Maintenance treatment with rucaparib (Rubraca) was associated with improvements in several post-progression efficacy end points, including progression-free survival (PFS), in a subgroup of patients with platinum-sensitive, recurrent ovarian cancer who harbored a non-BRCA homologous recombination repair (HRR) gene mutation, according to an analysis of the ARIEL clinical trial.
Importantly, previous rucaparib treatment did not adversely affect the possibility for patients in this subgroup to benefit from subsequent therapy. The data also showed that certain mutations in a subset of HRR genes, such as RAD51C or RAD51D, may confer greater sensitivity to poly (ADP-ribose) polymerase inhibitor treatment than other HRR genes.
“Together, these post-progression outcomes [show us] that the clinically meaningful improvements in PFS observed in the study can be maintained beyond the first progression event, can delay the need for subsequent therapy, and can persist across subsequent treatment,” reported David O’Malley, MD, Director, Gynecologic Oncology, The Ohio State University Comprehensive Cancer Center – James, Columbus, at the 2020 Society of Gynecologic Oncology Annual Meeting on Women’s Cancer.
In the placebo-controlled, phase 3 ARIEL3 trial, maintenance treatment with rucaparib significantly improved PFS compared with placebo in all predefined patient cohorts, with the strongest effects observed in patients with carcinomas deficient in HRR, such as a deleterious mutation in the BRCA gene.
“Here, we evaluated patients from ARIEL3 with tumors having mutations in HRR genes otherthan BRCA, to determine how rucaparib maintenance treatment affects post-progression outcomes for these patients,” explained Dr O’Malley.
In this trial, researchers randomized 564 patients in a 2:1 ratio to rucaparib 600 mg twice daily or placebo. Archival specimens from all patients were sequenced to identify deleterious mutations in a prespecified list of 30 HRR genes.
Exploratory post-progression end points of chemotherapy-free interval (CFI), time to first subsequent therapy (TFST), time to disease progression on subsequent line of therapy or death (PFS2), and time to second subsequent therapy (TSST) were assessed in the 43 patients with a non-BRCA HRR gene mutation (28 in the rucaparib arm and 15 in the placebo arm).
Treatment with rucaparib (versus placebo) was associated with improvements in all post-progression efficacy end points in patients with a non-BRCA HRR mutation: PFS (median 11.1 vs 5.5 months), CFI (18.2 vs 7.7 months), TFST (16.9 vs 6.3 months), PFS2 (21.1 vs 17.3 months), and TSST (24.4 vs 17.9 months).
Among patients whose tumors harbored a RAD51C/D mutation (10 in the rucaparib arm and 3 in the placebo arm), PFS was significantly longer in those in the rucaparib arm compared with those in the placebo arm: 9 of 10 patients treated with rucaparib were progression-free at 12 months versus none in the placebo group. Three patients with a RAD51C/D mutation had measurable disease at baseline, and all 3 achieved a confirmed response (1 complete response and 2 partial responses) with rucaparib, with responses ongoing at the time of data cutoff. Time on rucaparib treatment in patients whose carcinomas harbored a RAD51C/D mutation was almost 3 times longer than in patients with other non-BRCA HRR gene mutations.
“Interestingly, all RAD51C/D mutations were homozygous, suggesting that these alterations are indeed the driver mutation,” Dr O’Malley said.
The safety profile in this subgroup of patients was consistent with that in the overall ARIEL3 population. Compared with the overall population, incidence of grade ≥3 adverse events and adverse events leading to dose reduction and/or treatment interruption in the subgroup were 55.6% versus 59.7% and 66.7% versus 71.8%, respectively.