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

2020 Year in Review - Ovarian Cancer

Treatment with rucaparib was associated with improvements in progression-free survival, time to first subsequent treatment, and other post-progression efficacy end points.

Maintenance treatment with the poly (ADP-ribose) polymerase (PARP) inhibitor rucaparib improved a number of clinically meaningful end points compared with placebo 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 are 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. More important, prior treatment with rucaparib did not adversely affect 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.

For patients with recurrent ovarian cancer, maintenance therapy is intended to extend progression-free survival (PFS) without compromising post-progression survival. In the ARIEL3 study, maintenance treatment with rucaparib significantly improved PFS compared with that of 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.

Patients in the study were randomized 2:1 to receive oral rucaparib 600 mg twice per 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, BARD1, BRIP1, PALB2, RAD51C, and RAD51D mutations are significantly associated with hereditary ovarian cancer. Special attention was shown to patients with these mutations, because they have been shown to confer sensitivity to PARP inhibitors, Dr O’Malley 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 those, 28 patients were in the rucaparib group and 15 patients were in the placebo group. In these patients, treatment with rucaparib versus placebo was associated with improvements in all post-progression efficacy end points: 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, 10 were in the rucaparib group and 3 were in the placebo group. In addition, 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; all 3 achieved a confirmed response (1 complete response and 2 partial responses), with responses ongoing at the time of data cutoff. Time on treatment with rucaparib in patients with carcinomas associated with a RAD51C/D mutation was almost 3 times longer than that in patients with other non-BRCA HRR gene mutations, said Dr O’Malley.

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

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

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

Source: O’Malley DM, et al. Gynecol Oncol. 2020;159(1_suppl). Abstract 80.

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