Update on olaparib in ovarian cancer

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Published: 6 Jun 2016
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Prof Jonathan Ledermann - University College Hospital Medical School, London, UK

Prof Ledermann talks to ecancertv at ASCO 2016 about the updated survival data associated with the PARP inhibitor olaparib in a certain subset of ovarian cancer patients.

He also highlights the novel exploratory endpoints that were used for the first time within an oncology trial (TFST and TSST), and highlights that 15% of patients entered into the study possessing mutant strains of BRCA are still receiving maintenance therapy 5 years later.

For future clinical use, it is important to establish precisely those patients who will benefit the most, due to the cost of the drug.




ASCO 2016

Update on olaparib in ovarian cancer

Prof Jonathan Ledermann - University College Hospital Medical School, London, UK

This year I presented the updated survival results of Study 19. Study 19 is a trial of olaparib, a PARP inhibitor, that’s given as maintenance therapy in patients with platinum sensitive recurrent serous ovarian cancer. This trial was originally designed to look at the effect of maintenance in this trial but we then looked at the subgroup of patients who had a BRCA mutation and saw that the progression free survival was significantly improved in patients with a BRCA mutation. This has led to the licensing of the drug through the EMA and many other jurisdictions in the world.

So today what I did was to present the updated survival, this is the third update we’ve had on the survival, with an additional three years of follow-up. What that showed was that there was a significant improvement, a clinically significant improvement, in survival, a median difference of 4.7 months. It did not meet the criteria, the strict criteria, of clinical significance because of the alpha that had been used up on the previous interim analyses. But there are several reasons to believe that that difference of 4.7 months in the median is clinically significant. Firstly, the time from the patients entering the trial to beyond progression, the next time they started treatment was increased by 9.4 months on olaparib. So these women had a much longer time before they needed to have more chemotherapy.

Then we looked at another exploratory endpoint called the time to the second subsequent treatment. What that means is that after progression patients will have another line of chemotherapy and then at some point they will progress again. And what one wants to see is whether the effect of the drug is maintained into the second progression and indeed it is with a significant hazard ratio showing that the effect of olaparib continues beyond progression. Now, the reason that’s important is because it is quite difficult in many trials, particularly in ovarian cancer where patients live a long time after the trial drug, to show a difference in overall survival, a significant difference in overall survival, even if there’s a difference in progression free survival. One of the reasons for that is that patients often cross over to the experimental drug and, even though it was not licensed at the time, these patients with a BRCA mutation entered other trials with a PARP inhibitor and that has a confounding effect on overall survival. So to demonstrate a significant improvement in the time to second subsequent treatment really adds weight to the overall survival data.

The third way in which we feel encouraged by the results is that the trial closed to recruitment in 2010, the follow-up is now a median of 5.9 years. 15% of the patients with a BRCA mutation are still receiving the drug after five years of therapy. Now that is an exceptionally long time for patients with recurrent ovarian cancer. Even those with the BRCA wild-type, 12% have been on the drug for at least five years.

So these two observations, albeit in a small population, 15% and 12% of the trial population, indicate that for some of these women this drug provides a benefit for a very long period of time.

One of the concerns that always comes up when you start weighing up, for example we were talking at a press conference yesterday about a gain of a few months in patients, how that weighs against the cost of the medicine in question and then also any associated toxicities. Have you had any reports or any anecdotal evidence about the cost of the olaparib?

If we look at the cost issue of olaparib first, the drug is now licensed in Europe as maintenance therapy and it is a very expensive drug. Some jurisdictions within Europe are allowing patients to access this provided they have a BRCA mutation, others such as the UK, NICE has allowed it not in the second line but only the third line. So there are limitations depending on the country because it is an expensive drug. Of course that is something that has to be taken into consideration. But I would add that this drug is the first drug that we’ve had in ovarian cancer that targets a specific genotype of patient. So, whereas many of the drugs, many of the expensive drugs, are given to all patients with the disease here we would only use the drug in a fraction of patients, around about 18% of patients, who carry a BRCA mutation. So that immediately, as far as the global effect or the global cost of a treatment in the disease, makes it relatively cheaper because you’re only targeting a small group. Nevertheless, it is an expensive drug and we have to accept that for the moment.

As far as the toxicity is concerned, this is a particularly important question because this is a maintenance therapy and patients need to take this for a long period of time and, as I mentioned, some of these patients are on for about five years or more. What we saw was no worrying late toxicity signals in this trial so the common toxicities of nausea, fatigue and anaemia that we see with this drug, which are usually manageable, very few patients stop the treatment because of toxicity, were similar in the early part of the trail compared to those women who carried on for more than two years. So there were no late cumulative toxicities. There’s one toxicity that has been discussed quite a lot which is the development of myelodysplastic syndrome  and acute myeloid leukaemia, there were three cases in the trial, two of them were in patients taking olaparib and one taking placebo. So actually we don’t think it’s a particularly big problem with this drug. It’s obviously being monitored but we know patients who have ovarian cancer who have a BRCA mutation who have chemotherapy are more prone to MDS and AML.