PD-L1 and HRD Correlation Shows Prognostic Value in Ovarian Cancer

At the 2025 ESMO Gynecological Cancers Congress, an ancillary analysis of the phase 3 PAOLA-1/ENGOT-ov25 trial (NCT02477644) offered new insights into the prognostic role of PD-L1 expression and its relationship with homologous recombination deficiency (HRD) in patients with newly diagnosed advanced high-grade serous ovarian cancer (HGSOC).¹

In this retrospective biomarker analysis, PD-L1 positivity, evaluated using combined positive score (CPS) and immune cell (IC) score, was significantly more common in HRD-positive tumors and independently associated with improved overall survival (OS).

“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,” lead study author Isabelle Treilleux, MD, of the Department of Biopathology at Centre Léon Bérard in Lyon, France, said in a presentation of the data.

Although PAOLA-1 was originally designed to assess maintenance olaparib (Lynparza) plus bevacizumab (Avastin) in newly diagnosed patients responding to platinum-based chemotherapy, this ancillary work now adds a deeper biomarker dimension that could inform treatment personalization going forward.

PD-L1 Expression and HRD Status

The analysis examined 324 tumor samples from the PAOLA-1 population (n = 806), chosen based on the largest tumor area and cellular content. Patients included 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 a high genomic instability score.

PD-L1 expression was assessed via the IHC 22C3 pharmDx assay, an FDA-approved diagnostic that uses 3 scoring systems: CPS, IC, and tumor proportion score (TPS). Seven pathologists independently evaluated all slides to ensure scoring consistency.

Key findings from the study showed that 70.4% of the HRD-positive population (n = 189) had a PD-L1 CPS of at least 1 compared with 53% of HRD-negative tumors (n = 101; P =.002). Using IC scoring, 65.1% of HRD-positive tumors vs 52% of HRD-negative tumors had a CPS of at least 1 threshold (P =.012). These associations were statistically significant.

Across the full 324-patient cohort, the rates of PD-L1–positive tumors using CPS, IC, and TPS were 66.1%, 62.4%, and 38.2%, respectively. These data point to a statistically significant association between PD-L1 expression and HRD status, regardless of scoring methodology.

PD-L1 Positivity Linked to Better Survival Outcomes

In terms of prognostic relevance, Cox regression analyses demonstrated that PD-L1 positivity was independently associated with longer OS. In the univariate model, CPS positivity (HR, 0.62; 95% CI, 0.45-0.86; P =.005) and IC score positivity (HR, 0.60; 95% CI, 0.43-0.83; P =.002) both predicted improved survival.

These associations remained statistically significant in the multivariate analysis: CPS positivity was associated with an HR of 0.70 (95% CI, 0.50-0.97; P =.037), and IC score positivity was associated with an HR of 0.68 (95% CI, 0.49-0.95; P =.025).

Notably, these survival benefits were observed independently of other clinical variables, including age, FIGO stage, surgery timing, treatment arm, residual disease status, and HRD status. Although progression-free survival (PFS) 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 [require] additional studies,” Treilleux added.

These findings add new dimensions to the PAOLA-1 trial, which previously led to the May 2020 FDA approval of olaparib plus bevacizumab for maintenance therapy in patients with HRD-positive advanced epithelial ovarian, fallopian tube, or primary peritoneal cancer. That approval was based on the trial’s demonstration of improved PFS with the PARP inhibitor and antiangiogenic combination in patients whose tumors exhibited HRD, either through BRCA mutation or genomic instability.¹

The ancillary PD-L1 analysis now suggests that PD-L1 may serve as a complementary biomarker to HRD, potentially identifying subgroups with distinct tumor biology and prognostic profiles. According to Treilleux, PD-L1 expression as assessed by CPS is associated not only with HRD positivity but also with improved OS, regardless of standard clinical and treatment-related variables. She emphasized that the findings are exploratory and warrant further study, particularly in the context of immunotherapy research.

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.

Additional Trial Background

Those enrolled in the trial received olaparib at a dose of 300 mg twice daily for up to 24 months plus bevacizumab 15 mg/kg every 3 weeks for up to 15 months in total, or placebo plus bevacizumab.³

The patient cohort included in the ancillary analysis was representative of the broader PAOLA-1 study. The mean age of patients was 59.3 years.¹ Most had a primary ovarian tumor (87.3%) and FIGO stage IIIC disease (67.9%). Metastatic disease was absent in 75.9% of cases. Regarding surgery, 34.3% underwent primary debulking with macroscopic resection, 25.3% had primary debulking without macroscopic resection, 25.6% underwent interval debulking with macroscopic resection, and 10.2% had interval debulking without macroscopic resection. Only 4.6% of patients did not undergo any surgery.

HRD status was positive in 58.4% of the cohort overall. In the olaparib arm (n = 216), 60.6% of patients were HRD-positive, while in the placebo arm (n = 108), 53.7% were HRD-positive. HRD status was unknown in 10.5% (n = 34), and these patients were excluded from the correlation analysis between PD-L1 and HRD.

Taken together, the data from this analysis suggest that PD-L1 expression, particularly when assessed by CPS or IC scoring, may be a meaningful biomarker in HGSOC, not only in identifying HRD-positive tumors but also in predicting improved overall survival.

REFERENCES:

1. Treilleux I, Bataillon G, Cyrille S, et al. Prognostic value of PD-L1 expression and correlation with HRD in high grade serous ovarian cancer: an ancillary analysis of the PAOLA-1/ENGOT-ov25 trial, a GINECO study. Presented at: 2025 ESMO Gynecological Cancers Congress; June 19-21, 2025; Vienna, Austria. Abstract 74MO.

2. FDA approves olaparib plus bevacizumab as maintenance treatment for ovarian, fallopian tube, or primary peritoneal cancers. FDA. May 8, 2020. Accessed July 8, 2025. https://tinyurl.com/5whb8rh5

3. Harter P, Mouret-Reynier MA, Pignata S, et al. Efficacy of maintenance olaparib plus bevacizumab according to clinical risk in patients with newly diagnosed, advanced ovarian cancer in the phase III PAOLA-1/ENGOT-ov25 trial. Gynecol Oncol. 2022;164(2):254-264. doi:10.1016/j.ygyno.2021.12.016