it outside of more data, that’s the problem. When you consider adjuvant therapy you’re talking about five years or maybe even longer of therapy and to require people to come in every month for intramuscular injection without any data in the adjuvant setting is a problem.
So in a nutshell how would you sum up that study right now for doctors around the world?
That and other studies suggest that 500mg of fulvestrant may be the best endocrine therapy we have, at least for metastatic breast cancer. It probably should be used a little more frequently than it is.