Rucaparib Improves Postprogression Outcomes in Non-BRCA HRR Mutated Ovarian Cancer

Jonathan Ledermann MD, FRCP

Rucaparib (Rubraca) was associated with superior outcomes among women with ovarian cancer harboring a non-BRCA homologous recombination repair (HRR) gene mutation compared with placebo, according to an analysis of specimens collected in the phase III ARIEL3 trial (NCT01968213).

Investigators examined archival specimens from all patients in ARIEL3 (N = 564) sequenced to identify deleterious mutations in a prespecified list of 30 HRR genes. Patients were randomly assigned to receive 600 mg twice-daily oral rucaparib in 28-day cycles (n = 375) or placebo (n = 189).

In the experimental group, 28 patients (7.5%) had a mutation in a non-BRCA HRR gene, most often in RAD51C or RAD51D (RAD51C/D, n = 10). In the placebo group, 15 patients (7.9%) had a non-BRCA HRR gene mutation, most commonly in BRIP1 (n = 5) and RAD51C/D (n = 3).

Investigators observed significantly longer progression-free survival (PFS) among patients with a tumor associated with a RAD51C/D mutation who received rucaparib compared with placebo (log rank P = .0184). Nine of 10 patients assigned to rucaparib were progression-free at 12 months versus zero of 3 assigned to placebo.¹

Treatment with rucaparib versus placebo was associated with improvements in postprogression efficacy end points in patients with tumors associated with non-BRCA HRR gene mutation. Time to disease progression on subsequent line of therapy or death favored treatment with rucaparib at 21.1 months versus 17.3 months with placebo (HR, 0.30; 95% CI, 0.12-0.72. The chemotherapy-free interval was 18.2 months versus 7.7 months, respectively (HR, 0.21; 95% CI, 0.09-0.52). Additionally, rucaparib outperformed placebo in the time to start of first subsequent therapy (16.9 vs 6.3 months; HR, 0.16; 95% CI, 0.06-0.40) and time to start of second subsequent therapy (24.4 vs 17.9 months; HR, 0.43; 95% CI, 0.18-1.04).¹

Safety in this subgroup was consistent with that in the overall ARIEL3 safety population.

The FDA approved rucaparib as a maintenance treatment for patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to platinum-based chemotherapy based on data from ARIEL3 in April 2018. Median PFS in the intention-to-treat populations was 10.8 months with rucaparib versus 5.4 months with placebo. There was a 77% reduction in the risk of progression or death in those with either germline or somatic BRCA mutations with rucaparib compared with placebo (HR, 0.23; 95% CI, 0.16-0.34; P <.0001).²

The safety population included all patients who received placebo and 99% of patients who received rucaparib. Fifty-six percent of patients in the experimental arm and 15% in the placebo arm reported grade ≥3 treatment-emergent adverse events (TRAEs). In the rucaparib group, the most common grade 3 TRAEs were anemia (18%), increased alanine aminotransferase or aspartate aminotransferase (10%), fatigue (7%), and neutropenia (5%). The only grade 4 TRAEs reported were neutropenia (2%), thrombocytopenia (2%), and anemia (1%).

Investigators presented data on the effect of rucaparib in patients with recurrent disease who achieved a complete response (CR) or partial response (PR) to chemotherapy at the 2019 European Society for Medical Oncology Congress. Jonathan A. Ledermann, BSc, MD, FRCP, professor of medical oncology with UCL Cancer Institute at University College London and an honorary consultant medical oncologist for UCL Hospitals, said patients who had either CR or PR derived a similar benefit from the PARP inhibitor.

“We also saw that a proportion of patients who had measurable disease at the time they ended chemotherapy had a further response to rucaparib—in the BRCA-mutated population, that was a 37% response rate,” he added. “The drug is not only a drug of maintenance, it’s also a drug of therapy in patients with ovarian cancer.”

References

1. O’Malley DM, Lorusso D, Oaknin A, et al. Postprogression outcomes in patients with ovarian carcinoma associated with a mutation in a non-BRCA homologous recombination repair gene receiving rucaparib maintenance treatment: results from the phase III study ARIEL3. Data made available as part of the virtual platform for the SGO 2020 Annual Meeting. Abstract 80.
2. Coleman RL, Oza AM, Lorusso D, et al. Rucaparib maintenance treatment for recurrent ovarian carcinoma after response to platinum therapy (ARIEL3): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;390(10106):1949—1961. doi: 10.1016/S0140-6736(17)32440-6.

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