Evaluation of homologous recombination deficiency biomarkers in patients with ovarian cancer treated with PARP inhibitors.

Leticia Campoverde University of Miami Miller School of Medicine/Sylvester Comprehensive Cancer Center, Miami, FL info_outline Leticia Campoverde, Laercio Lopes Da Silva, Hyan Silveira, Wilson Coelho Nogueira, Lida A. Mina, Gilberto Lopes, Felipe Batalini

Authors Leticia Campoverde University of Miami Miller School of Medicine/Sylvester Comprehensive Cancer Center, Miami, FL info_outline Leticia Campoverde, Laercio Lopes Da Silva, Hyan Silveira, Wilson Coelho Nogueira, Lida A. Mina, Gilberto Lopes, Felipe Batalini Organizations University of Miami Miller School of Medicine/Sylvester Comprehensive Cancer Center, Miami, FL, MetroWest Medical Center, Framingham, MA, Universidade Federal do Paraná, Cuiabá, Brazil, Universidade Estadual do Piauí, Teresina, Brazil, Mayo Clinic, Phoenix, AZ, University of Miami Miller School of Medicine, Miami, FL Abstract Disclosures Research Funding No funding received Background: Germline BRCA1/2 mutations are associated with response to Poly(ADP-ribose) polymerase inhibitors (PARPi). In addition to BRCA1/2 mutations, there are other Homologous Recombinations Deficiency (HRD) biomarker candidates already available in clinical practice including genome-wide loss-of-heterozygosity (gLOH) and myChoice score. Inconsistencies in biomarkers used in clinical trials with PARPi are a challenge to clinical interpretation. This study aims to compare clinically available HRD biomarkers in terms of benefits from PARPi. Methods: We performed database search for phase II or III randomized clinical trials comparing PARPi versus chemotherapy, and meta-analysis using generic inverse variance and a random-effects model. Patients were classified into three categories according to their HRD status: 1) BRCAmut (patients with BRCA1/2 mutation of germline or somatic origin), 2) non-BRCA HRD (patients BRCA wild-type (wt) with a different HRD biomarker - gLOH or myChoice); and 3) homologous recombination proficiency (HRP) (BRCAwt and without HRD biomarkers). From those that were BRCAwt, we compared myChoice+ with gLOH-high. Results: Eight studies (n = 4372 patients) with PARPi as first-line and recurrence settings were included. BRCAmut had PFS HR 0.29 (95%CI, 0.24-0.35), BRCAwt & HRD 0.43 (95%CI, 0.34-0.53) and HRP 0.74 (95%CI, 0.62-0.89). In a secondary analysis by HRD stratification method, patients with BRCAwt & myChoice > = 42 had PFS HR 0.43 (95%CI, 0.34-0.56), similar to patients with BRCAwt & gLOH-high with PFS HR 0.42 (95%CI, 0.28-0.62). Conclusions: Patients with BRCA mutations benefited the most from PARPi. From patients with BRCA1/2 wild-type, a similar benefit was found in patients with gLOH-high and those myChoice+, which was superior to HRP patients. The clinical development of further HRD biomarkers (i.e. Sig3, HRDetect) may help identify more patients who benefit from PARPi.