Mansoor Raza Mirza, MD
The PARP1/2 inhibitor niraparib significantly improved progression-free survival (PFS) in patients with platinum-sensitive recurrent ovarian cancer, according to results from the phase III NOVA trial presented at the 2016 ESMO Congress and simultaneously published in The New England Journal of Medicine
After a median follow-up of 16.9 months, the median PFS with maintenance niraparib was 21 months compared with 5.5 months for placebo in patients with germline BRCA mutations (HR, 0.27; 95% CI, 0.17-0.41; P <.001). These findings remained consistent across subgroups of patients, regardless of BRCA mutation and homologous recombination deficiency status.
“This is going to change our way of thinking about ovarian cancer,” said lead investigator Mansoor Raza Mirza, MD, chief oncologist at Rigshospitalet, Copenhagen, Denmark. “When patients with ovarian cancer relapse, we had to tell them that this is a deadly disease, and patients will receive chemotherapy again and again, and eventually die of the disease. We are talking about turning this into a chronic disease, so patients can live with minimal toxicity after treatment, and have a normal life for a very long time.”
In an interview with OncLive
, Mirza discussed the design of the study, the most significant findings, and the impact that these results stand to have on the treatment of patients with ovarian cancer.
OncLive: Could you provide an overview of the NOVA trial?
: Our hypothesis was that all patients, regardless of BRCA status, would benefit from niraparib. For patients who have relapsed, who have platinum-sensitive disease, they typically receive around 6 courses of chemotherapy as a standard of care. At the end of treatment, at the time of response, they were invited to enter our trial.
We performed central germline BRCA testing and divided patients into 2 cohorts: one characterized as gBRCA population, and the rest were non-gBRCA. These patients were, in each cohort, randomized 2:1 to niraparib and placebo, given once daily until progression of disease. In the non-gBRCA cohort, we further tested patients for tumors with HRD. These patients were grouped into HRD-positive and HRD-negative disease.
The data show that all 553 patients had a clinically significant benefit when treated with niraparib. If we take the gBRCA population, the hazard ratio is 0.27 with a median PFS increase from 5.5 months to 21 months. The main message would be that these curves are separated all the way to follow-up, with half of patients on niraparib at the time of data cutoff, and they had not progressed.
In the non-gBRCA cohort, the whole population, again, benefitted in a clinically meaningful way. The patients had a median PFS benefit increase from 3.9 months to 9.3 months. That was extremely positive, with a hazard ratio of 0.45. Again, one-third of patients remained on treatment for a long time without progression at the time of data cutoff, showing the durability and efficacy of the drug for these patients.
So we performed, as I said, the subgroup analysis, the HRD test in this population, and we see benefit in the patients who were HRD-positive, and we see clinically meaningful benefit in the patients who were HRD-negative as well. So the HRD-positive hazard ratio was 0.38, and the HRD-negative hazard ratio was 0.58, which is clearly clinically meaningful, with these survival curves separated, and staying separated to follow-up. And one-fifth of patients are on treatment at the end of follow-up without progression.
This shows that, regardless of BRCA status, regardless of HRD status, we have benefit of niraparib in the whole population, and this is something that is very big because we have a new treatment which has significant effect and which improves PFS significantly, regardless of any markers. So the biomarker for niraparib would be platinum-sensitive disease.
What results did you find in the safety analysis of this trial?
The toxicity of niraparib is classic toxicity seen with PARP inhibitors, which is hematological lab abnormalities, easily adjustable by dose reduction. And that made it possible for these patients to be on treatment for a very long time. For example, for thrombocytopenia, only 3% of patients went off of the treatment due to thrombocytopenia. Other toxicities were fatigue and hypertension, and for hypertension, we don’t know what the cause is of that.
But, toxicity did not affect the quality of life with these patients. We did quality-of-life questionnaires with our patients, and we have seen absolutely no detrimental effect on quality of life all the way through the whole course of treatment. So this is a treatment that is well tolerated by patients for a very long period of time.
What sort of impact do you think these findings will have on the treatment landscape in ovarian cancer?
This is going to change our way of thinking about ovarian cancer. When patients with ovarian cancer relapse, we had to tell them that this is a deadly disease, and patients will receive chemotherapy again and again, and eventually die of the disease. We are talking about turning this into a chronic disease, so patients can live with minimal toxicity after treatment, and have a normal life for a very long time. It’s not a small subgroup of patients; these are all patients with high-grade endometrial cancer. These are landmark results that will change our practice and how we treat our patients.
What do you hope to see in the treatment of ovarian cancer in the next 5 to 10 years?
I hope that now we will have PARP inhibitors, some combinations of PARP inhibitors with other drugs, like anti-angiogenic drugs. We’re already doing trials with that, or with immunotherapies, and we’re already doing trials with that. We’re really in a very interesting era, and we’re seeing some major gains for our patients.
- Mirza MR, Monk BJ, Oza A, et al. A randomized, double-blind phase 3 trial of maintenance therapy with niraparib vs placebo in patients with platinum-sensitive recurrent ovarian cancer (ENGOT-OV16/NOVA trial). Presented at: 2016 ESMO Congress; October 7-11, 2016; Copenhagen, Denmark. Abstract LBA3_PR.
- Mirza MR, Monk B, Herrstedt J, et al. Niraparib maintenance therapy in platinum-sensitive recurrent ovarian cancer [published online October 8, 2016]. N Engl J Med. doi: 10.1056/NEJMoa1611310.