Exploratory biomarker analysis in the phase III L-MOCA study of olaparib maintenance therapy in patients with platinum-sensitive relapsed ovarian cancer

BMC Med. 2024 May 16;22(1):199. doi: 10.1186/s12916-024-03409-9.

Abstract

Background: The prospective phase III multi-centre L-MOCA trial (NCT03534453) has demonstrated the encouraging efficacy and manageable safety profile of olaparib maintenance therapy in the Asian (mainly Chinese) patients with platinum-sensitive relapsed ovarian cancer (PSROC). In this study, we report the preplanned exploratory biomarker analysis of the L-MOCA trial, which investigated the effects of homologous recombination deficiency (HRD) and programmed cell death ligand 1 (PD-L1) expression on olaparib efficacy.

Methods: HRD status was determined using the ACTHRD assay, an enrichment-based targeted next-generation sequencing assay. PD-L1 expression was assessed by SP263 immunohistochemistry assay. PD-L1 expression positivity was defined by the PD-L1 expression on ≥ 1% of immune cells. Kaplan-Meier method was utilised to analyse progression-free survival (PFS).

Results: This exploratory biomarker analysis included 225 patients and tested HRD status [N = 190; positive, N = 125 (65.8%)], PD-L1 expression [N = 196; positive, N = 56 (28.6%)], and BRCA1/2 mutation status (N = 219). The HRD-positive patients displayed greater median PFS than the HRD-negative patients [17.9 months (95% CI: 14.5-22.1) versus 9.2 months (95% CI: 7.5-13.8)]. PD-L1 was predominantly expressed on immune cells. Positive PD-L1 expression on immune cells was associated with shortened median PFS in the patients with germline BRCA1/2 mutations [14.5 months (95% CI: 7.4-18.2) versus 22.2 months (95% CI: 18.3-NA)]. Conversely, positive PD-L1 expression on immune cells was associated with prolonged median PFS in the patients with wild-type BRCA1/2 [20.9 months (95% CI: 13.9-NA) versus 8.3 months (95% CI: 6.7-13.8)].

Conclusions: HRD remained an effective biomarker for enhanced olaparib efficacy in the Asian patients with PSROC. Positive PD-L1 expression was associated with decreased olaparib efficacy in the patients with germline BRCA1/2 mutations but associated with improved olaparib efficacy in the patients with wild-type BRCA1/2.

Trial registration: NCT03534453. Registered at May 23, 2018.

Keywords: BRCA1/2; Biomarker; Homologous recombination deficiency; L-MOCA trial; Olaparib; PARP inhibitors; PD-L1 expression; Platinum-sensitive relapsed ovarian cancer.

Publication types

  • Clinical Trial, Phase III
  • Multicenter Study

MeSH terms

  • Adult
  • Aged
  • Antineoplastic Agents / therapeutic use
  • B7-H1 Antigen*
  • BRCA1 Protein / genetics
  • BRCA2 Protein / genetics
  • Biomarkers, Tumor* / genetics
  • Female
  • Homologous Recombination
  • Humans
  • Maintenance Chemotherapy* / methods
  • Middle Aged
  • Neoplasm Recurrence, Local / drug therapy
  • Ovarian Neoplasms* / drug therapy
  • Ovarian Neoplasms* / genetics
  • Phthalazines* / therapeutic use
  • Piperazines* / therapeutic use
  • Prospective Studies

Substances

  • olaparib
  • CD274 protein, human
  • BRCA2 protein, human
  • BRCA1 protein, human

Associated data

  • ClinicalTrials.gov/NCT03534453