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Rucaparib maintenance therapy provided consistent benefits across all subgroups of patients grouped by prognostic factors of their homologous recombination deficiency-negative ovarian cancer tumors.

Vanda Salutari, MD, of the Gynecology Oncology Unit at Policlinico Agostino Gemelli in Rome, Italy, presented this and other findings of a subgroup analysis of the ATHENA-MONO trial at ESMO Gynecological (ESMO Gyn) Cancers Congress 2025.

Homologous recombination deficiency (HRD)-negative disease represents the largest subgroup in ovarian cancer, comprising approximately 44% of patients in the ATHENA-MONO study, Salutari noted in her presentation. These patients, characterized as BRCA wild-type with low loss of heterozygosity (< 16%), experience worse progression-free survival (PFS) and overall survival outcomes than those with BRCA mutations or HRD-positive disease.

The trial revealed encouraging efficacy data for the treatment regimen in patients who are historically associated with poor prognosis, the investigator said.

In the original ATHENA-MONO analysis, rucaparib imparted a 35% reduction in progression risk compared with placebo in this subgroup of HRD-negative patients, and this “was also supported by an interim analysis of overall survival,” she explained.

The ATHENA-MONO trial enrolled patients with newly diagnosed stage III-IV advanced high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who had completed frontline platinum-doublet chemotherapy and achieved complete or partial response. Patients were randomized 4:1 to receive oral rucaparib 600 mg twice daily or placebo for up to 24 months.

In the HRD-negative population (189 patients receiving rucaparib, 49 receiving placebo), rucaparib demonstrated an improvement in investigator-assessed PFS. The median PFS was 12.1 months in the rucaparib group compared with 9.1 months in the placebo group (hazard ratio [HR], 0.65; 95% CI, 0.45-0.95).

The subgroup analysis revealed strong benefits in specific patient populations. The most pronounced benefit was observed in patients with measurable disease (HR, 0.25; 95% CI, 0.08-0.80) and in those with elevated CA-125 levels (HR, 0.29; 95% CI, 0.10-0.84). Patients with residual disease after chemotherapy (HR, 0.38; 95% CI, 0.19-0.79) and those who underwent interval debulking surgery (HR, 0.53; 95% CI, 0.32-0.88) also derived strong benefits.

Salutari concluded her presentation by describing what she saw as the clinical implications of her research.

“First-line rucaparib maintenance reduced the risk of progression in patients with advanced, HRD-negative high-grade ovarian cancer across all prognostic factors evaluated,” Salutari emphasized. “These data suggest that rucaparib is a potential beneficial therapeutic option for all patients, including those with HRD-negative tumors.”

Potential Mechanisms Driving Efficacy

Jean-Emmanuel Kurtz, MD, PhD, of the University of Strasbourg, Strasbourg, France, serving as the external discussant, explained that the benefit of PARP inhibitor therapy in HRD-negative disease seen in this trial was somewhat unexpected.

“In HRD-negative cells, in theory, PARP inhibition would not drive any outcome benefit because of synthetic lethality,” Kurtz said. “However, we know from the PRIMA study that [PARP inhibitors] provide PFS benefit in HRD-negative patients, and this was also found in ATHENA-MONO.”

Kurtz explained that PARP inhibitors may work through alternative mechanisms in HRD-negative cells, including immune activation.

“PARP inhibitors do something in those cells. They induce a senescence-like phenotype and upregulate a series of cytokines and chemokines. This senescence-associated phenotype recruits immune cells to the tumor that potentially activate immune responses,” he said.

Kurtz added that tumor burden appears to also be a driver of rucaparib efficacy in the HRD-negative population. “What is interesting here is that the hazard ratio differences might be driven by patients with poor prognosis risk factors, such as FIGO, CR-125, and measurable disease,” he said.

Manageable Safety Profile

The safety analysis revealed no new safety signals in the HRD-negative population, with an adverse event profile consistent with that in previous rucaparib studies.

The most common any-grade treatment-emergent adverse events in patients who received rucaparib were asthenia (63.5%), nausea (59.3%), and anemia (46.6%).

Salutari said that grade 3 or higher treatment-emergent adverse events were manageable, with anemia (26.5%), neutropenia (14.8%), and elevated liver enzymes (13.2%) being the most common grade 3 or higher treatment-emergent adverse events in the rucaparib group.

Implications and Future Directions

According to Kurtz, the results of this analysis add to growing evidence that PARP inhibitors may have utility beyond their established role in HRD-positive disease. He noted the complexity of ovarian cancer biology, describing it as “like a jigsaw puzzle with different shapes” that includes BRCA wild-type, HRD non-BRCA, genomic and somatic BRCA-mutated populations, and a “grey zone” of testing failures and undetected mutations.

He added that the ATHENA-MONO findings complement results from other maintenance trials, including PRIMA with niraparib, suggesting a potential class effect of PARP inhibitors in HRD-negative disease.

“Data from the ATHENA-MON demonstrated that rucaparib efficacy is associated with HRD, but in HRD-negative patients, tumor burden may drive the drug efficacy,” Kurtz concluded.

Further research is needed to identify biomarkers that could better predict which HRD-negative patients are most likely to benefit from maintenance therapy with PARP inhibitors, he added.

Salutari reported financial relationships with MSD, AbbVie, AstraZeneca, GSK, ImmunoGen, and Menarini. Kurtz reported financial relationships with AstraZeneca, Eisai, GSK, Chugai Pharma, PharmaMar, and MSD.

Christos Evangelou, PhD, is a freelance medical writer and science communications consultant.