Irman Forghani, MD
Clinical Assistant Professor
Division of Clinical and Translational Genetics
University of Miami
Homologous recombination repair mutation gene panels (excluding BRCA) are not predictive of maintenance olaparib plus bevacizumab efficacy in the first-line PAOLA-1/ENGOT-ov25 trial
Pujade-Lauraine E. Presented at: 2021 Society of Gynecologic Oncology Annual Meeting. March 19-25. Virtual.
Specific HRD Testing Helps to Clarify the Role for PARP Inhibition in Ovarian Cancer
Until recently, the only treatment options for advanced ovarian cancer was debulking surgery in combination with chemotherapy. Randomized phase 3 trials, in last few years, proved that the addition of a PARP inhibitor, significantly prolongs the progression-free survival (PFS) in patients with high-grade ovarian cancer. This is particularly significant in ovarian tumors with homologous recombination deficiency (HRD) which is defined as having a deleterious BRCA mutation, and/or genomic instability (GIS). Consequently, PARP inhibitors have been approved by the FDA and the European Medicines Agency as first-line maintenance therapies for patients with advanced ovarian cancer.
The phase 3 PAOLA-1/ENGOT-ov25 trial showed significant PFS benefit in using olaparib in combination with the angiogenesis inhibitor bevacizumab as a first-line maintenance therapy in patients with advanced ovarian cancer with HRD, regardless of the presence of a deleterious BRCA mutation. The FDA has approved the maintenance therapy with olaparib plus bevacizumab therapy for advanced ovarian cancers with HRD. The FDA also approved Myriad myChoice HRD PLUS assay as a companion diagnostic test for olaparib to assess the GIS and HRD status of the tumor.
In addition to Myriad genomic instability score assay, next generation sequencing (NGS) panels of genes involved in homologous recombination repair (HRR) pathway have been suggested for HRD testing. At this year’s Society of Gynecologic Oncology (SGO) Annual Meeting, Pujade-Lauraine and colleagues presented data evaluating the value of these gene panels and their effect on PFS in the PAOLA-1 trial.
Pujade-Lauraine and colleagues found that these gene panels cannot predict PFS in patients receiving olaparib and bevacizumab maintenance therapy. The investigators explored mutations in genes involved in HRR pathway with the exception of BRCA. They demonstrated that Non-BRCA HRR gene panels testing captured only a small proportion of the patients with high-grade ovarian cancer (3.7%-9.8%) in compare to the GIS assay (20%). HRD detected by genomic instability score was not equivalent to HRD detected by Non-BRCA HHR mutation test in this study. Furthermore, tumors harboring a Non-BRCA HHR mutation did not show a statistically significant improvement in PFS in olaparib plus bevacizumab vs olaparib plus placebo. In contrast, even in a small non-BRCA HRR mutation positive population, positive GIS test, appeared to be predictive of a PFS improvement in olaparib vs placebo group.
Advancement in molecular technologies has facilitated revolutionary discoveries in ovarian cancer pathology and subsequently treatment options. Maintenance olaparib and bevacizumab combination therapy in PAOLA-1 trial yields a great promise in the treatment of advanced ovarian cancer, particularly those patients with HRD. Nonetheless, proper patient selection is the key to maximize the PFS benefits in these patient population.
This study compares the available methods for HRD testing, genomic instability assay and NGS gene panel testing in the PAOLA-1 trial. The results showed that GIS assay is superior to gene panel testing for maintenance olaparib and bevacizumab combination therapy.
Myriad has recently appointed a more comprehensive HRD assay as Myriad myChoice® CDx PLUS test, that combines the GIS assay with tumor mutation status of 15 genes involved in HRR including BRCA1/BRCA2, ATM, BARD1, BRIP1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L. However, due to the lack of supportive evidence, it is premature to use these results to determine who is best for PARP inhibition therapy.
Future studies on larger subgroups of ovarian cancers with non-BRCA HHR deleterious mutation should be considered to confirm the findings presented in this study. In the meantime, GIS assay is the best predictive test for PFS benefit in maintenance olaparib plus bevacizumab therapy in advance ovarian cancer with HRD.