Hayes, J. F.

Abstract Background: Clinical benefit with PARP inhibitors (PARPi) has been demonstrated in patients (pts) with HER2-negative (HER2−) metastatic breast cancer (mBC) and germline or tumor mutations in BRCA1 or BRCA2 (g/tBRCAm). Understanding real-world PARPi use and its impact on clinical outcomes may improve the treatment of pts with BRCAm HER2− mBC. Methods: This retrospective study captured data from US pts aged ≥18 years diagnosed with HER2− mBC from January 12, 2018, to March 31, 2024, in the deidentified electronic health record-derived Flatiron Health Research Database. PARPi use and outcomes were described by tumor subtype (hormone receptor-positive [HR+]/HER2− mBC or triple-negative mBC [mTNBC]), g/tBRCA status, disease stage at diagnosis (de novo or recurrent), line of therapy (LoT), and prior treatments. Real-world overall survival (rwOS) by PARPi use was estimated using the Kaplan-Meier method. Results: Of 848 pts with gBRCAm mBC, 352 (42%) received PARPi (Table), with consistent PARPi initiation rates of 42%-48% from 2018-2022. PARPi was initiated in 223/566 (39%) pts with gBRCAm HR+/HER2− mBC, 125/275 (45%) pts with gBRCAm mTNBC, and 4/7 (57%) pts with unknown tumor subtype. Among 304 pts with gBRCAm who had received ≥3 LoT by the end of follow-up, 93/225 (41%) pts with HR+/HER2− mBC and 18/78 (23%) pts with mTNBC received PARPi in the third LoT or later (3L+); 50/103 (49%) pts with de novo mBC and 54/184 (29%) pts with recurrent mBC received PARPi in 3L+. PARPi was also initiated in 13/231 (6%) pts with gBRCA variants of uncertain significance (VUS) and 176/662 (27%) pts with tBRCAm and non-gBRCAm/unknown gBRCAm status. Among 539/1573 (34%) pts with g/tBRCAm who received PARPi, 167 had not received prior chemotherapy in any setting; 40 of these pts (39 with HR+/HER2− mBC and 1 with mTNBC) received PARPi in 3L+. With a median follow-up of 17.0 months from initiation of 1L therapy, median rwOS was numerically longer among pts with gBRCAm who received PARPi versus pts who did not (HR+/HER2− mBC: 39.3 months [95% CI: 35.5-46.8], n=208 vs 24.2 months [95% CI: 21.4-33.0], n=259; mTNBC: 27.6 months [95% CI: 18.0-41.7], n=119 vs 16.9 months [95% CI: 14.5-31.9], n=81). Among pts with tBRCAm who were negative for gBRCAm, median rwOS was numerically longer in pts who received PARPi versus pts who did not. Conclusions: Pts with HR+/HER2− mBC had slightly lower rates of PARPi use, and received PARPi later, than pts with mTNBC. Although improved efficacy with PARPi use in earlier LoT has been demonstrated, many pts first received PARPi in 3L+, suggesting unmet potential to ensure timely testing and optimize treatment. Although immortal time bias and other factors should be considered, rwOS was numerically longer in pts with BRCAm HR+/HER2− mBC and with BRCAm mTNBC who initiated PARPi versus pts who did not. Further research into PARPi use and survival trends in pts with BRCAm and/or other actionable biomarkers in mBC is needed. Citation Format: S. Yadav, Q. Li, Z. Tan, K. E. Mishkin, J. F. Hayes, X. Xu, F. J. Couch. Real-world PARP inhibitor use and clinical outcomes in US patients with HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-02-08.

Abstract Background: International guidelines recommend that all patients (pts) with metastatic breast cancer (mBC) are offered testing for germline BRCA1/BRCA2 mutations (gBRCAm) and other biomarkers to aid treatment decisions. This retrospective study describes real-world testing patterns for germline/tumor (g/t)BRCAm and other biomarkers among US pts with HER2-negative [HER2−] mBC. Methods: Data were captured from US pts aged ≥18 years with HER2− mBC from January 12, 2018, to March 31, 2024, in the deidentified, electronic health record-derived Flatiron Health Research Database. Demographics, clinical characteristics, and testing patterns for g/tBRCAm and other actionable biomarkers were examined. Testing rates, test timing, and biomarker status were described across subgroups defined by demographics (including age, race, and ethnicity), tumor subtype (hormone receptor-positive [HR+]/HER2− mBC or triple-negative mBC [mTNBC]), and disease stage at mBC diagnosis (recurrent/de novo). Results: The BRCA testing rate among pts with mBC increased from 2018 (48%) to 2023 (62%); the overall testing rate was 19,820/34,379 (58%): 5880 pts (17%) received a gBRCA test only, 7285 (21%) received a tBRCA test only, and 6655 (19%) received both gBRCA and tBRCA tests. BRCA testing rates were numerically lower in pts with HR+/HER2− mBC (56%) versus mTNBC (68%), and in pts aged >65 years (HR+/HER2− mBC, 48%; mTNBC, 62%) versus ≤65 years (HR+/HER2− mBC, 64%; mTNBC, 74%; Table). The proportion of pts who received a test before initiation of first-line (1L) therapy was lower among pts with HR+/HER2− mBC than with mTNBC (recurrent, 60% vs 81%; de novo, 37% vs 57%). Among tested pts, 1067/15,168 (7%) with HR+/HER2− mBC and 494/4539 (11%) with mTNBC had a positive result for g/tBRCAm; 365/1067 (34%) pts with g/tBRCAm HR+/HER2− mBC and 138/494 (28%) pts with g/tBRCAm mTNBC were aged >65 years. Among 528 pts with gBRCAm HR+/HER2− mBC, co-mutations in PIK3CA, ESR1, PTEN, and AKT1 were identified in 48 (9%), 38 (7%), 20 (4%), and 3 (<1%) pts, respectively. Among pts diagnosed with gBRCAm HR+/HER2− mBC in 2020-2023 (median follow-up: 15 months), 175/371 (47%) did not receive a test for PIK3CA mutations at any time, and 48/97 (49%) pts diagnosed in 2023 (median follow-up: 6 months) did not receive a test for ESR1 mutations. In 2021-2023, 72/256 (28%) pts with g/tBRCAm mTNBC had tumors with programmed cell death-ligand 1 (PD-L1) combined positive score ≥10; 88 (34%) pts did not receive a PD-L1 test. Conclusions: Although BRCA testing rates increased from 2018 to 2023, 38% of US pts diagnosed with HER2− mBC in 2023 did not receive any BRCA test. BRCA testing rates were low among pts with HR+/HER2− mBC and/or aged >65 years, suggesting that many g/tBRCAm remained undetected. Wider and timelier testing for germline and tumor biomarkers is warranted to identify pts who are eligible for targeted therapies. Citation Format: S. Yadav, Q. Li, Z. Tan, K. E. Mishkin, J. F. Hayes, X. Xu, F. J. Couch. Real-world biomarker testing patterns in US patients with HER2-negative metastatic breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PD4-08.