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)

초록

Emerging evidence indicates that homologous recombination deficiency (HRD) contributes to resistance to CDK4/6 inhibitors (CDK4/6i) + endocrine therapy (ET). Patients (pts) with germline or somatic (g/s) mutations in BRCA1, BRCA2, and/or PALB2 genes (BRCA1m/BRCA2m/PALB2m) and HR+/HER2– advanced breast cancer (BC) have poorer outcomes with first-line CDK4/6i + ET than pts without these mutations. Clinical benefit with PARP inhibitors (PARPi) has been demonstrated in pts with HRD BC, and PARPi are approved for the treatment of pts with gBRCA1/BRCA2m and HR+/HER2– early or advanced BC. Clinical trials showed 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 with 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 + camizestrant, a next-generation oral selective estrogen receptor degrader (SERD) and pure estrogen receptor antagonist, vs physician’s choice of CDK4/6i + ET or CDK4/6i + camizestrant in pts with g/s BRCA1m/BRCA2m/PALB2m HR+/HER2– advanced BC. EvoPAR-Breast01 is a randomized, open-label, 3-arm, multicenter, global study that will enroll pts ≥18 years of age with histologically confirmed estrogen receptor-positive/HER2– advanced BC. Pts 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. Pts with disease progression ≤84 days from the last dose of (neo)adjuvant chemotherapy for early BC or ≤365 days from the last dose of adjuvant CDK4/6i, PARPi, and/or platinum chemotherapy, or oral SERD for early BC are excluded, as are pts who have received prior systemic treatment for locoregionally recurrent or metastatic BC. Pts with uncontrolled cardiovascular disease and history of/suspected myelodysplastic syndrome/acute myeloid leukemia are not eligible for inclusion. Participants will be randomized 2:2:1 to receive saruparib + camizestrant, physician’s choice CDK4/6i (abemaciclib/ribociclib/palbociclib) + physician’s choice ET (fulvestrant/letrozole/anastrozole/exemestane), or physician’s choice CDK4/6i + 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 + camizestrant vs CDK4/6i + 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. Approximately 500 participants will be randomized across the three arms. Enrollment is ongoing.