BRCA-Like Classification May Be a Useful Biomarker for Olaparib Response in Ovarian Cancer

Adding olaparib to maintenance therapy with bevacizumab was associated with significantly longer survival among patients with ovarian cancer whose tumors have a BRCA-like genomic profile, but not among those with non-BRCA-like tumors, according to a secondary analysis of the PAOLA-1 trial published in JAMA Network Open.¹ The findings suggest a BRCA-like genomic copy number aberration profile classifier could be used as a biomarker for olaparib maintenance for ovarian cancer.

In the primary analysis of the randomized, double-blind, phase 3 PAOLA-1 (NCT02477644) trial, adding maintenance olaparib to first-line standard bevacizumab to olaparib significantly improved progression-free survival (PFS), with substantial benefits seen in patients with homologous-recombination deficiency (HRD)-positive tumors, including those without a BRCA mutation.² Based on these findings, the FDA expanded the approval of olaparib to its combination with bevacizumab as first-line maintenance therapy for advanced high-grade ovarian carcinoma.³

However, patients with HRD-negative tumors or tumors of unknown HRD status treated with olaparib experienced similar median PFS to the bevacizumab plus placebo group in PAOLA-1.² The authors of the current study explained that there remains a need for consistency in defining patient subgroups and to assess HRD phenotypes in ovarian cancer.¹

“A wide range of potential tests to identify HRD tumors are available, ranging from mutational testing and mutational and copy number signatures to functional assays,” the study authors wrote.¹ “However, there is a need for improvement of defining the patient subgroups, as globally there is a lack of consistently defined subgroups, a lack of negative predictive value in most of these tests, and an inadequate assessment of the complex and dynamic nature of HRD phenotype.”

AI image of microscope looking at ovarian cancer cells | Image credit: Justlight - stock.adobe.com

The new study was a secondary biomarker-by-treatment interaction analysis that aimed to determine whether olaparib maintenance treatment confers longer survival among patients with ovarian cancer with and without a previously established BRCA-like genomic profile.¹ The study authors previously created a BRCA-like genomic copy number aberration profile classifier (BRCA-like classifier) that determines whether a tumor has mutations like those seen among patients with BRCA1 and BRCA2 germline pathogenic variants and may identify HRD-positive tumors.⁴

To determine whether adding olaparib to maintenance therapy in first-line advanced ovarian cancer correlates with longer survival among those with BRCA-like tumors than non–BRCA-like tumors, the BRCA-like classifier was used on a subgroup of 469 patients who took part in PAOLA-1.¹ The median patient age was 60 years (range, 26-80 years), and the cohort included women with stage III (76%) high-grade serous (95%) ovarian cancer based on International Federation of Gynecology and Obstetrics criteria and those with no evaluable disease or who were in complete remission at initial or interval debulking surgery (76%).

Pathogenic BRCA mutations were present in 31% (n = 138) of tumor samples, and BRCA-like classification was conducted for 442 patients. There was a total of 336 PFS and 245 overall survival (OS) events in the cohort, that had a median follow-up of 54.1 months (IQR, 28.5-62.2 months) and a total follow-up of 21,711 months available for analysis.

Median PFS was 36.4 months among patients with BRCA-like tumors treated with olaparib vs 18.6 months among patients who received a placebo (HR, 0.49; 95% CI, 0.37-0.65; P < .001). However, there was no significant difference in median PFS between patients with non­–BRCA-like tumors treated with olaparib vs placebo (17.6 vs 16.6 months; HR, 1.02; 95% CI, 0.68-1.51; P = .93).

Median OS was 75.2 with olaparib vs 54.9 months with placebo among those with BRCA-like tumors (HR, 0.64; 95% CI, 0.45-0.90; P = .01). Among patients with non–BRCA-like tumors treated with olaparib, median OS was 38.8 months vs 52.3 months among those in the placebo group (HR, 1.48; 95% CI, 0.94-2.33; P = .09). While there was no significant difference in ovarian cancer prognosis based on BRCA status alone, the interaction between BRCA-like status and treatment was significant for both OS (P = .004) and PFS (P = .004).

The study was limited as it was a post hoc exploratory analysis. Despite being prespecified, the authors noted the findings should be carefully interpreted regarding statistical testing and multiplicity, the authors noted. Additionally, only a subgroup of patients was available for the analysis, and not all molecular results were known. However, the study offered a unique opportunity to validate and further assess a new biomarker for HRD.

“In this cohort study, the addition of olaparib was associated with longer PFS and OS in patients with advanced, high-grade epithelial OC with a BRCA-like tumor but not in patients with a non–BRCA-like tumor,” the authors concluded. “Therefore, BRCA-like status may serve as a predictive biomarker in this patient population. The benefits of the BRCA-like classifier include a lower dropout rate and a larger group of patients with biomarker-positive tumors compared with the reference HRD test.”

The classifier will be tested further in the AGO-OVAR28 study (NCT05009082), the authors noted.

Reference

1. Schouten PC, Schmidt S, Becker K, et al. Olaparib addition to maintenance bevacizumab therapy in ovarian carcinoma with BRCA-like genomic aberrations. JAMA Netw Open. Published online April 1, 2024. doi:10.1001/jamanetworkopen.2024.5552

2. Ray-Coquard I, Pautier P, Pignata S, et al. Olaparib plus bevacizumab as first-line maintenance in ovarian cancer. N Engl J Med. 2019;381(25):2416-2428. doi:10.1056/NEJMoa1911361

3. FDA approves olaparib plus bevacizumab as maintenance treatment for ovarian, fallopian tube, or primary peritoneal cancers. News release. FDA. May 8, 2020. Accessed April 30, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-olaparib-plus-bevacizumab-maintenance-treatment-ovarian-fallopian-tube-or-primary

4. Schouten PC, Richters L, Vis DJ, et al. Ovarian cancer–specific BRCA-like copy-number aberration classifiers detect mutations associated with homologous recombination deficiency in the AGO-TR1 Trial. Clin Cancer Res. 2021;27(23):6559-6569. doi:10.1158/1078-0432.CCR-21-1673