Geneva HRD Test Predicts Survival Benefit From Olaparib Plus Bevacizumab in Advanced Ovarian Cancer

The Geneva homologous recombination deficiency (HRD) test has demonstrated predictive value for progression-free survival (PFS) and overall survival (OS) benefit from frontline maintenance therapy with olaparib (Lynparza) plus bevacizumab (Avastin) in patients with advanced-stage high-grade ovarian cancer, according to findings from a retrospective analysis of the phase 3 PAOLA-1 trial (NCT02477644) published in JCO Precision Oncology.

The Geneva HRD test is a genomic assay designed to assess deficiency based solely on a measure of genomic instability, the normalized large-scale state transition (nLST) score.

Among patients identified as HRD positive by the Geneva test, olaparib plus bevacizumab reduced the risk of disease progression or death by 59% compared with bevacizumab plus placebo (HR, 0.41; 95% CI, 0.30-0.57). However, no PFS benefit was observed with the olaparib combination among HRD-negative patients identified via the Geneva HRD test (HR, 1.20; 95% CI, 0.86-1.7). The OS analysis similarly favored the HRD-positive subgroup (HR, 0.56; 95% CI, 0.37-0.85). In contrast, HRD-negative patients derived no benefit and experienced inferior OS outcomes with olaparib plus bevacizumab (HR, 1.6; 95% CI, 1.1-2.3).

“Although olaparib has brought unprecedented and historic survival benefit as first-line maintenance monotherapy in BRCA-mutated high-grade ovarian cancer, and in combination with bevacizumab in HRD-positive patients, our results suggest a potential detrimental effect of frontline maintenance with olaparib and bevacizumab in the HRD-negative population as defined by the Geneva HRD test,” lead study author Yann Christinat, PhD, a clinical bioinformatician at Geneva University Hospitals in Switzerland, and colleagues wrote. “Overall, these findings emphasize the importance of HRD testing for precision medicine and choosing the appropriate frontline maintenance therapy for patients with high-grade ovarian cancer.”

Study Design

This analysis was conducted within the framework of the ENGOT HRD initiative, coordinated by the French Groupe des Investigateurs Nationaux pour l’Étude des Cancers de l’Ovaire (GINECO). A total of 469 tumor samples were selected from the PAOLA-1 cohort with advanced-stage high-grade ovarian cancer.

Sample selection prioritized tumor material with the highest DNA content, sourced from the ARCAGY-GINECO tumor bank at Institut Curie in Paris, France. DNA was extracted from formalin-fixed paraffin-embedded tumor sections, with preference for specimens obtained prior to initiation of systemic therapy. Of the samples analyzed, 76.5% (n = 359) were collected from prechemotherapy biopsies, and 21.5% (n = 101) were from postchemotherapy biopsies. From each specimen, 100 ng of tumor DNA was isolated, transferred to 96-well plates, and shipped to Geneva at –80°C following authorization from the French regulatory authority. Genomic profiling was performed using the OncoScan assay.

The primary selection criterion was the availability of sufficient tumor DNA to distribute to the 10 laboratories participating in the ENGOT HRD initiative. Among the 469 patients included, the magnitude of benefit from maintenance olaparib plus bevacizumab compared with bevacizumab alone was comparable to that observed in the overall PAOLA-1 study population.

Within this subset, patients had a median age of 60 years, and all had histologically confirmed high-grade ovarian adenocarcinoma with a response to first-line platinum-based chemotherapy in combination with bevacizumab. BRCA mutations were identified in 32% of patients, closely matching the prevalence in the broader trial population (29%). The clinical database was locked on March 22, 2022, corresponding to a median follow-up of 5 years and 55% data maturity for OS analyses.

Comparisons of Efficacy

“Although the Geneva HRD and the Myriad MyChoice tests are similar, they are not equivalent,” Christinat explained. “The Myriad test includes the BRCA mutation status in its algorithm, and the HRD score is computed with a different method. These differences might explain why the trend toward a detrimental effect on OS of olaparib with bevacizumab in the HRD-negative subpopulation was not significant with the Myriad test [HR, 1.2; 95% CI, 0.81-1.7].”

Notably, the Geneva test identified an additional subgroup of patients with intermediate HRD scores in which nLST score demonstrated both predictive and prognostic relevance, offering potential refinement in patient selection beyond what is achieved with the Myriad assay.

Patients with intermediate nLST scores (15-20; HRD-positive–mid) exhibited distinct clinical behavior compared with those with high nLST scores (≥ 20; HRD-positive–high). In prior observations, HRD-positive–mid patients showed an initial favorable response to olaparib plus bevacizumab maintenance therapy but tended to relapse earlier.

This pattern was confirmed in the final PFS analysis, which showed that HRD-positive–mid patients derived a magnitude of benefit from olaparib plus bevacizumab comparable to that seen in HRD-positive–high patients. A similar trend was observed for OS, with both subgroups demonstrating benefit from combination maintenance therapy.

In contrast, within the placebo plus bevacizumab arm, the HRD-positive–mid subgroup had inferior outcomes compared with HRD-positive–high patients, with shorter long-term PFS and OS rates. Although the HRD-positive–mid group was small in this arm, the OS difference compared with HRD-positive–high patients was statistically significant.

Moreover, there was a trend toward shorter OS for HRD-positive–mid patients compared with HRD-negative patients, though this did not reach statistical significance. Multivariate Cox analysis confirmed that the survival difference between HRD-positive–mid and HRD-positive–high patients persisted after adjusting for BRCA mutation status, response to primary chemotherapy, and subsequent PARP inhibitor therapy.

“These results will be validated on the remaining samples of the PAOLA-1 trial and should be challenged in the setting of other randomized phase 3 trials, such as ATHENA [NCT03522246], that used another HRD test and a different PARP inhibitor,” study authors added.

Reference

Christinat Y, Labidi-Galy I, Ho L, et al. Geneva homologous recombination deficiency test is predictive of survival benefit from olaparib and bevacizumab maintenance in ovarian cancer. JCO Precis Oncol. 2025;9:e2400825. doi:10.1200/PO-24-00825