TIPS-21 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)

Abstract BACKGROUND Despite progress in the treatment of brain metastasis (BrM) for HER2+ breast cancer (BC), outcomes patients with HER2-negative BC BrM remain poor. Current standard care consists surgery and/or radiotherapy followed by systemic therapy. Preclinical studies show inhibitors poly(ADP-ribose) polymerase (PARP) are effective together as DNA damage response inhibitors. Triple-negative (TNBC) has higher rates homologous recombination deficiency compared to other subtypes, and HER2-negative, BRCA-mutated would be particularly sensitive PARP inhibition. inhibition immunotherapy demonstrated promising efficacy germline BRCA-mutant metastatic TNBC clinical trials (MEDIOLA, TOPACIO). In addition, stereotactic radiosurgery (SRS) is associated favorable BrM. We hypothesize that this biologically-driven combination will enhance local control SRS-treated through synergy inhibition, while controlling micrometastatic disease extracranial sites potentiating immune response. METHODS conducting a multi-institution, Phase I/II trial SRS plus olaparib, durvalumab (with physician’s choice therapy), (any BRCA status) or (germline somatic) [NCT04711824]. The primary objectives evaluate safety tolerability (Phase I) intracranial at 6 months II). Secondary include assessing global progression-free survival, overall intracranial/extracranial rate. Exploratory assess potential biomarkers response, including changes circulating tumor cells/DNA blood cerebrospinal fluid, mutations repair pathway genes, PD-L1 expression, well quality life patient-reported outcomes. A surgical sub-study (n=5) olaparib concentration/distribution resected As January 2023, cohort 1 phase I been completed without dose-limiting toxicity.