Combination of olaparib, durvalumab and fulvestrant in patients with advanced ER+/HER2- breast cancer and selected genomic alterations: results of the DOLAF trial

Purpose: Previous data suggest synergy between PARP inhibition and immune checkpoint blockade in different genetic settings. The estrogen receptor (ER) pathway remains a key target in metastatic breast cancer whatever the genomic context. This study assess the activity of the combination of PARP, ER, and PDL1 inhibition among patients with metastatic breast cancer and relevant genomic alterations. Patients and Methods: In this multicenter single arm phase II clinical trial, we used a Simon’s two-stage design to evaluate the activity and safety of a combination of durvalumab, olaparib and fulvestrant as second- or third-line in patients with ER+/HER2- metastatic breast cancer. Patients with either somatic or germline mutations of an HRR-gene, an MSI status or an endocrine resistance-related mutation were eligible. Primary endpoint was 24-week progression-free survival rate (PFSR). Results: The 172 (100%) patients included received prior endocrine therapy for metastatic breast cancer, 86% a CDK4/6 inhibitor, and 67 (39%) had a previously documented gBRCA1/2m. The 24-week PFSR was 66.7% (95% CI: 58.6-74.1) in the evaluable population and 76.3% (95% CI: 63.4-86.4) in gBRCA1/2m patients. Median PFS was 9.3 months (95% CI: 7.5-12.7) and 12.6 months (95% CI: 8.2-16.7) in the ITT and gBRCA1/2m populations, respectively. Median OS was 30 months (95% CI: 26.6-NR). Most common adverse events of any grade were nausea (59%) and asthenia (43%). No new toxicity warning was detected. Conclusion: In patients with ER+/HER2- metastatic breast cancer and selected genomic alterations, this triplet combination was active and had an acceptable toxicity profile (NCT04053322).