Individualized Dosing Regimen Reduces Side Effects in Ovarian Cancer Maintenance Therapy

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Side effects decreased among patients with high-risk ovarian cancer who received an individualized starting dose of Zejula (niraparib), based upon baseline bodyweight and platelet counts, compared with a fixed starting dose.

“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, M.D., 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 at Arizona Oncology, said during his presentation at the 50th SGO Annual Meeting, held March 16-19 in Honolulu, Hawaii.

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 that 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 and 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.”

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

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

Of note, there was approximate 80 percent reduction in grade 4 thrombocytopenia (3.6 percent vs. 16.8 percent) with the individualized dosing. With this, Monk added it was important for the researchers to track patients’ 10,000 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 percent to 2.4 percent.”

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

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

He also 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.”