HRR mutational status is prognostic and predictive biomarker olaparib activity

Homologous recombination repair (HRR) mutation status in patients with recurrent, platinum-sensitive ovarian cancer is prognostic for progression-free survival (PFS) and predictive for activity of olaparib compared with chemotherapy, results from pre-planned exploratory analysis of the NRG-GY004 trial showed.

Homologous recombination deficiency (HRD) is associated with improved efficacy of PARP inhibitors in patients with (recurrent) platinum-sensitive ovarian cancer, but interaction between HRD and combined anti-angiogenics and PARP inhibitors is unclear. Previously presented results from the randomised phase 3 NRG-GY004 trial (NCT02446600) did not show an improved PFS or overall response rate (ORR) of the combination cediranib/olaparib compared with platinum-based chemotherapy [1]. Assessment of outcomes by HRD status was a pre-planned translational endpoint. Results were presented by Dr Joyce Liu (Dana-Farber Cancer Institute, MA, USA) [2].

Associations between clinical outcomes, HRR mutation status, and loss of heterozygosity (LOH) in 470 patients were evaluated. Core HRR genes were wildtype (HRRwt) in 323 patients, mutant (HRRmt) in 147, and not assessable (NA) in 21. Over 90% of HRRmt were BRCA-mutated. LOH was low in 147 patients, high in 79, and NA in 265, mostly due to inadequate tumour content. Across all patients, HRRmt was prognostic for a longer PFS versus HRRwt (median PFS 13.7 vs 8.3 months; HR 0.41: P<0.0001). In patients with HRRmt, median PFS was 12.3, 13.1, and 20.4 months for chemotherapy, olaparib, and cediranib/olaparib, respectively. In patients with HRRwt, median PFS was 9.0, 6.4, and 8.5 months for chemotherapy, olaparib, and cediranib/olaparib. So, HRR status predicted olaparib response versus chemotherapy (P=0.0176) but not cediranib/olaparib response versus chemotherapy (P=0.1009). LOH was not an independently prognostic and/or predictive biomarker for activity versus chemotherapy.

“In NRG-GY004 patients, HRR mutational status, but not LOH, was prognostic for PFS and predictive for activity of olaparib compared with chemotherapy,” summarised Dr Liu.

1. Liu JF, et al. J Clin Oncol 38: 2020 (suppl; abstr 6003).
2. Liu JF, et al. Association of homologous recombination deficiency (HRD) with clinical outcomes in a phase III study of olaparib or cediranib and olaparib compared to platinum-based chemotherapy in recurrent platinum-sensitive ovarian cancer (PSOC): Biomarker analyses from NRG-GY004. Abstract LBA34, ESMO Congress 2021, 16–21 September.

 

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Posted on 19 November 202117 May 2024