PFS increase but no OS increase for niraparib in advanced ovarian cancer

Dr Antonio González-Martín - Cancer Center Clínica Universidad de Navarra, Madrid, Spain

The PRIMA study was designed just to test if the addition of niraparib as maintenance therapy for high-grade serous or endometrial  advanced ovarian cancer that has responded to first-line platinum-based chemotherapy could improve the outcomes of the patients. The primary endpoint was progression free survival and it was tested hierarchically, first in the HRD population, then in the overall population. The overall survival was a key secondary endpoint that was evaluated when 60% of the events were reached.

I would like to highlight that the population included in PRIMA was a population of high risk from the clinical perspective to have a relapse. But we have presented the long-term progression free survival in this meeting with a median follow-up of 6.2 years and we have shown that the rate of patients without progression and alive at five years is 35% in the HRD group compared with 15% in the same group that received placebo. So there is a difference of 20% in favour of niraparib. The hazard ratio is maintained from the primary analysis and the curves remain separated which means that the effect of niraparib in the HRD population remains and is sustained along the follow-up of the study.

For the overall population we have the same findings. That’s important because at least twice the patients that received niraparib compared to those with placebo were progression free at five years.

In addition to that, we have provided also the data of the overall survival. The analysis was done first in the overall population and we have observed a hazard ratio of 1.01 which means that we haven’t observed any benefit in the overall survival in the long-term for the overall population. Therefore we didn’t proceed to the hierarchical analysis but we have done a descriptive analysis of the overall survival according to the molecular classification. What we have seen is that the results are consistent with the overall population so no benefit in overall survival in the HRD and HR proficient population.

What is intriguing and is really unexpected is the high rate of overall survival at five years in the population included in the PRIMA study, both in the experimental and in the control arm. Not only in the overall population but also in the HRD population and the HRP population. So that overall survival was globally higher than expected.

One of the potential explanations for this absence of difference in overall survival with a clear impact in progression free survival could be the baseline patient characteristics, could be the long median post-progression survival that we have observed. Because, for instance, in the HRD population the median post-progression survival was five years in the patients that were treated in the placebo arm. We know that a long post-progression survival lowers the probability of impacting overall survival.

Finally, a third factor could be the subsequent therapy. We have analysed what are the further anti-cancer systemic therapies that the patients have received in the PRIMA study. We realised that the patients in the placebo arm received threefold higher times the PARP inhibitors at relapse compared with the patients that were treated with niraparib. So what I mean is that there was a high rate of crossover that was most significant in the HRD population. Almost half of the patients in the placebo arm received PARP inhibitor at progression. When we see this specific group of patients with BRCA mutations it was almost 60% of the patients. So it is the vast majority.

The final comment before coming to the summary is that the long-term safety profile is consistent with the well-known safety profile of niraparib. There are no new safety issues. The individualised starting dose reduced the haematological toxicity and the rate of MDS and AML remains very low – 2.3% with niraparib, 1.6% with placebo.

So taking together all these data have informed us that the use of niraparib as maintenance therapy in the front line impacts significantly the progression free survival and that that benefit is sustained along the follow-up of the study. There is no difference in overall survival but with that long post-progression free survival and that rate of crossover we cannot expect sometimes that impact in overall survival. Finally, the long-term safety remains as well known.

So we can conclude that niraparib remains one of the standard options as maintenance therapy for patients in first-line advanced ovarian cancer that have responded to platinum-based therapy. Thank you very much.