1655P - Association of location of BRCA1/2 pathogenic variants with benefit from PARP-inhibitors in metastatic castration-resistant prostate cancers: Results from the PROGRESS study

Background

BRCA (likely) pathogenic variants (PVs) have been consistently associated with aggressive phenotypes and adverse clinical outcomes in prostate cancer (PC). Recent research showed the association of location of BRCA PVs with benefit from olaparib in ovarian cancer. In PC, although lower cancer risk for BRCA2 carriers has been observed for PVs in a specific BRCA2 region (OCCR), the magnitude of PARP-inhibitor (PARPi) benefit according to the BRCA PV location is still unknown.

Methods

This was a real-world, multicenter, study including PC patients undergoing BRCA/Homologous Recombination Repair (HRR) germline (g), somatic (s), and liquid biopsy (lb) testing between January 2020 and April 2024. In the current analysis, prognostic factors and treatment outcomes were evaluated according to PV location within the functional domains (FDs) of BRCA genes.

Results

946 metastatic PC patients, aged 40 to 91, were included; 198 (20.9%) showed germline (54, 5.7%) or somatic (144, 15.2%) PVs in HRR genes: 21 BRCA1 (4 gBRCA1, 2%; 17 sBRCA1, 8.6% ), 124 BRCA2 (39 gBRCA2, 19.7%; 85 sBRCA2, 42.9%), and 56 no-BRCA HRR genes (11 gHRR, 5.5%; 45 sHRR, 22.7%). Liquid biopsy identified PVs in 39 patients out of 238 tested (16.4%), including 12 (5%) not detected through s/g testing, considerably expanding the therapeutic window for PARPi use. When we compared BRCA1 and BRCA2 subgroups, median PFS to PARPi was significantly longer for BRCA2 [7.0 months (95%CI 5.4-8.6) vs 11.0 months (95%CI 5.7-16.2), p=0.01]. Notably, differences in OS and PFS were observed depending on BRCA PV location. Greater benefit from PARPi was in patients with PVs in the DBD FDs of BRCA2, compared with RAD51-BD, or other location [15.0 months (95%CI 9.6-20.3) vs 8.0 months (95%CI 2.2-13.8) vs 7.0 months (95%CI 3.6-10.4), respectively; p=0.03], emphasizing the critical role of PV location on treatment outcomes. Outcomes following ARSi and taxanes, tissue used and timing of genetic testing were also assessed.

Conclusions

To our knowledge, this is the first real-world study providing preliminary evidence that not all BRCA2-mutated PCs are equally sensitive to PARPis, and the benefit could depend on the PV location within BRCA FDs.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.