Rucaparib trumps chemo in relapsed, advanced BRCA+ ovarian cancer

The PARP inhibitor rucaparib significantly improves progression-free survival (PFS) in patients with recurrent, advanced BRCA-positive ovarian cancer compared with standard-of-care chemotherapy, according to the ARIEL4 study presented at the SGO 2021 Meeting.

The primary endpoint of PFS was significantly longer in patients treated with rucaparib than with standard chemotherapy (median, 7.4 vs 5.7 months; p=0.001) in the intention-to-treat (ITT) population — corresponding to a 36 percent reduction in risk of disease progression or death (hazard ratio [HR], 0.67; p=0.002). [SGO 2021, abstract 11479]

The findings remained in the efficacy population, which excluded patients with BRCA reversion mutations (HR, 0.64; p=0.001).

In an exploratory analysis of a subset of patients (n=23) with BRCA-reversion mutations — which restore DNA homologous recombination repair and thus confer tumour resistance to drug treatment — the reverse was seen. Median PFS was longer in the chemotherapy group than the rucaparib group in this subset (5.5 vs 2.9 months; HR, 2.77, 95 percent confidence interval [CI], 0.99–7.76).

“This is the first prospective report from a randomized study demonstrating that the presence of a BRCA reversion mutation predicts for primary resistance to rucaparib,” said lead author Dr Rebecca Kristeleit of Guy's and St. Thomas' Hospital in London, UK.

The phase III, multinational, open-label, prospective study randomized 349 patients (median age 58 years) in a 2:1 ratio to receive oral rucaparib 600 mg twice daily or standard chemotherapy until disease progression, intolerable adverse effects, or death. Participants were patients with advanced, relapsed ovarian cancer associated with deleterious BRCA1/2 mutations, including high-grade epithelial ovarian, fallopian tube or primary peritoneal cancer. They had been treated with ≥2 chemotherapy regimens previously but were naïve to PARP-inhibitor therapy.

Those in the chemotherapy arm were stratified based on response status to prior platinum therapy: resistant (1–6 months), partially sensitive (6–12 months), and fully sensitive (≥12 months). Resistant and partially sensitive patients received weekly paclitaxel whereas those who were fully sensitive received platinum-based chemotherapy.

While the objective response rate (ORR) was higher in the rucaparib group vs the chemotherapy group (40.3 percent vs 32.3 percent; p=0.13), the difference between groups was not significant. Nonetheless, duration of response was significantly longer with rucaparib than chemotherapy (9.4 vs 7.2 months, HR, 0.59, 95 percent CI, 0.36–0.98).

There were no significant differences in quality-of-life outcomes between the two groups.

Previously, rucaparib was granted accelerated approval by the US FDA for previously treated BRCA-positive advanced ovarian cancer. ARIEL4 is a confirmatory trial to gather additional data for final regulatory approval.

“Overall survival [data] will be presented once death events are mature (when 51 percent of death events had occurred),” said Kristeleit.

“Rucaparib safety profile was consistent with that reported in prior studies,” she reported.

Anaemia, nausea, and fatigue were the most common treatment-emergent adverse events (TEAEs) in both groups during the study. Acute myeloid leukemia and myelodysplastic syndrome occurred in four patients receiving rucaparib (one during treatment and three during follow-up) and none in the chemotherapy arm.