Deleterious BRCA Mutations More Likely on Long-Term Responders to Rucaparib

2020 Year in Review - Ovarian Cancer

In patients with high-grade ovarian cancer harboring BRCA mutations and a confirmed response to rucaparib, BRCA homozygous deletion or rearrangement was associated with a significantly longer duration of response.

In patients with recurrent ovarian cancer, long-term responders to rucaparib (Rubraca) are more likely to harbor deleterious BRCA mutations, particularly homozygous deletion or rearrangements, than short-term responders. In a pooled analysis of Study 10, Part 2 and ARIEL 2, studies of rucaparib for the treatment of patients with recurrent high-grade ovarian cancer, deleterious BRCA mutations were identified in 71.1% (27 of 38) of long-term responders and 51.7% (15 of 29) of short-term responders, reported Elizabeth M. Swisher, MD, Director, Division of Gynecologic Oncology, University of Washington, Seattle, and Director, Breast and Ovarian Cancer Prevention Program, Seattle Cancer Care Alliance, at this year’s American Society of Clinical Oncology Virtual Scientific Program.

The molecular characterization of patients who derive durable benefit from poly (ADP-ribose) polymerase inhibitor treatment may provide insights into improving outcomes, she said. According to the pooled analysis (N = 545), 25% of patients had a Response Evaluation Criteria in Solid Tumors response to rucaparib and 40 responders (29%) had long-term confirmed responses, defined as response duration ≥1 years, and 16 (12%) had a duration of response >2 years. Twenty-nine (21%) patients had short-term responses, defined as ≤20 weeks. Baseline characteristics and the number of previous chemotherapies were not significantly different between long- and short-term responders.

Although deleterious BRCA mutations were identified in more long- versus short-term responders, the distribution of BRCA germline and founder mutations, as well as the fraction of BRCA1 versus BRCA2 mutations, was similar for long- and short-term responders. When mutation type was examined, “homologous deletion or rearrangement was more common in long-term responders than in short-term responders,” said Dr Swisher. BRCA homozygous deletion or rearrangements were detected in 15% (4 of 27) of long-term responders versus 0% (0 of 15) of short-term responders.

In an expanded analysis of patients with high-grade ovarian cancer harboring BRCA mutations and a confirmed response to rucaparib (N = 95), BRCA homozygous deletion or rearrangement was associated with a significantly longer duration of response than other mutation types (median duration of response, not reached vs 0.6 years; hazard ratio, 0.22; P = .016).

High genome-wide loss of heterozygosity, a characteristic of homologous recombination deficiency, was seen in 9 (82%) of 11 of the long-term responders with BRCA wild-type ovarian cancer. Only 5 (36%) of 14 of the short-term responders with BRCA wild-type ovarian cancer had high loss of heterozygosity. In the long-term responder group, 2 patients had RAD51C/D mutations.

Median treatment duration among long-term responders was 2.5 years and median dose intensity was 0.82. Approximately three-fourths (74%) of long-term responders required ≥1 dose reductions, and 47% had ≥2 dose reductions. Anemia, asthenia/fatigue, nausea, and neutropenia were the most common treatment-emergent adverse events that led to dose reduction.

Source: Swisher EM, et al. J Clin Oncol. 2020;38(15_suppl). Abstract 6015.

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