As reported in The Lancet Oncology by Rebecca Kristeleit, MD, of Guy’s and St. Thomas’ NHS Foundation Trust, and colleagues, the phase III ARIEL4 trial has shown a statistically significant improvement in progression-free survival with rucaparib vs chemotherapy in relapsed ovarian cancer with deleterious BRCA1/2 mutations.1
In the open-label trial, 349 patients from sites in 12 countries who had platinum-resistant, partially platinum-sensitive, or platinum-sensitive disease and had received at least two prior chemotherapy regimens were randomly assigned 2:1 between March 2017 and September 2020 to receive rucaparib at 600 mg twice daily until disease progression or unacceptable toxicity (n = 233) or chemotherapy (n = 116). Randomization was stratified by progression-free interval after the most recent platinum-containing therapy. Overall, 51% of patients had platinum-resistant disease, 28% had partially platinum-sensitive disease, and 21% had fully platinum-sensitive disease.
Rebecca Kristeleit, MD
Chemotherapy in patients with platinum-resistant or partially platinum-sensitive disease was paclitaxel on days 1, 8, and 15 in 28-day cycles, with no cap on the number of cycles (n = 88). Those with fully platinum-sensitive disease received investigator’s choice of platinum-based chemotherapy consisting of single-agent cisplatin or carboplatin (n = 9) or platinum-doublet chemotherapy with carboplatin/paclitaxel, carboplatin/gemcitabine, or cisplatin/gemcitabine (n =16) in 21-day or 28-day cycles for up to eight cycles (3 patients did not start chemotherapy). Patients in the chemotherapy group could cross over to receive rucaparib upon disease progression.
As of data cutoff (September 2020), median follow-up was 25.0 months (interquartile range = 13.8–32.5 months). In the efficacy population, 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 analyses in the efficacy population, median progression-free survival by progression-free interval after most recent platinum-containing therapy was 6.2 vs 5.7 months (HR = 0.79, 95% CI = 0.55–1.14) for an interval of between 1 and 6 months (113 vs 51 patients), 9.1 vs 5.5 months (HR = 0.38, 95% CI = 0.23–0.62) for an interval of between 6 and 12 months (63 vs 29 patients), and 12.9 vs 9.6 months (HR = 0.69, 95% CI = 0.36–1.34) for an interval of at least 12 months (44 vs 25 patients).
In an analysis by platinum sensitivity status, median progression-free survival was 6.4 vs 5.7 months (HR = 0.78, 95% CI = 0.54–1.13) for platinum-resistant disease (110 vs 51 patients), 8.0 vs 5.5 months (HR = 0.40, 95% CI = 0.24–0.65) for partially platinum-sensitive disease (62 vs 28 patients), and 12.9 vs 9.6 months (HR = 0.69, 95% CI = 0.37–1.29) for fully platinum-sensitive disease (48 vs 26 patients).
In an analysis by BRCA mutation status, median progression-free survival was 7.4 vs 5.7 months (HR = 0.68, 95% CI = 0.49–0.92) for BRCA1 mutation (173 vs 74 patients), 8.3 vs 5.6 months (HR = 0.51, 95% CI = 0.29–0.89) for BRCA2 mutation (47 vs 31 patients), 7.4 vs 5.7 months (HR = 0.60, 95% CI = 0.45–0.80) for germline mutations (187 vs 88 patients), and 7.5 vs 7.3 months (HR = 0.67, 95% CI = 0.32–1.40) for somatic mutations (33 vs 16 patients).
Among 211 vs 96 patients with measurable disease in the efficacy population, objective response was observed in 85 (40%) in the rucaparib group vs 31 (32%) in the chemotherapy group (P = .13), with complete responses in 5% vs 2%. The median duration of response was 9.4 months (95% CI = 7.5–11.1 months) vs 7.2 months (95% CI = 4.0–11.4 months).
While overall survival data were not mature at the time of analysis, final overall survival data have since been reported.2 In the intention-to-treat population, median overall survival was 19.4 months in the rucaparib group compared to 25.4 months in the chemotherapy group, resulting in a hazard ratio of 1.31 (95% CI, 1.00–1.73; P = .0507). Although there was a decrement in overall survival for rucaparib compared to chemotherapy, the overall survival analysis was heavily confounded by crossover to rucaparib for patients initially randomized to chemotherapy (69% [80/116] of patients; in total 90% [313/349] of trial participants received rucaparib). The overall survival result in patients with platinum-resistant ovarian cancer appeared to be driving the difference observed in the intention-to-treat population: in the platinum-resistant subgroup, the hazard ratio was 1.51 (95% CI = 1.05–2.17). In the platinum-sensitive subgroup (comprising those with partially or fully platinum-sensitive disease), there was no significant difference in overall survival between patients randomized to rucaparib vs chemotherapy, with a hazard ratio of 1.07 (95% CI = 0.71–1.62).
In the primary analysis, grade ≥ 3 adverse events occurred in 59% of patients in the rucaparib group and 38% of patients in the chemotherapy group. The most common adverse events in both groups were anemia/decreased hemoglobin (22% vs 5%) and neutropenia/decreased neutrophil count (10% vs 15%).
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.”
DISCLOSURE: The study was funded by Clovis Oncology. Dr. Kristeleit has received institutional funding from Clovis Oncology for this clinical trial; reports clinical trial grants from Merck Sharp & Dohme; served as a consultant for Basilea Pharmaceutica and Shattuck Pharma; has received honoraria from Clovis Oncology, AstraZeneca, GlaxoSmithKline, and Incyte; received travel support from AstraZeneca, Clovis Oncology, GlaxoSmithKline, and Sierra Oncology; has served on data safety monitoring boards or advisory boards for Clovis Oncology, AstraZeneca, BeiGene, Eisai, GlaxoSmithKline, Incyte, iTeos Therapeutics, PharmaMar, and Roche. For disclosures of the other study authors, visit thelancet.com.
1. Kristeleit R, Lisyanskaya A, Fedenko A, et al: Rucaparib versus standard-of-care chemotherapy in patients with relapsed ovarian cancer and a deleterious BRCA1 or BRCA2 mutation (ARIEL4). Lancet Oncol 23:465-478, 2022.
2. Clovis Oncology, Inc: Dear Healthcare Professional Letter, May 2022. Available at https://clovisoncology.com/pdfs/US_DHCPL_final_signed.pdf. Accessed June 15, 2022
In March 2022, Kristeleit et al reported the results of the ARIEL4 trial1 of rucaparib in relapsed BRCA-mutant ovarian cancer in The Lancet Oncology (summarized in this issue of The ASCO Post) and are to be congratulated on this accomplishment. This report, along with the almost simultaneous...