An ancillary analysis of the phase 3 PAOLA-1/ENGOT-ov25 trial has revealed significant correlations between PD-L1 expression and homologous recombination deficiency (HRD) status in patients with newly diagnosed, advanced high-grade serous ovarian cancer (HGSOC), with PD-L1 positivity demonstrating independent prognostic value for overall survival.
The findings, presented at the 2025 ESMO Gynecological Cancers Congress, showed that PD-L1 positivity was significantly more common in HRD-positive tumors across multiple scoring methodologies. Among the 324 patients analyzed, 70.4% of the HRD-positive population (n = 189) had a PD-L1 combined positive score (CPS) of at least 1 compared with 53% of patients with HRD-negative tumors (n = 101; P = 0.002).
Strong Association Between PD-L1 and HRD Status
The correlation between PD-L1 expression and HRD status was consistent across different scoring methods. Using immune cell (IC) scoring, 65.1% of HRD-positive tumors versus 52% of HRD-negative tumors met the CPS threshold of at least 1 (P = 0.012). These associations were statistically significant and suggest a biological relationship between immune activation and DNA repair deficiency.
"PD-L1 positivity assessed by CPS is associated with [increased] HRD-positive status and better OS, independent of age, surgery timing, treatment arm, residual disease, FIGO stage, or HRD status," said lead study author Isabelle Treilleux, MD, of the Department of Biopathology at Centre Léon Bérard in Lyon, France.
In the overall population of 324 patients, the rates of PD-L1–positive tumors using CPS, IC, and tumor proportion score (TPS) were 66.1%, 62.4%, and 38.2%, respectively.
Independent Prognostic Value for Survival
Cox regression analyses demonstrated that PD-L1 positivity was independently associated with improved overall survival across multiple scoring methods. In univariate analysis, PD-L1 positivity by CPS showed a hazard ratio of 0.62 (95% CI, 0.45-0.86; P = 0.005), while IC score positivity demonstrated an HR of 0.60 (95% CI, 0.43-0.83; P = 0.002).
These survival benefits remained statistically significant in multivariate analysis, with CPS positivity associated with an HR of 0.70 (95% CI, 0.50-0.97; P = 0.037) and IC score positivity showing an HR of 0.68 (95% CI, 0.49-0.95; P = 0.025). Importantly, these associations were independent of other clinical variables including age, FIGO stage, surgery timing, treatment arm, residual disease status, and HRD status.
While progression-free survival showed a favorable trend in PD-L1–positive patients, the difference did not reach statistical significance. "A [positive] trend [was] observed for PFS, although not statistically significant. [These findings] from a subgroup study…from PAOLA-1 requires additional studies," Treilleux noted.
Study Design and Patient Characteristics
This retrospective biomarker analysis examined 324 tumor samples selected from the broader PAOLA-1 population of 806 patients, chosen based on the largest tumor area and cellular content. All patients had FIGO stage III or IV HGSOC.
HRD status was determined using the Myriad MyChoice® CDx HRD assay, which defines HRD positivity as the presence of a BRCA mutation and/or high genomic instability score. PD-L1 expression was assessed using the PD-L1 Immunohistochemistry 22C3 pharmDx assay, an FDA-approved companion diagnostic, with seven experienced pathologists independently reviewing all slides.
The patient cohort was representative of advanced ovarian cancer populations, with a mean age of 59.3 years. Most patients had primary ovarian tumors (87.3%) and FIGO stage IIIC disease (67.9%), with 75.9% having no metastases. HRD positivity was reported in 58.4% of patients overall, including 60.6% in the olaparib arm and 53.7% in the placebo arm.
Clinical Implications
The PAOLA-1 trial previously led to FDA approval in May 2020 of olaparib plus bevacizumab for first-line maintenance treatment of adult patients with advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in complete or partial response to first-line platinum-based chemotherapy and whose cancer is associated with HRD-positive status.
These new findings suggest that PD-L1 expression may serve as a complementary biomarker to HRD, potentially identifying subgroups with distinct tumor biology and prognostic profiles. While immune checkpoint inhibitors are not currently standard of care in ovarian cancer, PD-L1 has been explored as a potential predictive biomarker in ongoing clinical trials combining immunotherapy with PARP inhibitors or antiangiogenic agents.
The exploratory nature of these findings warrants further validation in prospective studies, particularly as the field continues to investigate the role of immunotherapy in ovarian cancer treatment strategies.
