Rucaparib Findings Highlight Need for More Data in BRCA+ Ovarian Carcinoma

Data show that rucaparib yielded a median OS of 19.4 months compared with 25.4 months with chemotherapy in relapsed BRCA-mutated ovarian carcinoma.

Final overall survival (OS) analysis and other post-progression outcomes from the phase 3 ARIEL4 trial (NCT02855944), which evaluated rucaparib (Rubraca) vs standard-of-care chemotherapy in patients with relapsed BRCA-mutated ovarian carcinoma, demonstrated that further research is needed to determine the most appropriate treatment options for patients who progressed on a PARP inhibitor, according to a study published in Lancet Oncology.¹

At a median follow-up of 41.2 months (IQR, 37.8-44.6), the median OS among all patients was 19.4 months (95% CI, 15.2-23.6) in the rucaparib group vs 25.4 months (95% CI, 21.4-27.6) in the chemotherapy group (HR, 1.3; 95% CI, 1.0-1.7; P = .0472). At the April 10, 2022 data cutoff of the final analysis, 70% of all patients had died; 167 (72%) were in the rucaparib group and 77 (66%) were in the chemotherapy group.

The median OS among patients with platinum-resistant disease was 14.2 months (95% CI, 11.8-17.4) with rucaparib vs 22.2 months (95% CI, 15.4-26.2) with chemotherapy (HR, 1.5; 95% CI, 1.1-2.2; P = .022). In each respective arm, the median OS was 21.1 months (95% CI, 13.9-30.4) vs 23.2 months (95% CI, 15.6-27.6) in the partially platinum-sensitive subgroup (HR, 0.97; 95% CI, 0.58-1.60; P = .95) and 36.3 months (95% CI, 28.1-40.7) vs 47.2 months (95% CI, 22.9-53.0) in the fully platinum-sensitive subgroup (HR, 1.20; 95% CI, 0.62-2.5; P = .49). The median OS in each arm was 29.4 months (95% CI, 23.1-37.4) vs 27.6 months (95% CI, 21.9-47.2) in the combined platinum-sensitive subgroup (HR, 1.1; 95% CI, 0.71-1.6; P = .72).

Previous analysis of progression-free survival (PFS) showed that 90% of patients in the rucaparib group experienced disease progression or died compared with 95% of patients in the chemotherapy group; of those with partially platinum-resistant disease, 88% and 97%, respectively, had progression or died; of those with fully platinum-sensitive disease, 71% and 88% had progression or died; and of those with partial and fully platinum-sensitive disease combined, 81% and 93% had progression or died.

“[OS] favored those randomly assigned to chemotherapy vs rucaparib in the intent-to treat [ITT] population but was similar between treatment groups among patients with platinum-sensitive disease,” lead study author Amit M Oza, MD, BSc, MBBS, FRCPC, head of the Division of Medical Oncology & Hematology and medical director of the Cancer Clinical Research Unit at Princess Margaret Cancer Centre, wrote with coauthors.¹ “In 2022, PARP inhibitor indications in ovarian cancer were restricted to the maintenance setting, removing the monotherapy treatment indication for relapsed BRCA-mutated disease, further highlighting the need for better understanding of the most appropriate treatment for patients with ovarian cancer who have progressed on a PARP inhibitor.”

A total of 349 patients were randomly assigned, in a 2:1 ratio, to receive either rucaparib (n = 233) or chemotherapy (n = 116). Rucaparib was given at 600 mg orally twice daily in 28-day cycles; chemotherapy was given to patients with platinum-resistant or partially platinum-sensitive disease at 60 to 80 mg/m² of paclitaxel (Taxol) on days 1, 8, and 15 of each 28-day cycle. Patients with fully platinum-sensitive disease received investigator’s choice of platinum-based chemotherapy given in 21-day or 28-day cycles per institutional guidelines.

Eligible patients were women 18 years or older with a histologically confirmed diagnosis of high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer with a somatic or deleterious germline BRCA1 or BRCA2 mutation.² Additionally, patients had to have received at least 2 prior therapies, including at least 1 platinum-based regimen; confirmed relapse or progressive disease; an ECOG performance status of 0 or 1; evaluable disease per RECIST v1.1 criteria; and a treatment-free interval of at least 6 months after their initial chemotherapy regimen.

Platinum-refractory disease and previous treatment with a PARP inhibitor, single-agent paclitaxel, and nab-paclitaxel (Abraxane) were grounds for exclusion.

The primary end point of ARIEL4 was PFS. Secondary end points included objective response rate (ORR), duration of response, and combined ORR.

After disease progression, 69% of patients in the chemotherapy group switched over to the chemotherapy group.

Median duration of treatment during the randomization phase of the trial was 5.6 months (95% CI, 4.8-6.4) in the rucaparib group and 4.4 months (95% CI, 3.5-5.3) in the chemotherapy group for the platinum-resistant subgroup; 7.6 months (95% CI, 6.8-8.4) and 4.5 months (95% CI, 3.3-5.7), respectively, in the partially platinum-sensitive group; and 13.7 months (95% CI, 12.4-15.0) and 3.4 months (95% CI, 2.6-4.2), respectively, in the fully platinum-resistant group. Of patients who crossed over to rucaparib from chemotherapy, median duration of treatment was 9.4 months (95% CI, 7.4-11.4), 9.7 months (95% CI, 7.9-11.5), and 9.9 months (95% CI, 7.9-11.9) in the platinum-resistant, partially platinum-sensitive, and fully platinum-sensitive subgroups, respectively.

Regarding safety, the most common treatment-emergent adverse events (TEAEs) of grade 1 to 2 in the rucaparib and chemotherapy groups were alanine aminotransferase or aspartate aminotransferase increases (57% vs 19%, respectively), nausea (52% vs 35%), asthenia or fatigue (47% vs 46%), and abdominal pain (35% vs 19%); the most common TEAEs of grade 3 were anemia or decreased hemoglobin (23% vs 6%), asthenia or fatigue (9% vs 4%), neutropenia or decreased absolute neutrophil counts (7% vs 14%), and leukopenia (3% vs 4%).

Deaths due to TEAEs were observed in 10 patients (5%) of the rucaparib group and 1 patient in the chemotherapy group.

Reference

1. Oza AM, Lisyanskaya A, Fedenko A, et al. Rucaparib versus chemotherapy for treatment of relapsed ovarian cancer with deleterious BRCA1 or BRCA2 mutation (ARIEL4): final results of an international, open-label, randomised, phase 3 trial. Lancet Oncol. 2025;26(2):249-264. doi:10.1016/S1470-2045(24)00674-0
2. ARIEL4: A study of rucaparib versus chemotherapy BRCA mutant ovarian, fallopian tube, or primary peritoneal cancer patients. ClinicalTrials.gov. Updated June 9, 2023. Accessed February 12, 2025. https://tinyurl.com/ycx938mn