Summary
A recent analysis found that long-term responders to rucaparib include ovarian cancer patients with BRCA mutation, particularly homozygous deletion or rearrangements, as well as BRCA1 hypermethylation, and RAD51C/D mutations, according to findings presented at the ASCO 2020 Annual Meeting (Abstract 6015).
“Cancers that are defective in homologous recombination repair, such as those with a BRCA1 or BRCA2 mutation, are sensitive to platinum-based chemotherapies and PARP inhibitors,” noted study author Elizabeth M. Swisher, MD, Professor and Director of the Division of Gynecologic Oncology at the University of Washington.
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Original Article
Long-Term Responses to Rucaparib in Recurrent Ovarian Cancer
Oncology Times
By Catlin Nalley
A recent analysis found that long-term responders to rucaparib include ovarian cancer patients with BRCA mutation, particularly homozygous deletion or rearrangements, as well as BRCA1 hypermethylation, and RAD51C/D mutations, according to findings presented at the ASCO 2020 Annual Meeting (Abstract 6015).
“Cancers that are defective in homologous recombination repair, such as those with a BRCA1 or BRCA2 mutation, are sensitive to platinum-based chemotherapies and PARP inhibitors,” noted study author Elizabeth M. Swisher, MD, Professor and Director of the Division of Gynecologic Oncology at the University of Washington.
“Molecular characterization of patients who derive durable benefit from PARP inhibitor treatment may provide insights into improving outcomes,” she said during her ASCO presentation. “Here, we describe long-term responders from the Study 10 Part 2 and ARIEL2 studies of the PARP inhibitor rucaparib for the treatment of patients with recurrent, high-grade ovarian cancer.”
Methodology & Results
Patients from the Study 10 Part 2 and ARIEL2 studies were included in this exploratory post-hoc analysis. Treatment included oral rucaparib at a starting dose of 600 mg twice daily until disease progression, unacceptable toxicity, or death. Final results from Study 10 (n=54) and ARIEL2 (n=491) were pooled.
Researchers defined long-term responders as patients with a duration of response (DOR) longer than 1 year, and short-term responders as those with a DOR of 20 weeks or less. To detect deleterious mutations and loss of heterozygosity (LOH) in tumors, targeted next-generation sequencing was used.
“Overall, 25 percent (138/545) of enrolled patients had a response to rucaparib, 38 (28%) responders had long-term confirmed responses that were greater than 1 year, and 12 percent had a duration of response greater than 2 years,” reported Swisher. “Twenty-nine patients had short-term responses, including 16 patients with a confirmed response.”
Baseline characteristics and prior number of chemotherapies were not significantly different between long- and short-term responders.
When comparing characteristics of BRCA mutations between long- and short-term responders, researchers identified deleterious, BRCA mutations in 71 percent of long-term responders and in 52 percent of short-term responders, according to Swisher.
“The distribution of germline and somatic BRCA mutations, as well as the fraction of BRCA1 versus BRCA2 mutations were similar for long- and short-term responders,” she said. “When we looked at mutation type, homozygous deletion or rearrangement was more common in long-term responders than in short-term responders. BRCA homozygous deletions or rearrangements were detected in 15 percent of the long-term versus 0 percent of the short-term responders.”
The researchers performed an expanded analysis of the 95 patients with a BRCA mutation and confirmed response to further understand the impact of homozygous deletions or rearrangements. “BRCA homozygous deletion or rearrangement was associated with significantly longer duration of response than other mutation types,” Swisher noted.
“High genome-wide LOH, a characteristic of homologous recombination deficiency, was seen in nine of 11 (82%) of the long-term responders that had BRCA wild-type high-grade ovarian cancer and only 36 percent of the short-term responders had high LOH,” she reported. In the long-term responder group, two of these patients had a deleterious RAD51C/D mutation.”
The researchers noted that, among long-term responders, median treatment duration was 2.5 years and median dose intensity was 0.82. “Most long-term responders (74%) had one or more dose reductions and 47 percent had two more,” they said. “The most common treatment-emergent adverse events leading to dose reduction were anemia, asthenia/fatigue, nausea, and neutropenia.”
Between the long- and short-term responders, the incidence rates of treatment-emergent adverse events were similar. There were no cases of myelodysplastic syndrome or acute myeloid leukemia in either group.
“In conclusion, 28 percent of patients with recurrent high-grade ovarian cancer and a confirmed response to rucaparib had a response greater than 1 year, including 12 percent with a response lasting greater than or equal to 2 years,” Swisher said. “The majority of the long-term responders to rucaparib harbored a deleterious BRCA mutation, particularly homozygous deletion or rearrangements, which would not be susceptible to somatic reversion mutations.
“Most long-term responders with BRCA wild-type ovarian cancer had tumors with high genome-wide LOH, a genomic scar indicative of homologous recombination deficiency,” she concluded. “In two patients with a long-term response, high genomic LOH was observed in the context of a deleterious RAD51C/D.”
Catlin Nalley is a contributing writer.