Homologous recombination deficiency analysis predicts PARP inhibitor benefit for ovarian cancer
Next-generation sequencing used to detect homologous recombination deficiency may predict responses to rucaparib in patients with BRCA wild-type platinum-sensitive ovarian cancers, according to results from the international, multicenter, open-label phase 2 trial ARIEL2 study.
Further, benefit from rucaparib (Rubraca, Clovis Oncology) appeared greater in patients with BRCA–mutant or BRCA wild-type and loss of heterozygosity (LOH)–high ovarian carcinomas.
PARP inhibitors have demonstrated antitumor activity in ovarian carcinomas with homologous recombination deficiency; however, the optimal method to identify which BRCA wild-type cancers are most likely to respond is still unknown. Along with BRCA1 and BRCA2 mutations, genomic LOH might also represent homologous recombination deficiency.
Elizabeth M. Swisher, MD, professor of gynecologic oncology at University of Washington and director of the Breast and Ovarian Cancer Prevention Program at Seattle Cancer Care Alliance, and colleagues assessed the ability of tumor genomic LOH, assessed via next-generation sequencing, to predict response to the PARP inhibitor rucaparib.
The analysis included data from 206 patients with recurrent, platinum-sensitive, high-grade ovarian carcinoma enrolled into one of the following subgroups:
- BRCA mutant (deleterious germline or somatic, n = 40);
- BRCA wild-type and high LOH (n = 82); or
- BRCA wild-type and low LOH (n = 70).
Patients were treated with 600 mg of oral rucaparib twice daily for continuous 28-day cycles until disease progression or any other reason for discontinuation.
PFS served as the primary endpoint.
At the data cutoff date, 204 patients had been treated with rucaparib for a median duration of 5.7 months, with 28 patients still on study medication.
Disease progression or death occurred in 24 patients in the BRCA–mutant subgroup, 56 patients in the LOH–high subgroup, and 59 patients in the LOH–low subgroup.
Patients in the BRCA–mutant subgroup achieved the longest median PFS (12.8 months; HR = 0.27; 95% CI, 0.16-0.44) compared with the LOH–high group (5.7 months; HR = 0.62; 95% CI, 0.42-0.9) and the LOH–low subgroup (5.2 months).
In addition, a greater proportion of patients in the BRCA–mutant subgroup achieved 12-month PFS (50%; 95% CI, 33-65) than patients in the LOH–high subgroup (28%; 95% CI, 18-39) and LOH–low subgroup (10%; 95% CI, 4-19).
More patients achieved confirmed RECIST responses in the LOH–high subgroup (29%; 95% CI, 20-40) than the LOH–low subgroup (10%; 95% CI, 4-20).
Median duration of response was longer in the BRCA–mutant (9.2 months; 95% CI, 6.4-12.9) and LOH–high subgroups (10.8 months; 5.7-not reached) than in the LOH–low subgroup (5.6 months; 95% CI, 4.6-8.5).
“Our results add to the increasing body of evidence showing the potential of homologous recombination deficiency analysis to identify patients who will benefit from PARP inhibitor treatment,” Swisher and colleagues wrote.
The most common grade 3 or worse treatment-emergent adverse events included anemia or decreased hemoglobin (22%), and elevations in alanine aminotransferase or aspartate aminotransferase (12%).
Serious adverse events included small intestinal obstruction (5%), malignant neoplasm progression (5%) and anemia (4%).
Treatment-emergent adverse events led to dose reductions in 39% of patients.
Three patients died during the study, including two deaths from disease progression and one from sepsis and disease progression; no treatment-related deaths occurred.
“Additional studies should assess whether the homologous recombination deficiency assay developed in ARIEL2 predicts sensitivity to rucaparib and other PARP inhibitors in patients with other cancer types, including nonserous ovarian cancer, and gastric, pancreatic, prostate or breast cancers,” the researchers wrote.
Regarding the predictive value of the assay, the differences detected the LOH–high and LOH–low subgroups may not be clinically relevant, Antonio González Martín, MD, from MD Anderson Cancer Center Madrid, wrote in an accompanying editorial.
A planned post-hoc analysis of this study demonstrated that a refined cutoff for tumor genomic LOH of 16% more efficiently discriminated a difference in PFS between the LOH–high and –low subgroups compared with a cutoff of 14% (HR = 0.51; 95% CI, 0.34-0.74).
“[The ARIEL 2] trial constitutes a valuable effort in the challenge of identifying which patients with wild-type BRCA can benefit from PARP inhibition,” González Martín wrote. “However, an assay that is efficient and produces clinically meaningful results is still some way off.” – by Kristie L. Kahl
Disclosure: This study was funded by Clovis Oncology, the U.S. Department of Defense Ovarian Cancer Research Program OC120506, a V Foundation Translational Award and a Stand Up To Cancer–Ovarian Cancer Research Fund Alliance–National Ovarian Cancer Coalition Dream Team Translational Research Grant. Swisher reports no relevant financial disclosures. Please see the full study for a list of all other researchers’ relevant financial disclosures. Martín reports speaker/advisor roles with AstraZeneca, Clovis, PharmaMar and Roche.