Results from a multicenter, retrospective study found that the location in the functional domain and type of BRCA mutation may impact the effectiveness of poly (ADP-ribose) polymerase (PARP) inhibitors for patients with advanced ovarian cancer receiving PARP inhibitors as maintenance after a response to platinum-based chemotherapy in the first line.

At the 2023 ESMO Gynecological Cancers Congress, Claudia Marchetti, MD, Sapienza University of Rome, Italy, reported results from the study.

Between December 2008 and October 2021, 202 patients with advanced ovarian cancer were treated with PARP inhibitors. Of those, 122 (60.4%) were treated with PARP inhibitors in the first-line setting and 80 received PARP inhibitor treatment at recurrence. In the first group, 73 (60%) were BRCA1-positive and 49 (40%) had the BRCA2 mutation. BRCA1 mutations were located in the functional domains of RING in 3 (2.5%) patients, in DNA binding domain (DNA-BD) in 8 (6.6%) patients, and BRCT in 21 (17.2%) patients. BRCA2 mutations were detected in functional domains of RAD51-BD in 25 (20.5%) patients and DNA-BD in 5 (4.1%) patients.

At a median follow-up of 20 (range: 4 to 100) months, patients with BRCA1/2 mutations in DNA-BD experienced a 2-year progression-free survival (PFS) of 100% vs 80% in all mutations in other domains (log rank P = .079). Additionally, patients with missense BRCA1 mutations also experienced a 2-year PFS of 100% vs 50% of patients with a splicing mutation (log rank P = .021) and 75% of patients with a nonsense mutation (log rank P = .049).

The study did not analyze mutation types in BRCA2 due to the small sample size.

Citing previous clinical data from the PAOLA1 study indicating mutations in DNA binding domain (DNA-BD) of BRCA1 may cause patients to be more sensitive to the combination of olaparib and bevacizumab and that patient outcomes were favorable when mutations occurred in the DNA-BD of BRCA2, Dr Marchetti concluded that the presented results, “confirmed that mutations in the DNA-BD region in the BRCA 1/2 genes confer longer PFS,” relative to other functional domains.

Source:

Marchetti C. “Efficacy of maintenance with PARPi in advanced ovarian cancer according to the location of BRCA mutation.” Presented at ESMO Gynecological Cancers Congress; February 23-25, 2023; Barcelona, Spain. Abstract 42P

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