Comment on SOLO-1 for advanced ovarian cancer

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Published: 21 Oct 2018
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Dr Jonathan Ledermann - University College London, London, UK

Dr Jonathan Ledermann speaks with ecancer at ESMO 2018 in Munich about the SOLO1 study of 2 years maintenance olaparib following platinum-based chemotherapy for patients with newly diagnosed advanced ovarian cancer and a BRCA1/2 mutation.

He emphasises the improved PFS at 3 years with the PARP inhibitor (HR 0.3), with no change in health-related quality of life from standard care.

These results were first presented by Dr Kathleen Moore in a conference session.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.

SOLO-1 is a trial of first line treatment in women with ovarian cancer who carry a BRCA mutation. This is the first time that the drug olaparib, a PARP inhibitor, has been evaluated in the first line setting. The trial design was very similar to the other PARP inhibitor trials in recurrent ovarian cancer in that patients were treated with chemotherapy and then they were randomised either to maintenance olaparib or placebo and the progression free survival was the primary endpoint.
The difference in this study, apart from the fact that it was a first line study, is that the drug was only given for two years and not continued until disease progression. The group of patients that were tested were a fairly standard group of patients in so far as they all had either stage 3 or 4 disease, they’d undergone either primary surgery or neoadjuvant chemotherapy followed by surgery. In fact, 20% of the patients had only a partial response at the end of chemotherapy before they were allocated to olaparib or placebo.

The results of the trial were really quite striking. It showed a very big difference in the progression free survival between olaparib maintenance and placebo; the hazard ratio was 0.3 and, in fact, the median progression free survival for the olaparib arm has not yet been reached. For the control arm it was very much what you’d expect with no maintenance treatment after chemotherapy and by three years, and all the patients have been followed now for at least three years, by three years 60% of the patients in the olaparib arm were progression free whilst only 26% of the patients in the control arm were progression free, so a very big difference. One of the other striking things about the progression free survival curves is that although the drug stopped at two years the curves remained apart and didn’t seem to becoming together beyond that time. Even beyond three years, which is where we’ve got the most robust data because all patients were followed for at least three years before the analysis was done, but you go beyond three years there is still a separation of the curve that looks very similar to the two years. In fact, when they looked at a secondary endpoint which was the progression free survival 2, or PFS2, which is the time to the next progression, so you take patients who have progressed, you treat them again with another drug and then you measure the time to the subsequent progression, that’s still 60% for the olaparib arm, suggesting probably that there haven’t been very many progressions since the three year endpoint took place.
So overall what we’ve seen is really a remarkable improvement in the progression free survival in this first line setting and the toxicity of the drug has been very much as it has been in the recurrent disease settings which is usually very manageable, a few patients discontinuing because of toxicity but the majority continue to the two year point unless they progress before then.

The health related quality of life really stood out to me as something to even more strongly endorse the idea that this could be or should be the new standard of care in this indication.

Yes. I think quality of life measurements are quite difficult in this setting because if you give a drug versus no drug and it has any side effects it could have an adverse effect on quality of life. So there are ways that have been looked at now in the recurrent disease setting with a different analysis, what’s called a TWIST analysis, time without symptoms, which gives you an area under the curve relating to the time that patients are free of symptoms before progression occurs. Now, in a situation like SOLO-1 where the drug is only given for two years and very few patients have progressed, it becomes harder to interpret the quality of life measurements. But the amount of toxicity is relatively minor and the benefit in terms of length of time free of progression greatly outweighs those minor effects.

It seems to be a ringing endorsement for its adoption worldwide. Are there any concerns regarding the implementation for cost, for access, for any comorbidities? Anything to hold this back?

Undoubtedly this is a landmark study and it resets the new standard of care for patients with a BRCA mutation. There are, of course, going to be some difficulties in not only accessing the drug but also testing patients for a BRCA mutation early on at diagnosis. Because in many parts of Europe, or indeed now even in North America, bevacizumab is often used as a first line treatment in stage 3/4 ovarian cancer. But if a patient has a BRCA mutation then you probably wouldn’t give them bevacizumab, you’d get the response and then put them on olaparib. So you need to know early on whether the patient has a BRCA mutation so that you can decide whether to go down the pathway of bevacizumab or whether to use olaparib. Testing those patients, getting the results within a few weeks, is going to be quite challenging in a number of different countries and regions. I think that’s something that we’re going to all have to work on to try and get those processes running more smoothly.

Cost, of course, is another issue. These are expensive drugs and more than half the patients will be on the drug for two years and that’s a significant cost. Again, it depends on whether the payers in the different jurisdictions will accept that cost benefit.

The key thing is that we’ve just not seen such improvements in progression free survival in the first line setting for more than twenty years. We’ve made big strides in improving the treatment of recurrent disease, patients are living longer although they’re not cured, and the real challenge has been to improve that time to first progression because we know that when women with ovarian cancer progress it effectively means that they’re eventually going to die of their disease. So what we really need to do is to avoid that first progression and this trial is the first for many, many years that has significantly delayed time to first progression. So that’s a big step forward in the treatment of patients with ovarian cancer.