CLTR-10 PHASE I/II STUDY OF STEREOTACTIC RADIOSURGERY WITH CONCURRENT OLAPARIB FOLLOWED BY ADJUVANT DURVALUMAB AND PHYSICIAN’S CHOICE SYSTEMIC THERAPY IN SUBJECTS WITH BREAST CANCER BRAIN METASTASES (SOLARA)

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Abstract Purpose Outcomes for patients with HER2-negative breast cancer with brain metastases remain poor. Therapeutic strategies that enhance radiation-induced DNA damage and anti-tumor immune response may improve intracranial control. We evaluated toxicity and intracranial disease control in patients receiving combination stereotactic radiosurgery (SRS), olaparib (PARP inhibitor), and durvalumab (anti-PD-L1). Patients/Methods This multi-institution, phase I/II trial (NCT04711824) enrolled patients with triple negative breast cancer (TNBC; any BRCA status) or hormone receptor (HR)-positive/HER2-negative with BRCA-mutated (germline or somatic) breast cancer with brain metastasis from May 2022-December 2024. SRS was delivered concurrently with olaparib (Phase I 3 + 3 dose escalation: 100mg-300mg twice daily; phase II at the maximum tolerated dose), followed by durvalumab (with physician’s choice systemic therapy) every 3 weeks. Primary objectives assessed safety and tolerability (Phase I) and intracranial disease control at 6 months (Phase II). Secondary objectives included intracranial and global progression-free survival, overall survival, and intracranial/extracranial response rate. Results The study closed early due to slow enrollment. Thirteen patients initiated treatment in Phase I/II (median age 55 [range, 29-79], race/ethnicity 77% non-Hispanic White and 23% non-Hispanic Black). The majority (77%) had TNBC, while 23% had HR+/HER2- disease with BRCA mutation. Patients had a median of 4 brain metastases (range, 1-18). Common physician’s choice therapies included olaparib (n = 6) and capecitabine (n = 4). Nine patients completed treatment in phase I with no dose-limiting toxicities, establishing olaparib 300mg twice daily with SRS as the recommended phase II dose. Among 7 evaluable patients treated with the recommended phase II dose, 6-month intracranial disease control was 57.1%. Secondary analyses are ongoing. Conclusions Concurrent SRS and olaparib followed by durvalumab demonstrated acceptable safety and encouraging intracranial disease control in this small cohort. These results support further evaluation of radiation, PARP inhibition, and immunotherapy in patients with HER2-negative breast cancer with brain metastases.

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