Niraparib Prolongs Progression-Free Survival Without Toxicity in Ovarian Cancer

Ursula A. Matulonis, MD

Patients with recurrent ovarian cancer who were in response to their most recent platinum-based chemotherapy were randomly assigned to niraparib or placebo in the phase III ENGOT/OV16/NOVA study, which demonstrated an improved progression-free survival (PFS) among patients who received the PARP inhibitor. A time without symptoms or toxicity (TWiST) analysis also demonstrated that these patients received a 4-fold benefit of PFS without experiencing symptoms or toxicity compared with placebo.

This analysis also evaluated the outcomes of patients with either germline BRCA-positive disease and non-germline BRCA-positive disease. The mean TWiST benefit among patients in the germline BRCA-positive arm was 2.95 years versus 1.34 years in the non-germline BRCA-positive arm. The average PFS benefit from niraparib was 3.23 years with a mean toxicity time of 0.28 years in the germline BRCA-positive arm compared with 1.44 years and 0.11 years in the non-germline BRCA-positive arm, respectively.

Overall, niraparib has shown promising outcomes for patients with ovarian cancer. More recently, the phase III PRIMA study, which evaluated the PARP inhibitor in this patient population, led to the FDA’s approvalof the agent as first-line maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to frontline platinum-based chemotherapy.

In an interview with Targeted Oncology, Ursula A. Matulonis, MD, director, Gynecologic Oncology, Dana-Farber Cancer Institute, professor of medicine, Harvard Medical School, discussed the findings from a TWiST analysis of the ENGOT-OV16/NOVA study, which evaluated the time without symptoms or toxicities in patients with recurrent ovarian cancer who received niraparib as maintenance.

TARGETED ONCOLOGY: What was the basis for conducting the TWisT study of niraparib in patients with recurrent ovarian cancer?

Matulonis: The NOVA study was published in the New England Journal of Medicine in 2016, and this was a trial of several hundred women who had high-grade serous ovarian cancer, platinum-sensitive, were in response to platinum, and also had platinum sensitivity to their penultimate platinum. At the completion of platinum-based chemotherapy, they were randomized 2:1 to either niraparib versus placebo. There were 2 prespecified groups: germline BRCA-positivity, and non-germline BRCA-positivity. These 2 groups were enrolled simultaneously and analyzed also at the same time. We saw in the all 3 prespecified analysis groups, so germline BRCA-positivity, non-germline BRCA-positivity, and HRD-positive non-BRCA-mutated, niraparib showed improvement in PFS compared to placebo with the strongest results being in the germline BRCA-positive group.

TARGETED ONCOLOGY: Can you provide background on the TWisT analysis?

Matulonis: What the TWiST analysis did was look at specific toxicities and try to understand how those toxicities are being thought of in combination with PFS. TWiST is Time Without Symptoms of Progression and Toxicities. Women have to be progression-free, meaning they are theoretically enjoying time without evidence of cancer and also trying to determine their time without toxicities. The toxicities we looked at, which is a typical TWiST analysis, were nausea, vomiting, and fatigue. It had to be grade 2 or higher, and we looked at the germline BRCA group and the non-germline BRCA group. For the germline-BRCA group, there was a 4-fold improvement in TWiST compared to placebo. In the non-germline BRCA group, it was about a 2-fold improvement in TWiST. That shows for at least those toxicities measured of that particular grade, women were hopefully enjoying time without progression but also having time without toxicities.

As part of this analysis, we looked at a 20-year analysis, so we examined the use of PARP inhibitor or placebo over 20 years, which seems like a long-time, but this analysis has been justified by the English and Scottish equivalent of the FDA. Theoretically, it is also biologically plausible that women will be on PARP inhibitors for a long period of time. However, we also looked at shorter time points, so 5 and 10 years, and we saw proportional benefits of TWiST in patients receiving niraparib versus placebo. Even when looking at shorter times, we still see the same magnitude of benefit.

TARGETED ONCOLOGY: What are the current safety issues with niraparib compared with the other PARP inhibitors?

Matulonis: There are toxicities that we see with all PARP inhibitors, and those are gastrointestinal (GI) side effects, hematologic toxicities, fatigue, and then there are toxicities that may be specific to certain medications. For example, hematologic toxicities include drop in white blood cell count, drop in neutrophil count, drop in platelets, and anemia. PARP inhibitors all have those toxicities. Niraparib, with that non-platelet dosing, has about a 33% rate of grade 3 or higher thrombocytopenia, but when you do individualized dosing, that thrombocytopenia risk grade 3/4 drops significantly. It is much more comparable with the other 2 PARP inhibitors.

The GI toxicities include nausea, vomiting, upset stomach, diarrhea, constipation, and these can be problematic. They are more often grade 1/2, but even grade 2 toxicities can affect women. We manage that with anti-nausea medications prophylactically. Those side effects interestingly tend to dissipate over time. Fatigue is a problem, but there are also some more side effects that are unique to the different PARP inhibitors. For example, we see elevation of liver enzymes with rucaparib, but that can sometimes be seen with niraparib as well.

Niraparib can be associated with hypertension, so it is important to monitor the patient’s blood pressure with that. Rucaparib can lead to an increase in cholesterol values. Olaparib can lead to lung problems, such as pneumonitis, so that has to be watched out for if a patient begins to complain of shortness of breath.

_Reference

_{Matulonis UA, Walder L, Nøttrup TJ, et al. Time without symptoms or toxicity in patients with recurrent ovarian cancer receiving niraparib maintenance treatment versus placebo: A TWIST analysis of the ENGOT-OV16/NOVA trial. Presented at: 2019 SGO Annual Meeting. March 16-19, 2019; Honolulu, HI. Abstract 1.}