Genomic Scarring Predicts Rucaparib Activity in Ovarian Cancer

Genomic Scarring Predicts Rucaparib Activity in Ovarian Cancer

Dr. Elise C. Kohn

Results of the phase II ARIEL2 trial signify a breakthrough in identifying a broader group of patients with ovarian cancer who stand to benefit from inhibitors targeting the poly(ADP-ribose) polymerase (PARP) family of proteins involved in DNA repair. The study successfully reached beyond BRCA-mutant disease to find other tumors with faults in DNA repair that responded to rucaparib, an investigational PARP inhibitor recently granted a Breakthrough Therapy designation from the U.S. Food and Drug Administration (Abstract 5508).

“This is the first clinical study to demonstrate prospectively that a genome scarring (homologous recombination deficiency [HRD]) signature can identify BRCA wild-type tumors that will benefit from rucaparib,” said Iain A. McNeish, BA, BMBCh, PhD, MRCP, FRCP, of the Institute of Cancer Sciences at the University of Glasgow, United Kingdom, who presented the results during the Gynecologic Cancer Oral Abstract Session on Monday, June 1.

Dr. Iain A. McNeish
 PARPs normally spring into action to repair single-strand breaks in DNA. Blocking PARP activity causes these breaks to accumulate, but other pathways of DNA repair often step in to fix the damage and maintain genomic integrity. The trick for enhancing PARP inhibitor activity is to use these agents in tumors deficient in other DNA repair mechanisms to leave DNA damage unrepaired, resulting in cell lethality—a strategy not fully leveraged during the development of some prior PARP inhibitors, which led to their demise.

PARP inhibitors succeed in patients with tumors harboring BRCA mutations because mechanisms that repair double-strand DNA via homologous recombination are defective. Other mutations can also derail homologous recombination (e.g., RAD51C, PALB2) but are present at low frequencies in ovarian cancer, making it hard to identify non-BRCA–mutated tumors that may benefit from PARP inhibition. As Dr. McNeish explained, next-generation sequencing offers a way to catch these non-BRCA mutations by identifying tumor tissue with large areas of genomic scarring signaled by loss of heterozygosity—a natural consequence of HRD that produces a “BRCA-like” gene signature.

Fig 1. Enhanced Benefit from Rucaparib in Patients with BRCA Wild-Type Tumors

Click to Expand.

Fig 1. Enhanced Benefit from Rucaparib in Patients with BRCA Wild-Type Tumors

ARIEL2 put this genomic technology to the test. The trial featured a single-arm design assessing rucaparib efficacy in three prospectively defined molecular subgroups identified using next-generation sequencing: BRCA-mutant disease (20% of the cohort), BRCA-like disease (40% of the cohort), and disease negative for either of these biomarkers (34% of the cohort). A total of 204 individuals with high-grade serous or endometrioid ovarian cancer participated, all of whom had received at least one prior platinum-based regimen but who still had platinum-sensitive disease.

Rucaparib benefited patients with BRCA-mutant tumors, with a median progression-free survival (PFS) of 9.4 months and overall response rate (ORR) of 82% (Fig. 1). Compared with biomarker-negative disease, this translates into a 53% reduction in the risk of disease progression for patients with BRCA-mutant tumors (HR 0.47, 95% CI [0.35, 0.64]).

Notably, in patients with BRCA wild-type tumors, rucaparib also proved efficacious in the BRCA-like subgroup, which attained a median PFS duration of 7.1 months and an ORR of 45%. These results far exceeded those of the subgroup with biomarker-negative disease, which showed a median PFS duration of 3.7 months and an ORR of 21% (Fig. 1). The risk of disease progression in BRCA-like disease was reduced by 39% compared with biomarker-negative disease (HR 0.61, 95% CI [0.41, 0.92]).

“This is a very exciting step forward, showing a clear biomarker–treatment interaction and a true predictive value of the HRD score,” discussant Elise C. Kohn, MD, of the National Cancer Institute at the National Institutes of Health, said.

Watch the session: Visit the ASCO Virtual Meeting website.