Rubraca’s Benefit in Ovarian Cancer Hinges on Platinum Status, Previous Therapy
National Harbor, MD—Patients with relapsed high-grade ovarian cancer with BRCA mutation derived the greatest benefit from the poly ADP-ribose polymerase (PARP) inhibitor rucaparib (Rubraca) if their disease remained platinum sensitive, a new analysis of a large phase 2 clinical trial showed, as reported at the 2017 Society of Gynecologic Oncology meeting.
Patients with platinum-sensitive disease had a median progression-free survival (PFS) of 12.7 months compared with 7.3 months in patients with platinum-resistant disease, and 5 months with those who had platinum-refractory disease.
“The objective response rate [ORR] in patients with BRCA mutations was greater in platinum-sensitive patients, but varied according to the number of prior lines of therapy,” said Gottfried E. Konecny, MD, Lead Clinician for Gynecologic Oncology, Department of Medicine, University of California, Los Angeles. “The results demonstrated a beneficial effect regardless of whether the mutations were germline or somatic.”
The FDA granted rucaparib accelerated approval status in December 2016 as third-line therapy for advanced ovarian cancer associated with somatic or germline BRCA mutations.
Phase 3 clinical trials required for full FDA approval have begun. Available data can be useful to define the patients who benefit most from treatment with the new PARP inhibitor.
ARIEL Study Details
Dr Konecny reported findings from an integrated analysis of 1 of the 2 studies that initially established the safety and efficacy of rucaparib as maintenance therapy in advanced ovarian cancer. The objectives of the analysis were to perform the first assessment of ORR and PFS for the 2-part ARIEL 2 trial and to determine the impact of platinum sensitivity and number of prior lines of chemotherapy on ORR and PFS.
ARIEL 2 involved 493 patients with previously treated advanced ovarian cancer. The study included patients with germline or somatic BRCA1/BRCA2 mutations and with BRCA mutation wild-type.
The first part of the trial included 206 patients who received at least 1 previous chemotherapy regimen, received platinum as their most recent therapy, and who remained platinum sensitive. The second part of ARIEL 2 included patients who received 3 or 4 previous lines of therapy and whose disease was platinum sensitive, resistant, or refractory.
The analysis was limited to 134 patients with germline or somatic BRCA mutations: 41 from part 1 of ARIEL 2 and 93 from part 2. More than 80% of the patients had epithelial ovarian cancer, 58.2% had germline BRCA mutations, 17.2% somatic mutations, and 24.6% uncertain BRCA origin. Two-thirds of the patients had BRCA1 mutations.
Three-fourths of the patients had received at least 3 prior lines of therapy. Dr Konecny said 42.5% of the patients had platinum-sensitive disease and no intervening therapy since the last platinum agent, 10.4% exhibited platinum sensitivity and had received intervening treatment, 36.6% had platinum-resistant disease, and 10.4% of the patients were platinum refractory.
Patients with platinum-sensitive disease and no intervening therapy had an ORR of 70%. The ORR was 83% for patients with 1 previous therapy, 86% with 2 previous lines, and 52% for ≥3 previous lines. Patients with platinum sensitivity and intervening therapy had an ORR of 43%, and all had received at least 3 prior lines of therapy. Patients with platinum-resistant disease had an ORR of 25%, and no patient with platinum-refractory disease responded to rucaparib maintenance.
Analysis of PFS showed the best outcome in patients with platinum sensitivity and no intervening therapy (median, 12.7 months). The median PFS was 7.4 months in patients who were platinum sensitive and received intervening therapy versus 7.3 months in patients with platinum-resistant disease.
The duration of platinum-free interval also influenced the PFS benefit afforded by rucaparib. Patients with a platinum-free interval ≥18 months had a median PFS of 25.1 months, decreasing to 16.9 months with a platinum-free interval ≥12 months, 12.7 months with a platinum-free interval ≥6 months, and 7.4 months for patients with platinum-sensitive disease and intervening therapies.
The median PFS was virtually identical for platinum-sensitive patients with germline or somatic BRCA mutations (12.8 vs 12.7 months). Patients with platinum-sensitive disease derived a similar benefit whether they had BRCA1 or BRCA2 mutations.
Experience with rucaparib and olaparib has demonstrated a “clear clinical benefit” in patients with recurrent high-grade ovarian cancer and BRCA mutation, said discussant Jonathan A. Ledermann, MBBS, DM, MRCP, FRCP, Director, Cancer Research UK and UCL Cancer Trials Centre, University College, London.
“Single-agent activity correlates with the platinum-free interval and number of prior lines of therapy,” said Dr Ledermann. “BRCA status is the strongest determinant of benefit and should be assessed in all patients with high-grade tumors.”