Most patients with advanced ovarian cancer relapse after initial platinum-based therapy. The standard of care for patients with platinum-sensitive relapse is platinum-based therapy, followed by maintenance with targeted therapy in responding patients. Poly(ADP-ribose) polymerase (PARP) inhibitors are considered as the most active targeted therapies in ovarian cancer. While their greatest activity was demonstrated in patients harboring BRCA mutations, recent data indicate they are effective regardless of BRCA mutation status. The PARP inhibitors olaparib and niraparib both showed significant improvement of progression-free survival (PFS) as maintenance therapy for patients responding to platinum therapy regardless of BRCA status, and are approved for this indication. Rucaparib is the third PARP inhibitor available in the United States for patients with germline and/or somatic BRCA mutations who previously received two or more chemotherapies. However, results from the phase II ARIEL2 trial indicate that rucaparib is also effective in BRCA wild-type ovarian cancer with high genomic loss of heterozygosity (LOH), which is a potential biomarker of homologous recombination deficiency (HRD).
The randomized, double-blind, placebo-controlled phase III ARIEL3 trial (N = 564) examined the safety and efficacy of rucaparib (600 mg orally twice daily) as maintenance therapy following response to platinum-based chemotherapy in patients with recurrent, platinum-sensitive, high-grade ovarian cancer regardless of BRCA mutation status. The primary endpoint was investigator-assessed PFS in three cohorts: patients with BRCA mutations, patients with HRD with or without BRCA mutations, and the intention-to-treat (ITT) population.
Rucaparib maintenance significantly prolonged PFS compared to placebo in all cohorts of patients. Best responses were seen in patients with BRCA mutations, where rucaparib was associated with a median PFS of 16.6 months, compared to 5.4 months with placebo (HR 0.23; P<.0001). In patients with HRD, rucaparib resulted in an 8.2-month improvement in PFS over placebo (13.6 months vs 5.4 months; HR 0.32, P<.0001). In the entire ITT population, including patients without BRCA mutations or HRD, rucaparib maintenance doubled PFS compared to placebo (10.8 months vs 5.4 months; HR .36, P<.0001). Patients who were BRCA wild-type with high LOH at baseline achieved a median PFS of 9.7 months with rucaparib versus 5.4 months with placebo (HR 0.44, P<.0001), while low LOH was associated with a smaller benefit (6.7 months vs 5.4 months; HR 0.58, P = .0049).
Importantly, rucaparib was able to improve responses to platinum-based chemotherapy even in patients with measurable residual disease greater than 2 cm following chemotherapy. In patients with BRCA mutations, 15 of 40 patients (38%) with measurable residual disease treated with rucaparib achieved a confirmed response, compared with only 2 of 23 in the placebo group (9%). Similar results were seen in patients with HRD carcinoma (27% vs 7% achieved objective response). Overall survival (OS) data and patient-reported outcomes are not yet available and will be reported separately.
Adverse events (AEs) associated with rucaparib were generally mild and manageable. More patients treated with rucaparib experienced grade 3 or higher treatment-related AEs than with placebo (56% vs 15%). The most common grade 3 rucaparib-associated AEs were anemia (19%) and increased alanine or aspartate aminotransferase concentration (10%).
In a commentary accompanying this study, the authors indicated that these results add to the body of evidence that PARP inhibitors are effective in recurrent ovarian cancer regardless of BRCA mutation status, and that a PARP inhibitor as maintenance therapy should now be considered standard of care for women with recurrent, platinum-sensitive ovarian cancer. Studies investigating the potential for PARP inhibitors in the first-line setting are currently ongoing.