The standard of care and progress so far with PARP inhibitors for ovarian cancer

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Published: 25 Oct 2018
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Dr Susana Banerjee - The Institute of Cancer Research, London, UK

Dr Susana Banerjee speaks with ecancer at ESMO 2018 in Munich about the standard of care for ovarian cancer and the progress made so far with PARP inhibitors.

Dr Banerjee states that PARP inhibitors have transformed the treatment of relapsed ovarian cancer.

She goes on to describe the SOLO1 trial which looked at the use of PARP inhibitors in the front line setting.

For more on ovarian cancer, watch her press conference here.

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.

Ovarian cancer is a malignancy that is within the top ten cancers affecting women. Although it’s not as common as breast cancer, unfortunately the proportion dying of their disease is much higher with ovarian cancer. So the standard of care for women with newly diagnosed advanced ovarian cancer is surgery with platinum-based chemotherapy and also, in many countries, bevacizumab is part of standard of care.

There has been progress and advances in the treatments of ovarian cancer over the years and in particular if we focus on the more targeted therapies then bevacizumab and also PARP inhibitors have clearly changed the treatment landscape of advanced ovarian cancer. Bevacizumab is approved in the front line indication of newly diagnosed women with ovarian cancer in combination with chemotherapy and then followed with maintenance bevacizumab. Shortly afterwards, a year or so afterwards, we know that bevacizumab had activity with chemotherapy and as a maintenance treatment afterwards in the relapsed setting, both in the platinum sensitive setting but also platinum resistant disease.

The next wave of breakthroughs in terms of approvals has been PARP inhibitors and PARP inhibitors have transformed the treatment of relapsed ovarian cancer. What we heard today were the results of SOLO-1 which is maintenance olaparib in the front line indication.

You mentioned the new wave of PARP inhibitors, how does that really translate to a benefit for women who are going through the disease now?

As it currently stands there’s EMA approval for three PARP inhibitors, that’s olaparib, niraparib and rucaparib. Olaparib and niraparib are approved as a maintenance therapy in women that have platinum sensitive relapse that have responded to further platinum and then given these drugs as a maintenance treatment. There’s also EMA approval for rucaparib which is as a treatment for women with BRCA mutated ovarian cancer in the platinum sensitive setting. So overall, taking this together in terms of magnitude of benefit, in the maintenance setting the improvement is in the order of 75% with a hazard ratio of between 0.25 and 0.3, so a significant improvement. In terms of time, what does that mean for an individual patient? If we take olaparib, for example, in the SOLO-2 study the median progression free survival in the placebo arm was around 5.5. months and the women that received olaparib tablets, and that’s the BRCA mutated population, it was over 19 months.

It’s really life changing, practice changing information.

It is, the issue is and what brings us back to the front line setting is that unfortunately once cancer has relapsed, so ovarian cancer relapse, it’s rarely curable. It’s treatable but not really with curative intent as we stand today in the recurrent setting. But when women are diagnosed with ovarian cancer, even if it’s advanced, there is a chance where there is a potential for cure in that setting. So that brings us to the SOLO-1 trial.

Where we are today with the approvals of PARP inhibitors, they’re all in the recurrent, so relapsed, disease setting. The SOLO-1 trial is the first randomised trial of looking at the effects of a PARP inhibitor in the front line setting. So I’ll just talk a little bit about the design. It’s, as I say, a randomised phase III double-blinded study of maintenance olaparib versus placebo. This included patients with BRCA mutated ovarian cancer and they had advanced disease, so stage 3, stage 4. Patients would get surgery, as per standard care, followed by platinum-based chemotherapy and those women that obtained a complete response or partial response would then go on to be randomised to either olaparib or placebo and it was two to one randomisation. The primary endpoint of this study was progression free survival, so investigator assessed progression free survival and at the time of reporting the median follow-up was over 40 months.

So 391 women overall were enrolled into this study and the study met its primary endpoint. The hazard ratio for progression free survival benefit with olaparib was 0.3 so that is remarkable, that is outstanding for this group of patients in the front line setting. Looking at timelines, in terms of median progression free survival in the placebo arm it was around 13 months, just over 13 months, and it hasn’t been reached for the women treated in the olaparib arm yet. But if one extrapolates from the Kaplan-Meier estimates it appears to be potentially in the region of three years’ advantage for women who received maintenance olaparib in the front line setting. So I very much believe that this is going to lead to a fundamental shift in the way that we treat women with newly diagnosed advanced ovarian cancer and it highlights the importance and urgent need to ensure that women have access to BRCA mutation testing.

The presenter, Dr Moore, did seem pleasantly surprised that the two year benefit in the trial worked out as significantly as it did.

I’d just like to talk a little bit about that. In this study patients received olaparib for two years so if they had disease progression before that obviously they’d stop. If there was some disease still ongoing at the two year point then they could continue but the majority of women stopped olaparib at the two year point. But what we see, which is intriguing with this study, is that the benefit of olaparib does not trail off, the curves don’t come together, which means that the effects are maintained post-stopping olaparib and that’s really exciting. For our patients in clinical practice it means that some patients will have two years of treatment and then would stop being on treatment yet be disease free until the next progression. We don’t know at this point how long that will be and it’s really important that we wait for the overall survival data which, given this population, will take quite some time. We really need to know whether there is an overall survival advantage and therefore are we potentially curing more women with BRCA mutated ovarian cancer.

We also need to balance the toxicities that women may be subjected to with maintenance PARP inhibitors. What we saw in SOLO-1 is that there were no new signals compared to what we see in the relapsed setting. Most of the toxicities were generally considered mild or moderate. The grade 3 toxicities for anaemia were just over 20% and just under 10% for neutropenia. So it’s going to be very important in practice with regards to monitoring patients but there certainly was no new signal. The discontinuation rate was around 12% and about 50% needed dose interruptions and around 25% dose reductions.

Overall the results have been very warmly welcomed; other members of the panel this morning seemed very enthusiastic for what they described as a breakthrough, a landmark study.

I’m very excited about these results for our patients worldwide. I think this is a practice changing study and a fundamental shift, as I say, in how we think about treating women with newly diagnosed ovarian cancer. The theme of ESMO 2018 is accessing drugs and I very much hope that we move forward quickly in order to access olaparib in this setting. It’s important to also think about the trials that are going to report in the next couple of years – some of the key questions are whether there’s activity in women that don’t harbour a BRCA mutation, the PRIMA-1 study of maintenance niraparib will help address that, and also PAOLA-1 which is looking at olaparib in combination with bevacizumab in this setting as well.