Abstract P2-10-17: A randomized phase III study of first-line saruparib (AZD5305) + camizestrant vs CDK4/6i plus physician’s choice endocrine therapy or + camizestrant in patients w/ BRCA1/BRCA2/PALB2 mutations & HR+/HER2- advanced breast cancer (EvoPAR-Breast01)

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Abstract Background:Emerging evidence indicates that homologous recombination deficiency (HRD) contributes to resistance to cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) plus endocrine therapy (ET). Patients with germline or somatic (g/s) mutations in BRCA1, BRCA2, and/or PALB2 genes (BRCA1m/BRCA2m/PALB2m) and hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer have poorer outcomes with first-line standard-of-care CDK4/6i plus ET than patients without these mutations. Clinical benefit with poly(ADP-ribose) polymerase inhibitors (PARPi) has been demonstrated in patients with HRD breast cancer, and PARPi are approved for the treatment of patients with gBRCA1/BRCA2m and HR-positive/HER2-negative early or advanced breast cancer. Clinical trials have shown that PARPi use in early lines of therapy can result in a greater magnitude of benefit. PARPi use may also induce reversion mutations that restore homologous recombination proficiency, potentially sensitizing tumors to CDK4/6i. Saruparib (AZD5305) is a first-in-class highly selective PARP1 inhibitor that has increased potency and improved pharmacokinetic and pharmacodynamic properties compared with other approved PARPi. The phase III EvoPAR-Breast01 study (NCT06380751) is evaluating the efficacy and safety of saruparib plus camizestrant, a next-generation oral selective estrogen receptor degrader (SERD) and pure estrogen receptor antagonist, vs physician’s choice of CDK4/6i plus ET or CDK4/6i plus camizestrant in participants with g/s BRCA1m/BRCA2m/PALB2m HR-positive/HER2-negative advanced breast cancer. Trial design:EvoPAR-Breast01 is a randomized, open-label, 3-arm, multicenter, global study. This study will enroll pre-, peri-, and postmenopausal women, and men ≥18 years of age with histologically confirmed estrogen receptor-positive (expression in >1% of cells, irrespective of progesterone receptor status) and HER2-negative (immunohistochemistry score of 0, 1+, 2+/in situ hybridization non-amplified) advanced breast cancer. Patients must have an ECOG PS 0–1 and known BRCA1m/BRCA2m/PALB2m identified by local germline or central tumor testing. ET is permitted up to 28 days prior to randomization. Patients with disease progression ≤84 days from the last dose of (neo)adjuvant chemotherapy for early breast cancer or ≤365 days from the last dose of adjuvant CDK4/6i, PARPi, and/or platinum chemotherapy, or oral SERD for early breast cancer are excluded, as are patients who have received prior systemic treatment for locoregionally recurrent or metastatic breast cancer. Patients with uncontrolled cardiovascular disease and history of, or suspected, myelodysplastic syndrome/acute myeloid leukemia are not eligible for inclusion. Participants will be randomized 2:2:1 to receive saruparib plus camizestrant, physician’s choice CDK4/6i (abemaciclib, ribociclib, or palbociclib) plus physician’s choice ET (fulvestrant, letrozole, anastrozole, or exemestane), or physician’s choice CDK4/6i plus camizestrant, respectively. Treatment will continue until disease progression per RECIST v1.1, unacceptable toxicity, or participant-initiated withdrawal. The primary endpoint is progression-free survival (PFS) by blinded independent review committee in the saruparib plus camizestrant vs CDK4/6i plus ET arms. Overall survival (OS) is a secondary endpoint. Planned statistical analyses of PFS and OS will be conducted using a stratified log-rank test. Participant enrollment is ongoing. Approximately 500 participants will be randomized across the three arms. Citation Format: Pedram Razavi, Judith Balmaña, Stephen J. Luen, Mario Campone, Laura Cortesi, Norikazu Masuda, Kyong Hwa Park, Qingyuan Zhang, Emily Nizialek, Cathy Qi, Karen Cui, Sibylle Loibl, Mark Robson, Filipa Lynce. A randomized phase III study of first-line saruparib (AZD5305) + camizestrant vs CDK4/6i plus physician’s choice endocrine therapy or + camizestrant in patients w/ BRCA1/BRCA2/PALB2 mutations & HR+/HER2- advanced breast cancer (EvoPAR-Breast01) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P2-10-17.

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