ESMO 2016

Outcome of ovarian cancer patients was significantly improved with niraparib

Dr Mansoor Raza Mirza - Copenhagen University Hospital, Copenhagen, Denmark

Good morning. This is the first phase III trial of PARP inhibitors in ovarian cancer being presented ever. It’s a niraparib maintenance therapy in patients with recurrent ovarian cancer, the ENGOT-OV16/NOVA trial.

So why maintenance therapy? Patients with ovarian cancer who relapse, they get typically six courses of chemotherapy, because of toxicity you pause then wait until the next relapse, chemotherapy, relapse, the treatment free intervals get shorter and shorter and eventually all patients die of their disease. So there is a real need to extend the treatment free or the time from one therapy to the other with less toxic treatment. This trial was done in collaboration with ENGOT, the European Network of Gynaecologic Oncology Trials, with the lead group of the Nordic Society of Gynaecologic Oncology and fifteen countries were involved in this trial. Tesaro was the sponsor of this trial.

The trial paper has been just published a few minutes ago in The New England Journal of Medicine with a supplement so all the questions you would like to ask you can read in The New England Journal of Medicine.

So what was the hypothesis? The hypothesis is because ovarian cancer is quite a heterogeneous disease genetically and BRCA mutations and non-BRCA mutations still can affect the repair mechanism of DNA. PARP inhibitors can actually make it possible for hindering repair of DNA in cancer cells. In that way the disease can be controlled, very targeted mechanism of PARP inhibitors. And niraparib is a PARP inhibitor, it’s a selective PARP 1/2 inhibitor and our hypothesis was that all patients with platinum-sensitive recurrent ovarian cancer would have clinical benefit regardless of BRCA mutation status and regardless of HRD status, which is homologous recombination repair deficiency. So typically when patients relapse they get standard of care, six courses of chemotherapy, and have a response. At that time patients were invited to enter in the NOVA trial and centrally upfront a germline BRCA test was performed. According to that BRCA test patients were divided into two cohorts, two separate cohorts, and in each cohort patients received once daily oral niraparib or placebo in two to one randomisation. The capsules were continued until progression of disease.

553 patients were randomised, 203 patients who had germline BRCA mutation and the whole group of patients who had no germline BRCA mutation. In the non-germline BRCA mutation we went ahead and performed a HRD test that’s called myChoice HRD test. Patients were then divided into two separate groups within that cohort, those who were HRD positive and those who were HRD negative. So the statistics were performed as such in that cohort, that first HRD positive population was seen, the analysis was done and if that was positive the whole group of patients were analysed. I was asked to keep it to six minutes so I have not taken the Kaplan-Meier curves to make sure that you also attend the Presidential session.

So I will go through the results here. The conclusion is that niraparib significantly improves PFS in patients with platinum-sensitive recurrent ovarian cancer in the whole population, not in separate groups, cohorts, in the whole population. If you look at the gBRCA mute population the hazard ratio is 0.27. This is a 73% decrease in the risk of progression in the gBRCA mute population while median PFS increased from 5.5 months to 21 months. The most important thing you will see in the afternoon as well is the separation of Kaplan-Meier curves all the way, nicely plateauing at the end with half of the patients in active treatment at 18 months with the data cut-off we have. So half of the patients we haven’t actually reached the upper confidence interval of the patients who are in active treatment in this cohort.

The rest of the cohort which is non-gBRCA, that’s the rest of the patients, we could see clinically meaningful, statistically significant improvement in the whole group with a hazard ratio of 0.45, 55% risk reduction of progression in this group with median PFS increasing from 3.9 months to 9.3 months and one-third of the patients still on active treatment after eighteen months at the time we did the data cut-off. So again we will see a beautiful separation of Kaplan-Meier curves showing the durability of the efficacy of the treatment all along.

As I said, within that cohort we had a group of the HRD positive population and these patients had a hazard ratio of 0.38 with median progression free survival increasing from 3.8 months to 12.9 months. So then you will ask what happened to the HRD negative disease and in that that was not a primary endpoint but that was an exploratory endpoint. In these patients we see a statistically significant improvement in progression free survival with a durable efficacy and with a hazard ratio of 0.58 which is a 42% reduction in the risk of relapse. One fifth of these patients after eighteen months of data cut-off are still on active treatment so there is a beautiful separation of Kaplan-Meier curves all the way along.

That means that this drug has efficacy in the whole population of this trial. The toxicities were classic PARP inhibitor toxicities, basically lab abnormalities and fatigue. Lab abnormalities were very well adjusted by dose modifications and the major thing is that most of the patients were kept on trial so they did not discontinue the treatment due to toxicity. For example, for thrombocytopenia 3% of the patients were discontinued due to toxicity otherwise they were on the trial until progression. On top of it there was no detrimental effect in quality of life in the niraparib arm. That means that patients can stay home, come once a month, get her tablets, talk to the doctor, go home and do the normal daily life, work, children, family and everything else.

So these landmark results warrant… this is the first phase III trial ever in PARP inhibitors and it results that niraparib maintenance treatment should be given to the whole study population.