Introduction

BRCA1 and BRCA2 are the primary susceptibility genes for hereditary breast and ovarian cancer syndromes, responsible for 5%-7% of breast cancer cases and 10%-15% of ovarian cancer cases.

Aim

To determine the predictive value of the location of BRCA1/ BRCA2 mutations (BRCAm) on benefit from maintenance with Olaparib and bevacizumab

Patient Profile

Patients with advanced-stage (FIGO stage III and IV) high-grade carcinoma of the ovary (endometrioid, serous, or other epithelial non-mucinous).

Methods

• Post hoc analysis of data from the PAOLA-1 trials
• 233 women with BRCA1/BRCA2 mutations were included
• Patients received maintenance therapy bevacizumab (15 mg/kg q3w for 15 mos) + either olaparib (300 mg b.i.d. for 24 mos) or placebo
• PFS was analyzed in the subgroup of patients with BRCA1m/BRCA2m according to mutation location in the functional domains of BRCA1 [Really Interesting Gene (RING), DNA-binding domain (DBD), or C-terminal domain of BRCA1 (BRCT)] and BRCA2 [RAD51-binding domain (RAD51-BD); DBD].

Results

Effect of mutated gene and exon 11 on outcomes with olaparib & bevacizumab

• No differences in efficacy of Olaparib bevacizumab were observed according to which gene was mutated [BRCA1, HR 0.26; BRCA2, HR 0.22 ; interaction P 0.64]
• Patients with or without mutations located in exon 11 of both genes derived benefit from Olaparib plus bevacizumab [exon 11, HR 0.2 ;non-exon 11, HR 0.41].

Effect of location of mutations in BRCA1 on Benefit with olaparib and bevacizumab

• Variations in PFS were noted when comparing subgroups based on the mutation locations within the various domains of BRCA1
• After a median follow-up of 25.5 months, maintenance treatment with Olaparib plus bevacizumab showed benefits regardless of BRCAm location, particularly for BRCA1m located in the DBD, who had a 24-month PFS of 89% vs 15% with placebo plus bevacizumab, while  in patients with BRCA2m located in DBD had PFS rates of 90% and 100%, respectively. (Figure 1)

Figure 1: PFS according to the location of mutations in BRCA1 and BRCA2 located in DBD

DBD, DNA-binding domain

• A clinical benefit of Olaparib plus bevacizumab was observed in patients harbouring mutations located in the BRCA2 RAD51-BD [HR 0.31 interaction P 0.39], as well as in those carrying mutations in genomic locations other than DBD and RAD-51 BD (Table 1)

Table 1: PFS according to the location of mutations in BRCA1 and BRCA2

AA, amino acid; BRCT, C-terminal domain of BRCA1; CI, confidence interval; DBD, DNA-binding domain; HR, hazard ratio; NC, not calculated; NR, not reached; PFS, progression free survival; RAD51-BD, RAD51-binding domain; RING, Really Interesting New Gene.

• A clinical benefit of olaparib and bevacizumab was noted in patients with mutations in the BRCA2 RAD51-binding domain (RAD51-BD) [HR 0.31, interaction P =0.39], as well as in those with mutations located in other genomic regions outside of the DNA-binding domain (DBD) and RAD51-BD [HR =0.09, interaction P = 0.29]

Benefit of olaparib and bevacizumab according to mutation type

• No mutation types were found to modify the benefit of olaparib plus bevacizumab, (all interaction P> 0.01)

Conclusion

The study demonstrated that all women with BRCA1/BRCA2 mutations benefit from maintenance therapy with olaparib and bevacizumab, irrespective of the mutation locations in either gene, although the extent of benefit varies.

Reference

Ann Oncol. 2023 ;34(2):152-162