Niraparib in Patients With Newly Diagnosed Advanced Ovarian Cancer

Resumen:
The standard treatment for newly diagnosed advanced epithelial ovarian cancer involves cytoreductive surgery and platinum- taxane combination chemotherapy. Unfortunately, recurrence occurs in up to 85% of patients after completing this chemotherapy regimen. Approximately 15% to 20% of ovarian cancer cases involve a mutation in a BRCA gene. Inhibitors of poly(adenosine-diphosphate-ribose) (PARP) have shown significant increases in progression-free survival (PFS) among patients with BRCA mutations after response to first-line platinum-based chemotherapy. Niraparib, a selective PARP1 and PARP2 inhibitor, has demonstrated an increase in PFS among patients with and without BRCA mutated ovarian cancer, leading to its approval in patients with recurrent ovarian cancer who experienced a response to platinum-based chemotherapy. This randomized, double-blind, placebo-controlled, phase 3 trial (PRIMAtrial) aimed to examine the safety and efficacy of niraparib maintenance therapy in patients with newly diagnosed, platinum-sensitive, advanced ovarian cancer at high risk of relapse. This trial was conducted in 2 countries at 181 clinical sites. Patients were randomized in a 2:1 ratio to receive niraparib or placebo once daily for 3 years or until disease progression as demonstrated on computed tomography or magnetic resonance imaging performed every 12 weeks. Eligible subjects had newly diagnosed ovarian cancer classified as stage III or IV with previous partial or complete response to at least 6 cycles of first-line platinum-based chemotherapy. Tumor samples underwent homologous-recombinant deficiency (HRD) testing, where a deficiency was defined as either presence of a BRCA deleterious mutation or a score greater than 42 on the my-Choice test. The primary endpoint evaluated was PFS defined as time from randomization after completion of platinum-based chemotherapy to date of objective disease progression or death. A total of 733 subjects underwent randomization between July 2016 and June 2018. Of the cohort, 373 (50.9%) tested positive for HRD on my-Choice; of these 373, 223 had tumors with BRCA mutations, and 150 had no BRCA mutation. The median duration of PFS in the HRD group was 21.9 and 10.4 months for the niraparib and placebo groups, respectively (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.31-0.59; P < 0.001). In the total cohort, the median duration of PFS was 13.8 and 8.2 months for the niraparib and placebo groups, respectively (HR, 0.62; 95% CI, 0.50-0.76; P < 0.001). Secondary endpoint analysis found the probability of survival at 24 months in the total cohort to be 84% in the niraparib group and 77% in the placebo group (HR, 0.70; 95% CI, 0.44-1.11). When restricted to the HRD group, survival was estimated at 91% in the niraparib group and 85% in the placebo group (HR, 0.61; 95% CI, 0.27-1.39). The most common grade 3 or higher adverse events in the niraparib group were anemia (31.0%), thrombocytopenia (28.7%), and neutropenia (12.8%). Dose reduction occurred in 70.9% of patients in the niraparib group. The results of the PRIMA trial show a significantly increased period of PFS in patients with newly diagnosed platinum-sensitive advanced ovarian cancer receiving niraparib compared with placebo especially in patients with BRCA mutations and HRD.