Individualized Dosing Reduces Niraparib-Related TEAEs in Ovarian Cancer Maintenance

Bradley Monk, MD, FACOG, FACS

Adverse events (AEs) decreased among patients with high-risk ovarian cancer who received a 200- or 300-mg individualized starting dose of niraparib (Zejula), based upon baseline bodyweight and platelet count, compared with a 300-mg fixed starting dose, according to a recent analysis of the ongoing ENGOT-OV26/PRIMA study.¹

“The current analysis confirmed that a proactive approach to dosing using personalized data can get to the same point as if you do a reactive dosing convention as a result of toxicity,” Bradley Monk, MD, FACOG, FACS, professor and director of the Division of Gynecologic Oncology at Creighton University School of Medicine at St. Joseph's Hospital and Medical Center, Arizona Oncology, said during his presentation at the 2019 SGO Annual Meeting.

Treatment-emergent adverse events (TEAEs) decreased among any TEAE (92.7% vs 97.5%, respectively), those leading to treatment interruption (50.6% vs 60.3%), any grade 3 TEAE (42.5% vs 55.5%), those leading to dose reduction (39.7% vs 51.6%), and any serious AE (21.5% vs 26.6%) with the individualized dosing, compared with fixed dosing. However, TEAEs leading to end of treatment was higher among those treated with the individualized approach (10.5% vs 7.5%).

Similarly, grade 3 or higher hematologic toxicities decreased with individualized dosing, including an approximate 60% decrease in thrombocytopenia (9.7% vs 23.5%, respectively) and an approximate 40% decrease in neutropenia (6.1% vs 10.0%), compared with the fixed dose. In addition, grade 3 or higher anemia decreased to 13.8% among those treated with the individualized approached versus 22.7% in the fixed dosing arm.

Of note, there was an approximate 80% reduction in grade 4 thrombocytopenia (3.6% vs 16.8%) with the individualized dosing. With this, Monk added it was important for the researchers to track patients’ 10,000/μL platelet count threshold, “because that is generally the trigger for transfusions. You can see there is an important reduction in thrombocytopenia. In fact, we took a double-digit transfusion rate to a single digit from 11% to 2.4%.”

Lastly, symptomatic TEAEs decreased with the individualized dosing regimen, including nausea (40.5% vs 48.6%), fatigue (30.0% vs 31.4%), insomnia (16.2% vs 21.8%), vomiting (14.2% vs 19.5%), and hypertension (10.1% vs 12.3%) of any grade.

“This collaboration continues to be ongoing but is unique,” Monk said.

The researchers were prompted to conduct this study as a result of findings from the the pivotal phase III ENGOT-OV16/NOVA trial of niraparib²—a selective inhibitor of PARP1/2 approved by the FDA for maintenance treatment of patients with recurrent ovarian cancer who are in complete or partial response to platinum therapy regardless of BRCA or homologous recombination deficiency status.

In the NOVA trial, AE-related dose adjustments occurred in 69% of patients and tended to occur early, with most reaching their individualized dose within 3 months. A retrospective analysis of the study showed that patients with body weight <77 kg or platelet count <150,000/μL were more likely to be dose-reduced due to hematologic AEs. However, those patients who were dose-reduced appeared not to have a detriment in their clinical outcome, Monk explained.

Therefore, based on data from the NOVA trial, the researchers amended their double-blind, randomized, placebo-controlled phase III study—designed to evaluate the efficacy and safety of niraparib maintenance therapy in 728 patients with ovarian cancer following a response to frontline platinum-based chemotherapy who are considered at high risk for progressive disease. Progression-free survival by blinded independent central review serves as the primary endpoint in the ongoing trial.

“(We took) a more reactive approach to dosing based on toxicity, where two-thirds of the patients get treated with 200 mg versus a proactive dose based on baseline weight and platelet count getting to the same place where two-thirds of the patients get treated with 200 mg,” Monk said. “So, if a patient was greater than 77 kg or had a baseline platelet count greater than 150,000/μL they would start at 300 mg, but if they were underweight or had a low baseline platelet count, they were begun at 200 mg.”

Monk highlighted that the PRIMA study is different from the NOVA trial in 3 key ways: “First, it enrolled all comers, that is important because that may increase the availability of PARP inhibition in frontline maintenance. Second, it’s a much larger study. And third, compared to the recently listed FDA-approved BRCA-mutated cohort, it enrolls higher-risk patients, perhaps addressing the need for a greater unmet medical need.”

References

1. Monk BJ, Mirza MR, Vergote I, et al. A prospective evaluation of tolerability of niraparib dosing based upon baseline body weight and platelet count: Blinded pooled interim safety data from the ENGOT-OV26/PRIMA study. Presented at: 2019 SGO Annual Meeting. March 16-19, 2019; Honolulu, HI. Abstract 3.
2. Mirza MR, Monk BJ, Herrstedt J, et al. Niraparib Maintenance Therapy in Platinum-Sensitive, Recurrent Ovarian Cancer. N Engl J Med 2016;375:2154-2164. doi: 10.1056/NEJMoa1611310.

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