Combination olaparib and cyclophosphamide cancer therapy exacerbates ovarian reserve depletion in mice with conditional loss of Brca1 in oocytes.

Olaparib, a small-molecule poly(ADP-ribose) polymerase (PARP) inhibitor, selectively impairs single-strand DNA repair and improves outcomes in patients with BRCA1-mutant cancers by promoting the accumulation of unrepaired DNA damage in tumor cells. It is increasingly used in combination with chemotherapy to enhance therapeutic efficacy and overcome resistance; however, its impact on ovarian function in BRCA1 mutation carriers remains unknown. Here, we investigated whether BRCA1 deficiency alters ovarian sensitivity to combined cyclophosphamide and olaparib exposure. Adult wild-type (WT; Brca1 fl/fl Gdf9 +/+) and oocyte-specific Brca1 conditional knockout (cKO; Brca1 fl/fl Gdf9 cre/+) mice were treated with cyclophosphamide (75 mg/kg, single intraperitoneal injection) or vehicle, followed by daily olaparib (50 mg/kg, subcutaneous) or vehicle for 28 days. Ovarian reserve, endocrine function, estrous cyclicity, and IVF outcomes were assessed. Combination treatment did not affect serum AMH levels, estrous cyclicity, or IVF outcomes in either genotype, indicating no evidence of short-term impairment of reproductive function. Importantly though, Brca1 cKO mice exposed to combination treatment exhibited long-term effects, evident from a significant depletion of primordial follicles compared with genotype-matched vehicle controls, whereas ovarian reserve remained preserved in WT animals receiving the same treatment regimen. These findings demonstrate that BRCA1 deficiency may confer selective susceptibility of the ovarian reserve to combination chemotherapy and PARP inhibitor exposure without immediate impairment of endocrine or reproductive function. This study provides the first evidence that BRCA1 mutation carriers may be uniquely vulnerable to accelerated primordial follicle loss following chemotherapy PARP inhibitor combination therapy, with important implications for fertility preservation and long-term reproductive health in young women undergoing cancer treatment.