Promising Results Seen with Maintenance Rucaparib in Patients with Ovarian Cancer and Non-BRCA HRR Gene Mutations

Compared with placebo, maintenance treatment with the PARP inhibitor rucaparib improved a number of clinically meaningful end points in a small subgroup of patients with platinum-sensitive, recurrent ovarian cancer who harbored a non-BRCA homologous recombination repair (HRR) gene mutation. These findings come from the phase 3 ARIEL3 study, presented by David O’Malley, MD, at the Society of Gynecologic Oncology (SGO) Annual Meeting on Women’s Cancer. Importantly, prior rucaparib treatment did not adversely impact the possibility for patients in this subgroup to benefit from subsequent therapy.

“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 Dr O’Malley and colleagues from the James Cancer Hospital at Ohio State University.

Maintenance therapy for patients with recurrent ovarian cancer is intended to extend progression-free survival (PFS) without compromising post-progression survival. In the ARIEL3 study, rucaparib maintenance treatment significantly improved PFS compared with placebo in all predefined patient cohorts, whereas the strongest effects were seen in 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 other than BRCA, to determine how rucaparib maintenance treatment affects post-progression outcomes for these patients,” he explained.

In the study, patients were randomized 2:1 to receive oral rucaparib at a dose of 600 mg twice a day, or placebo. Archival specimens from all 564 patients in ARIEL3 were sequenced to identify deleterious mutations in a prespecified list of 30 HRR genes. Non-BRCA HRR gene mutation status was a prespecified randomization stratification factor of the study; in particular, mutations in BARD1, BRIP1, PALB2, RAD51C, and RAD51D are significantly associated with hereditary ovarian cancer, and special attention was shown to patients with these mutations, as these have been shown to confer sensitivity to PARP inhibitors, he added.

Exploratory post-progression end points of chemotherapy-free interval (CFI), time to first subsequent treatment (TFST), PFS on second-line therapy (PFS2), and time to second subsequent therapy (TSST) were assessed only in the 43 patients with a non-BRCA HRR gene mutation, of which there were 28 patients in the rucaparib group and 15 patients in the placebo group. Treatment with rucaparib versus placebo was associated with improvements in all post-progression efficacy end points in these patients: 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 with a tumor associated with a RAD51C/D mutation, of which there were 10 in the rucaparib group and 3 in the placebo group, PFS was significantly longer in those receiving rucaparib than in those receiving placebo: 9 of 10 rucaparib-treated patients 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 responses ongoing at the time of data cut-off. Dr O’Malley noted that time on rucaparib treatment in patients with carcinomas associated with a RAD51C/D mutation was almost 3 times longer than those with other non-BRCA HRR gene mutations.

“Interestingly, all RAD51C/D mutations were homozygous, suggesting that these alterations are indeed the driver mutation,” he said.

Safety in this subgroup was consistent with that observed in the overall ARIEL3 safety population. Compared with the overall population, incidence of grade ≥3 adverse events and adverse events leading to dose reduction and/or treatment interruption in this subgroup were 55.6% versus 59.7% and 66.7% versus 71.8%, respectively.

Although the number of patients in this subgroup was small, the investigators conclude that certain mutations in a subset of HRR genes, such as RAD51C/D, may confer greater sensitivity to PARP inhibitor treatment than other HRR genes.

  • SGO 2020 Annual Meeting on Women’s Cancer. Abstract 80. Presented May 7, 2020.

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