Niraparib Maintenance Improves Survival in BRCA Wild-Type Ovarian Cancer

Robert L. Coleman, MD, FACOG, FACS

Improvements in overall survival (OS) were observed among patients in a BRCA gene wild-type (BRCAwt) population with recurrent ovarian cancer treated in the second-line with maintenance therapy of niraparib (Zejula), according to data from a real-world study.

The trial evaluated second-line maintenance niraparib vs active surveillance for the treatment of this patient population, and showed that ata median follow-up of 16.8 months (range, 10.4-28.7) for niraparib and 10.2 months (range, 4.1-23.7), for active surveillance, respectively, second-line niraparib monotherapy elicited a median OS of 28.12 months (95% CI, 22.54-43.24), vs 21.45 months (95% CI, 14.72-27.04) with active surveillance (HR, 0.63; 95% CI, 0.45-0.88).

At 24 months, the OS rates were also improved with niraparib maintenance at 58.2% (95% CI, 47.5%-67.6%) compared with 46.1% (95% CI, 33.6%-57.7%), respectively.

This trial had enrolled a similar patient population to the NOVA trial (NCT01847274) but included an older and more diverse population than NOVA. Overall, informative data on OS outcomes in a BRCA gene wild-type population with recurrent ovarian cancer were demonstrated, showing the benefit of second-line maintenance therapy with niraparib.

“Our hope is that as real-world evidence emerges, like a trial like this, we can provide better confidence to the safety of using therapy like this, which for me, could be a large cohort of patients that did not receive a PARP inhibitor in the frontline setting,” Robert L. Coleman, MD, FACOG, FACS, told Targeted Oncology^TM, in an interview.

In the interview, Coleman, gynecologic oncologist with Texas Oncology, a practice in The US Oncology Network, and Co-Director of the Gynecologic Oncology Group (GOG) Partners Foundation, discussed the real-world findings from this trial evaluating second-line maintenance niraparib in patients with recurrent ovarian cancer.

Targeted Oncology: Can you provide a recap of the results from NOVA and the impact of niraparib since being approved in 2020?

Coleman: NOVA was initiated as a trial around the time that we were learning more about PARP inhibitors as treatment in patients who had biomarker annotated ovarian cancer. What I mean by that are tumors that we knew carried either a BRCA mutation or had a homologous recombination deficiency [HRD] test-positive signature. We soon had some phenomenal success using PARP inhibitors across the board as treatment.

The next kind of iteration for this was to look at it to prevent recurrence or treating patients who had a good response to platinum, and then went on to an additional line of therapy. In the recurrent settings, such as the platinum-sensitive recurrent setting, many patients have very high response rates to platinum-based combination strategies, but we knew that many of those patients had only partial responses. There were some patients that were left with residual disease after the completion of treatment. The concept of maintenance became popular to look at in the recurrent disease setting. Knowing that we could already shrink tumors that were being used or being treated with the PARP inhibitors made it a nice mix for providing a strategy where patients were either placed on placebo or a PARP inhibitor. In this case, it was niraparib.

The trial itself was set up in 2 kinds of protocols put in 1. One of the trials was focused on the germline BRCA mutation-positive population, and these were patients who had recurrent platinum-sensitive ovarian cancer who had had response to platinum but carried a germline mutation in BRCA1 and BRCA2. The other kind of component of this were patients who were not defined by a mutation, but tumors that could have had a BRCA mutation had a HRD test-positive signature, or were wild-type for those 2 features. The second part of the NOVA trial was looking at all the non-germline patients for the prevention or the probability for progression or death. Those were the primary end points of the trial since the trial was published. Obviously, it entered quickly into the space of gaining FDA approval, but there were post marketing commitments by all the companies making PARP inhibitors for the evaluation of PARP efficacy in other specific clinical situations. While this drug then became immediately available to us for the use of patients who have had a response to platinum reduction therapy as a maintenance strategy irrespective of their mutational profile, data gathered afterwards led to some concern about the use of PARP inhibitors as a strategy in this setting because of the potential for reduction of efficacy in the next-line therapy. Recently, there has been a retraction on the indications that were initially granted for niraparib where it was limited to the first part of NOVA, which was the germline BRCA mutation population.

Can you discuss some background of the real-world study data evaluating second-line maintenance niraparib?

One of the strategies that we've been very interested in looking at is therapies like niraparib as a maintenance treatment in patients with recurrent ovarian cancer performed in the wild. The clinical trial situation is a pretty constricted population that was defined by the eligibility and exclusion criteria for the clinical trial. In some sense, we purposefully try to make a treated population homogeneous so that we can interpret the results that potentially would be devoid of other confounding variables. That's very important in conducting a randomized trial. But in the real-world, things happen for all different kinds of reasons, and patients are not always even eligible for clinical trials, but are found to have good responses, for instance, to chemotherapy, and might be good candidates for a treatment like this. We're always wanting to validate that what we saw in the clinical trial is observed in a real-world population of patients that don't have such a narrow lane on who can enter and participate in a clinical trial. This study was set up to assess that experience. Patients were classified and identified from usage across multiple different practices, but with the intent of trying to evaluate whether patients who are placed on niraparib for second-line maintenance therapy were performing like we expected to see in the clinical trial.

What were the outcomes of the study?

The primary outcome that we were interested in was overall survival. As mentioned in the previous trial, NOVA, we were looking at those particular variables, but mostly on more proximal end points, such as progression-free survival. Because there was concern raised by the use of PARP inhibitors in this line of setting that could diminish the potential efficacy of long-term outcomes in these patients, we wanted to see whether or not in the real-world we would see the same type of effect.

What we found by doing a sophisticated way of trying to eliminate some confounding variables that might enter into this kind of study, we looked at overall survival as our primary end point, and then were able to show that in patients who had originally undergone a platinum-based induction therapy with a niraparib-based maintenance therapy, that in the long-term outcomes, this benefit that we saw in the short-term was still preserved. We showed that the hazard ratio for death in this trial was reduced by a little over 20%, around 23%, suggesting that there was a 23% reduction in the probability or hazard for death in patients who were placed on niraparib at time of their platinum-sensitive recurrent regimen. That was preserved through the next multiple lines of therapy for patients after they went on treatment.

Again, it shows a robust effect. It also brings into question that when we start a trial that has a proximal end point, like progression-free survival or objective response, and we look for long-term outcomes after that where we really don't have control of what patients get exposed to, that when we draw a conclusion from that, it does raise the question that we could potentially be interpreting that data wrong. This trial was looking at this distant end point, which was found to be adversarial in our NOVA trial. Initial results ultimately led to FDA concern that was not seen when we looked at this in the real-world through our real-world evidence trial balancing against confounding prognostic factors through our individualized probability weighted cohort. I think if anything, it gives us some level of comfort that if we treat these patients, we don't have to have concern as a group for long-term outcomes. But it also raises into question how we can potentially over interpret data from clinical trials that can't be controlled well for confounding variables.

Moving forward, how well do you think this research will influence space?

Ultimately, this space is going to be defined by the regulatory action that's taken on it. Currently, our regulatory action that was taken on NOVA was to retract the labels for PARP as a maintenance and treatment except for the cohort patient with the germline BRCA mutation. Our hope is that as real-world evidence emerges, like a trial like this, we can provide better confidence to the safety of using therapy like this, which for me, could be a large cohort of patients that did not receive a PARP inhibitor in the frontline setting. It does also provide a little bit of a window into how we would approach the oncoming trials that are going to help us redefine PARP inhibitors in the frontline setting, because many of those patients will ultimately recur, and they will have had an exposure to a PARP inhibitor.

The question is, in the second-line setting in a patient population that has received a PARP inhibitor before, is that going to change the efficacy and the potential long-term outcomes if they were to get it again? We don't have any great data for that, but we have some small inferences that we can make. There's also some interesting data that was presented at ASCO this year, that suggested that, at least in the PAOLA-1 trial [NCT02477644] which was bevacizumab [Avastin] and olaparib [Lynparza] combination vs bevacizumab, that in that cohort of patients who did not progress on a PARP inhibitor, that they did not see a penalty for that if they received it. In their subsequent lines of treatment. Although it doesn't directly address the question, it does provide us some opportunity to start reimagining how we use purple rivers in the recurrent space, and ultimately how to use our real-world evidence to provide confidence that it's safe to do so.

What other trials or recent research has caught your attention?

ASCO provides a nice exchange of information, and 1 of the things that we learned [this year] was to interrogate this idea of a PARP patient who progresses on PARP. It is important because not only does it provide inference on how we might look at PARP inhibitors after platinum induction in the recurrent setting, but it also gives us a little bit of better characterization of those patients that do progress in the frontline setting for whom we have to devise a treatment approach. In that way, we can look at the patients who, for instance, progress on a PARP inhibitor as a particularly resistant cohort of tumors that need maybe a new approach, even if they qualify for a platinum in that setting, because they have a long treatment interval. If they progress while they're taking their PARP inhibitor, they are probably not going to respond very well to additional platinum-based therapy. Maybe that's the opportunity to investigate different types of therapy in that space. We're starting to think about how we could devise a regulatory strategy around that cohort of patients that progressed in the frontline setting.

Another fascinating component is the MIRASOL trial [NCT04209855], which brings mirvetuximab soravtansine-gynx as an antibody-drug conjugate [ADC] into this space. But also, the ADC class overall. Not only the folate receptor alpha ADC, but also those that are targeting important proteins that we kind of abandoned, such as HER2 in ovarian cancer because it is so uncommonly amplified. With this new kind of catchment of ADCs, we're seeing impressive responses. Of course, it is a small sample size, but impressive responses in patients that don't carry amplified HER2-ovarian cancer. This is kind of opening the door for re-exploring a number of new ADCs as they enter the space. Hopefully future [meetings] will provide new opportunities for us to hopefully bring these medications to our patients.

REFERENCE:

1. Coleman RL, Perhanidis J, Kalilani L, Zimmerman NM, Golembesky A, Moore KN. Real-world overall survival in second-line maintenance niraparib monotherapy vs active surveillance in BRCA wild-type patients with recurrent ovarian cancer. J Clin Oncol. 2023;41(16):5592-5592. doi:.10.1200/JCO.2023.41.16_suppl.5592.