Time on treatment for systemic therapies for patients with hormone receptor-positive breast cancer and <i>BRCA1</i> , <i>BRCA2</i> , or <i>PALB2</i> pathogenic variants.

1096 Background: For patients with hormone receptor-positive/HER2- (HR+) metastatic breast cancer and pathogenic variants (PVs) in BRCA1 , BRCA2 or PALB2 ( mBRCA), data suggests longer cancer-specific survival compared to patients without PVs (wtBRCA). One hypothesis is that their innate DNA repair deficiency improves response to cytotoxic therapy, as seen in poly (ADP-ribose) polymerase inhibitors (PARPi), which results in longer progression free survival (PFS). However, it remains unclear whether mBRCA is associated with a longer PFS with other therapies such as endocrine therapies (ET), including aromatase inhibitors (AI) and Selective Estrogen Receptor Degraders (SERDs). Some data suggests a shorter PFS with CDK 4/6-inhibitors (CDK4/6i) for mBRCA. Therefore, we compared time-on-treatment (TOT), a real-world surrogate for PFS, for mBRCA vs wtBRCA treated with ET, CDK4/6i, or PARPi. Methods: DNA and RNA somatic sequencing were performed on tumors submitted to Caris Life Sciences. HR+ was defined by IHC per ASCO/CAP. TOT was calculated from first to last of treatment time based on insurance claims. Univariable Cox-proportional hazard analyses were utilized to assess TOT between mBRCA vs wtBRCA for each therapy (ET, PARPi and CDK4/6i). Protocol was approved prior by Caris research committee. Results: From 8263 HR+ breast cancer patients, 628 were mBRCA+ (median age: 57 years; range 23-90; 96% Female, 4% Male), and 7635 were wtBRCA (median age: 63 years; range 22-89; 98% Female, 2% Male). PVs were BRCA2 : 66%, BRCA1 : 19% and PALB2 : 15%. As shown in Table 1, there was a shorter TOT for AI, SERDs and CDK4/6i, but a longer TOT with PARPi among mBRCA. Patients with mBRCA and high tumor mutational burden (TMB-Hi ≥10 mutations/Mb) had shorter TOT across all analyzed treatments vs low TMB (27.9 vs 35.8 mos, HR=1.47 95%CI 1.14-1.89; p = 0.003), except AI where TMB-Hi had longer TOT (23.5 vs 16.9 mos; HR=0.79, 95%CI 0.62-1.021; p = 0.07). Conclusions: This real-world data analysis demonstrates distinct TOT patterns among ET, CDK4/6i and PARPi for mBRCA patients when compared to wtBRCA. This calls for further studies in this specific patient population to understand the various treatment responses, associated tumor biology and immunologic landscape of mBRCA. TOT comparisons by therapy between mBRCA and wtBRCA patients. Therapy TOT (months)mBRCA TOT (months)wtBRCA Hazard Ratio (HR), Confidence Interval (CI) at 95% Samples collected at all sites (including breast) AI 21.7 25.8 HR=1.16 (CI 1.04-1.29 p=0.009 SERDs 7.6 11.1 HR=1.40 (CI 1.21-1.62) p&lt;0.00001 CDK4/6i 10.3 13.6 HR=1.39 (CI 1.22-1.59) p&lt;0.001 PARPi 5.8 2.1 HR=0.51 (CI 0.36-0.73) p&lt;0.001 Samples collected at metastatic sites AI 25.2 28.3 HR=1.14 (CI 0.994-1.30; p=0.06 SERDs 6.4 11.5 HR=1.40 (CI 1.20-1.68; p&lt;0.0001 CDK4/6i 10.3 13.6 HR=1.31 (CI 1.12-1.54; p&lt;0.001 PARPi 5.8 1.8 HR=0.46 (CI 0.31-0.70; p&lt;0.001