Drugs Xagena
Some 90% of ovarian cancer are of epithelial cell type: among them, 75% of cases are represented by the high-grade serous ovarian cancer (HG-SOC) and the remaining 10% are non-epithelial ovarian cancer, which include mainly germ cell tumors, sex cord-stromal tumors, and extremely rare tumors such as small cell carcinomas. Some 57% of ovarian cancer cases are diagnosed as metastatic, with poor 5-year survival rates (median 30.8%). Indeed, ovarian cancer bears the highest mortality rate among gynecological tumors, with 5.4 deaths/100,000 inhabitants/year.
Type I epithelial ovarian cancer is suggested to be a relatively indolent and genetically stable group of tumors that typically arise from recognizable precursor lesions, such as endometriosis or borderline tumors with low malignant potential.
In contrast, type II epithelial ovarian cancer includes a more biologically aggressive group of tumors from the outset, with a propensity for metastasis even from small primary lesions: these include high-grade serous ovarian cancer.
The first-choice treatments for advanced ovarian cancer are Platinum-based regimens, but after initial benefits, two out of three patients relapse mainly within the first two years.
Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) are a class of antitumor agents whose mechanism of action relies on the exploitation of the defective DNA repair pathways in homologous recombination repair (HRR) gene deficient cells, a group of genes, including also breast cancer (BRCA)-1 and BRCA2, crucial for double-stranded breaks (DSBs) and interstrand crosslinks (ICLs) repairing pathways, whose mutations cause defective DNA repair, and finally lead to apoptosis. When lacking HRR function, double-stranded breaks will be processed by alternative but more error-prone repair pathways, such as the non-homologous end-joining repair (NHEJ), which impairs cell survival and induces apoptosis. Of note, 50% of ovarian cancers carry HRR deficiency (HRD), with 22% of cases bearing a germline or somatic mutation of BRCA1 and BRCA2, thus indicating the use of PARP inhibitors as a possible target therapy.
PARP inhibitors are approved as maintenance after a Platinum-based chemotherapeutic regimen. However, in first line patients, the approval of Olaparib only for BRCA mutant patients as monotherapy, or HRD in association with Bevacizumab, left an unmet need regarding the usefulness of PARP inhibitors for managing patients without genetic alterations.
PARP inhibitors are reshaping the ovarian cancer therapeutic scenario.
The phase III PRIME trial has demonstrated the efficacy of Niraparib versus placebo in newly diagnosed chinese ovarian cancer patients after first-line chemotherapy, including those who were resected at primary debulking surgery with an individualized starting dose of 300 mg once daily (OD), reduced to 200 mg once daily in case of body weight less than or equal to 77 kg and/or platelet count less than or equal to 150,000/μL. A total of 384 patients were randomized and, after a median follow-up of 27.5 months, median progression-free survival (mPFS) was 24.8 vs 8.3 months (HR 0.45, 95% CI 0.34–0.60; p less than 0.001). The study has enlarged the audience of candidates of Niraparib, as it includes some categories originally excluded from the PRIMA, such as the resected stage III.
Despite a slightly higher incidence of haematologic and cardiovascular toxicities compared to other PARP inhibitors, Niraparib maintains a generally good safety profile and quality of life. A peculiar advantage of Niraparib, compared with other PARP inhibitors such as Olaparib, is the single daily dosage, with the possibility of dose personalization based on patients’ clinical and laboratory characteristics, and limited pharmacological interactions.
Maiorano MFP et al, Pharmaceuticals (Basel) 2023;16(9):1261
XagenaMedicine_2023
