More ovarian cancer patients benefit from maintenance combined targeted therapy

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Published: 28 Sep 2019
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Prof Isabelle Ray-Coquard - The Université Claude Bernard Lyon, Lyon, France

Prof Isabelle Ray-Coquard speaks to ecancer at ESMO 2019 in Barcelona about the PAOLA-1/ENGOT-ov25 Phase III trial, which showed the benefits of treating advanced ovarian cancer patients with bevacizumab and PARP inhibitor olaparib in the first-line setting.

She explains that this intensive regimen was given to patients both with and without a BRCA mutation. While both groups were found to have extended progression-free survival, this was more pronounced in the subgroup of patients with BRCA mutations and those with homologous recombination deficiency (HRD).

Prof Ray-Coquard comments that these results suggest a new first-line standard of care for patients with advanced ovarian cancer, but she adds that the ability to test patients to determine their outcomes is an important aspect of providing this treatment.

Watch the press conference here.

Watch Dr Susana Banerjee's comment here

Read more about the study 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.

PAOLA-1 was born from the emergence of two important points. First, ovarian cancer, as you understand, is a worse prognostic and the current standard of care includes bevacizumab as maintenance as bevacizumab in first line increases the response rate and also prolongs progression free survival and also overall survival in some high risk subgroups. It is a current standard of care for the majority of patients with ovarian cancer.

In parallel, olaparib shows an unprecedented benefit in PFS as a frontline maintenance monotherapy in patients with BRCA mutations. We know also that the homologous recombination deficiency is not limited to BRCA and represents approximately 50% of the patients with an ovarian cancer. We have also the information that the PARP inhibitor in platinum sensitive relapse, not in first line, is efficient beyond BRCA and the efficacy is increased when we combine it with an antiangiogenic.

So, looking to the prognostic of this disease, if we would like to be in the goal to cure the patient the idea is combine both maintenance therapies, both effective maintenance therapies, in all patients with advanced ovarian cancer.

It is a randomised phase III. The hypothesis is to have a target hazard ratio of 0.75. For this reason we need to have more than 458 PFS events. We use a hierarchical testing model to evaluate further PFS; if the PFS is positive we can move to the PFS2. As we would like also to see something in overall survival if the PFS2 will be positive we can be able to explore the overall survival. We also have predefined subgroups according to BRCA mutation but also HRD tests. At the end we have included 806 patients. It is a randomisation two to one between olaparib plus bevacizumab versus bevacizumab alone.

PAOLA-1 met its primary endpoint for a statistically significant improvement in progression free survival in the intent to treat population in favour of the olaparib arm with a hazard ratio of 0.59. The median PFS increased from 16.6 months in the control arm up to 22.1 months in the olaparib arm. If you remember that the patients received the first line treatment with a median of 7 months before being randomised, finally the patients who received chemotherapy plus bevacizumab plus olaparib benefit from a median time of nearly 30 months without relapse.

What we observed in the clinical trial is that patients with an HRD test positive with BRCA mutation or without BRCA mutation have greatest benefit, a substantial benefit – in terms of hazard ratio 0.33 – but also in terms of median PFS, showing that this group of patients have a major impact to have a PARP inhibitor in first line.

What we observed is that the safety profile of olaparib is very similar to that we observed in previous clinical trials where olaparib was evaluated in monotherapy maintenance. For bevacizumab there was no increase of bevacizumab toxicity, including the rate of all grade severe hypertension.

The implication is that we will change the standard of care in first line. Looking to what we observe in PAOLA-1, the patients in first line receiving bevacizumab need to receive a PARP inhibitor in combination. Where we have to define more the detail is the group of patients, HRD positive patients, who have a real, huge benefit. The HRD negative is smaller so the question will be to consider when a test will be available to stratify patients with the test.