ABSTRACT
Introduction: Poly(ADP-ribose) polymerase (PARP) inhibitors, including rucaparib, are the only targeted class of therapeutics approved for recurrent epithelial ovarian carcinoma with a predictive biomarker. Currently, three different PARP inhibitors are approved for either the treatment of ovarian cancer or maintenance of remission following chemotherapy. The Foundation Focus CDxBRCA is an FDA-cleared next-generation sequencing tumor tissue assay that detects somatic and sometimes germline mutations in BRCA1 and BRCA2 genes.
Areas covered: The authors discuss the evolution of the ovarian cancer genomic testing landscape relative to PARP inhibition, with a focus on Foundation Focus CDxBRCA and CDxBRCA Loss of Heterozygosity (LOH), the complementary diagnostics (CDx) to rucaparib.
Expert opinion: Relatively early in PARP inhibitor development, women with somatic and/or germline mutations in the BRCA1 and BRCA2 genes were found to have higher response rates to PARP inhibitors with longer durability than women who were BRCA wildtype. Other measures of homologous recombination deficiency including LOH have proven to be predictive biomarkers also. Because PARP biomarkers are genomic and complex, co-development of high-performance companion diagnostics was a high priority. The Foundation Focus test began as a next-generation sequencing assay capable of detecting germline (gBRCA) and somatic (sBRCA) mutations that predict response to rucaparib treatment. The addition of LOH to the assay was validated by a clinical trial supporting expansion of the Rucaparib FDA label to include maintenance of chemotherapy response.
Article Highlights
Epithelial ovarian cancer tumor biology guided integration of biomarkers into the drug development process for the PARP inhibitors (PARPi), including rucaparib. Approximately half of high-grade serous epithelial ovarian cancers have defects in the homologous recombination pathway; this deficiency is exploited with PARPi targeted therapy.
Rucaparib was initially approved for the third-line treatment or greater of recurrent ovarian cancer in women with tumor-expressed BRCA mutations as detected by an FDA-cleared companion diagnostic test. The scope of the genomic testing evolved to incorporate multi-gene sequencing and loss of DNA heterozygosity (LOH) as the rucaparib’s indications expanded to include maintenance of a complete or partial remission following platinum-based chemotherapy.
PARP inhibitors, including rucaparib, have differential activity in women with germline or somatic BRCA mutations, BRCA wild-type women whose tumors exhibit homologous recombination deficiency (HRD), and in BRCA wild-type women without HRD.
The BRCA mutation biomarker might be germline (heritable) and identify an EOC patient’s individual risk for other malignancies in addition to potential risk for their blood relatives.
Declaration of interest
One author discloses consulting with AstraZeneca, Clovis Oncology, Tesaro. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewers Disclosure
Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.