PFS Increased With Niraparib Without Symptoms or Toxicity in Ovarian Cancer

Ursula A. Matulonis, MD

Treatment with maintenance niraparib (Zejula) led to extended progression-free survival (PFS) time in patients with recurrent ovarian cancer without the patients experiencing symptoms or toxicity compared with placebo, according to results of an analysis from the phase III ENGOT-OV16/NOVA trial. In patients with germline (g) BRCA-mutated disease, the benefit was increased 4-fold and in patients non—gBRCA-mutated ovarian cancer the benefit was increased 2-fold.

Treatment with niraparib compared with placebo in the gBRCA-mutated and non—gBRCA-mutated cohorts of the study resulted in a mean time without symptoms or toxicity (TWiST) benefit of 2.95 and 1.34 years, respectively.¹

In particular, treatment with niraparib resulted in a mean progression-free survival (PFS) benefit of 3.23 years and a mean toxicity time of 0.28 years compared with placebo in gBRCA-mutated patients, and a mean PFS benefit of 1.44 years and a mean toxicity time of 0.11 years in non—gBRCA-mutated patients.

When using alternative survival models to estimate PFS, the mean TWiST benefit of niraparib compared with placebo was 1.62, 1.64, 2.66, and 3.65 years, and 0.63, 0.73, 1.23, and 0.94 years using the lognormal, log-logistic, normal k = 1, and odds k = 3 distributions in the gBRCA-mutated and non—gBRCA-mutated cohorts, respectively.

“This TWiST analysis benefit means that patients treated with niraparib experienced more progression-free time without symptoms or toxicities due to nausea, vomiting, or fatigue compared to placebo,” Ursula A. Matulonis, MD, director and chief of gynecologic oncology at Dana-Farber Cancer Institute, said during her presentation at the 50th SGO Annual Meeting, held March 16-19 in Honolulu, Hawaii.

In the multicenter, double-blind, randomized-controlled trial, patients with recurrent ovarian cancer who were in response to their last platinum-based chemotherapy were randomly assigned 2:1 to receive either 300 mg of niraparib once daily as a maintenance treatment (gBRCA-mutated, n = 138; non—gBRCA-mutated, n = 234) or placebo (gBRCA-mutated, n = 65; non—gBRCA-mutated, n = 116).^2-3The researchers aimed to assess whether the benefits of extending PFS are offset by treatment-associated toxic effects that affect quality of life (QoL). The primary endpoint was PFS.

Patients had to have histologically diagnosed high-grade serous or high-grade endometroid cancer, at least 2 prior lines of platinum-based chemotherapy, and be platinum-sensitive to their penultimate platinum therapy.

Treatment with maintenance niraparib significantly delayed disease progression compared to placebo, with a median PFS of 21.0 vs 5.5 months (HR, 0.27; 95% CI, 0.17-0.41), respectively, in the gBRCA-mutated group and 9.3 vs 3.9 months in the non—gBRCA-mutated group (HR, 0.45; 95% CI, 0.34-0.61).

Quality of life remained stable through niraparib treatment and the pre-progression period compared with placebo.

In this portion of the trial, the researchers evaluated time without a certain level of 3 main symptoms: fatigue, nausea, and vomiting. Mean TWiST was calculated by subtracting mean toxicity from mean PFS to partition PFS into 2 health states: time with toxicity and time without symptoms or toxicity.

“In this analysis, there were 2 steps. The PFS was extrapolated over 20 years. Survival curves were used to extrapolate PFS of the NOVA data for niraparib versus placebo,” explained Matulonis. “The 20-year period was based on ovarian cancer clinical expert opinion and the biologic plausibility that a patient could be on PARP inhibitors for a long period of time. This approach has also been accepted by the [National Institute for Health and Care Excellence] as well as the Scottish medical authorities.

“The second step was to estimate the time with toxicity from the number of days patients experienced toxic effects due to grade 2 or higher nausea, vomiting, and fatigue in the NOVA trial. Adverse events were included post-randomization and prior to disease progression. Using these toxicity data, Kaplan-Meier curves were estimated for both the gBRCA-mutated and the non—gBRCA-mutated cohorts.”

References

1. 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.
2. Mirza MR, Monk BJ, Herrstedt J, et al; ENGOT-OV16/NOVA Investigators. Niraparib maintenance therapy in platinum-sensitive, recurrent ovarian cancer.N Engl J Med.2016;375(22):2154-2164. doi: 10.1056/NEJMoa1611310.
3. Oza AM, Matulonis UA, Malander S, et al. Quality of life in patients with recurrent ovarian cancer treated with niraparib versus placebo (ENGOT-OV16/NOVA): results from a double-blind, phase 3, randomised controlled trial.Lancet Oncol.2018;19(8):1117-1125. doi: 10.1016/S1470-2045(18)30333-4.