As reported in The Lancet Oncology by Rebecca Kristeleit, MD, and colleagues, the phase III ARIEL4 trial has shown a statistically significant improvement in progression-free survival with rucaparib vs chemotherapy in patients with relapsed ovarian cancer and deleterious BRCA1/2 mutations.

Rebecca Kristeleit, MD

Study Details

The open-label trial included 349 patients from sites in 12 countries with platinum-resistant/partially sensitive or platinum-sensitive disease who had received two or more prior chemotherapy regimens. Patients were randomly assigned 2:1 between March 2017 and September 2020 to receive rucaparib at 600 mg twice daily (n = 233), until disease progression or unacceptable toxicity, or chemotherapy (n = 116). Overall, 51% to 52% of patients had platinum-resistant disease, 27% to 28% had partially platinum-sensitive disease, and 21% to 22% had fully platinum-sensitive disease.

Chemotherapy in patients with platinum-resistant or partially platinum-sensitive disease was paclitaxel at 60 to 80 mg/m² on days 1, 8, and 15 in 28-day cycles, with no cap on number of cycles. Those with fully platinum-sensitive disease received investigator’s choice of platinum-based chemotherapy (consisting of single-agent cisplatin or carboplatin) or platinum-doublet chemotherapy with either carboplatin/paclitaxel, carboplatin/gemcitabine, or cisplatin/gemcitabine in 21-day or 28-day cycles for up to eight cycles. Patients in the chemotherapy group could cross over to receive rucaparib upon disease progression.

The primary endpoint was investigator-assessed progression-free survival assessed in the efficacy population, consisting of all patients without BRCA reversion mutations (ie, those restoring function to protein products that might confer resistance to poly [adenosine diphosphate-ribose] polymerase [PARP] inhibitors or platinum chemotherapy), and then in the intention-to-treat population. Baseline reversion mutations were present in 13 patients (6%) in the rucaparib group and 10 patients (9%) in the chemotherapy group. 

Progression-Free Survival

As of data cutoff (September 2020), median follow-up was 25.0 months (interquartile range = 13.8–32.5 months). In the efficacy population (220 patients in the rucaparib group and 105 in the chemotherapy group), median progression-free survival was 7.4 months (95% confidence interval [CI] = 7.3–9.1 months) in the rucaparib group vs 5.7 months (95% CI = 5.5–7.3 months) in the chemotherapy group (hazard ratio [HR] = 0.64, 95% CI = 0.49–0.84, P = .0010). In the intention-to-treat population, median progression-free survival was 7.4 months (95% CI = 6.7–7.9 months) in the rucaparib group vs 5.7 months (95% CI = 5.5–6.7 months) in the chemotherapy group (HR = 0.67, 95% CI = 0.52–0.86, P = .0017). Among the 23 patients with reversion mutations, median progression-free survival was 2.9 months (95% CI = 1.8–4.2 months) in those receiving rucaparib vs 5.5 months (95% CI = 1.9–6.6 months) in those receiving chemotherapy (HR = 2.77, 95% CI = 0.99–7.76, P = .053).

In subgroup analysis by platinum sensitivity status in the efficacy population, hazard ratios were 0.78 (95% CI = 0.54–1.13) for platinum-resistant disease, 0.40 (95% CI = 0.24–0.65) for partially platinum-sensitive disease, and 0.69 (95% CI = 0.37–1.29) for fully platinum-sensitive disease.

Adverse Events

Grade ≥ 3 adverse events occurred in 59% of patients in the rucaparib group and 38% of patients in the chemotherapy group. The most common in both groups were anemia/decreased hemoglobin (22% vs 5%) and neutropenia/decreased neutrophil count (10% vs 15%). Serious adverse events occurred in 27% vs 12% of patients in the chemotherapy group, most commonly (≥ 3% in either group) anemia/decreased hemoglobin (8% vs 2%) and thrombocytopenia/decreased platelet count (3% vs 1%). Myelodysplastic syndrome or acute myeloid leukemia was reported in five patients (2%) in the rucaparib group, including one during treatment and four during long-term follow-up; no cases were reported in the chemotherapy group. Three deaths were considered to be potentially related to rucaparib treatment, due to cardiac disorder, myelodysplastic syndrome, and an unconfirmed cause.

The investigators concluded, “Results from the ARIEL4 study support rucaparib as an alternative treatment option to chemotherapy for patients with relapsed, BRCA1-mutated or BRCA2-mutated ovarian carcinoma.”

Dr. Kristeleit, of the UCL Cancer Institute, University College London, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by Clovis Oncology. For full disclosures of the study authors, visit thelancet.com.