IGCS 2010, 23-26 October, Prague

The role of trabectedin in the treatment of ovarian cancer

Professor Bradley Monk – University of California at Irvine, USA

You presented here at the IGCS some new data on ovarian cancer, can you discuss this with us?

One of the real unmet needs in ovarian cancer is the lack of effective therapies. Obviously everyone is treated with carboplatin and paclitaxel initially but, unfortunately, most patients recur. So what I described at this meeting was further analysis of our pivotal trial looking at trabectedin, a novel anti-cancer therapy that is now available in most parts of Europe for women with recurrent ovarian cancer.

So how is this given? It’s given as second line?

This is approved in second line treatment in combination with another drug called liposomal doxorubicin, frequently known as Caelyx. This combination is more effective than liposomal doxorubicin alone and that has been shown in a large 672 patient randomised phase III trial.

So this is given during the interval after platinum?

That’s right.

And so then what happens to the patients after they finish their period on this trabectedin?

That was our presentation today, is what happens third line. So if front line therapy is carboplatin and paclitaxel, and then second line therapy at least in those that recur greater than six months, what are called platinum sensitive patients, is this liposomal doxorubicin trabectedin combination. We discussed today then what is next, third line therapy. The hypothesis is that if we use a non-platinum doublet, this trabectedin liposomal doxorubicin combination, that we can then use platinum third line and maybe even delay what’s called the platinum free interval; by doing that we can increase the likelihood of responding to platinum. So what we showed in a subset analysis of this group who have a platinum free interval between 6-12 months, what we call partially platinum sensitive disease, that if you treat patients in that 6-12 month recurrent interval with liposomal doxorubicin trabectedin, that we delay the time when they’re going to get platinum third line, we delay the time when they’re off treatment until third line is needed. And then we generated a hypothesis that maybe we can even improve survival 8.7 months, which if proven in our upcoming randomised phase III trial would be very beneficial to ovarian cancer patients.

But can it be used in the patients that are actually resistant to platinum?

In those that recur within the first six months after treatment, those are called platinum resistant patients, the efficacy has not been very great, it probably just adds mostly toxicity and, indeed, that is not according to the EMEA approved indications. So it’s only approved with liposomal doxorubicin after six months in the platinum sensitive situation.

So any other new data coming out of this meeting for treatment of ovarian cancer?

Recently, as you’ve probably heard, was this large randomised phase III trial called ICON7 which looked at bevacizumab integrating it into front line therapy. That was a confirmatory trial to the larger study done within the Gynaecologic Oncology Group, presented at ASCO this year. So these two trials together have investigated maybe we should add an antiangiogenesis drug, bevacizumab, to front line therapy. So at this meeting there has been considerable controversy because that benefit, at least at this current time, is in progression free survival and is progression free survival really something that’s a valuable endpoint or is it all about overall survival? So that has created a lot of controversy - is the level of evidence prolonging progression free survival acceptable to change clinical practice? And you may have interviewed other people that have given their opinions but that’s what we’re trying to do, is to figure out where bevacizumab fits in the front line regimen.

And people have touched briefly on the PARP inhibitors which are now being used and are actually quite active in BRCA1 and BRCA2 mutated patients. Can you say anything on this?

Yes, that’s the next level. The two established therapies are bevacizumab, we discussed it, and then before that trabectedin. Unfortunately there are no PARP inhibitors that are approved and so you can only participate or receive those drugs if you participate in a clinical trial. The problem with the PARP inhibitor research is the following: patients who have BRCA1 and 2 germline mutations have a better prognosis. So we study PARP inhibitors in that group of patients who are already supposed to do well and then we show that if they get a PARP inhibitor that they do well. So are they having a high response rate because PARP inhibitors are particularly active, period, or do they have a high response rate because we’re giving them to the patients who have the highest response rate, no matter what you give them. That’s why randomised clinical trials are necessary, do you understand what I’m saying? Are they working because the drug is good or are they working because the population is favourable?

In theory they should only work in people which have the mutation in the…

Not necessarily. We heard today that there are individuals that don’t have germline mutations but have defects in what we call homologous DNA repair. These are tumours that we say are BRCA-like, maybe BRCAness, and these are predominantly high grade serous tumours, these are patients that have high CA-125s, patients that have a long platinum free interval. But again those are also the highest, the best prognosis patients. So even though they work in other non-BRCA germline mutation patients, they also are only generally the best prognosis patients. So yes, they are exciting but I’m a little hesitant to jump on the bandwagon, if you will, until larger trials are done. And that’s why, with the bevacizumab paradigm, we now have two trials, both met their primary endpoint. With trabectedin we have a large trial, met its primary endpoint, we’re getting ready to do another one. But PARP inhibitors we don’t have large randomised phase III trials.

Thank you very much.