Résumé
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 regardless of genomic context. This study assesses the activity of the combination of PARP, ER, and PD-L1 inhibition among patients with metastatic breast cancer and relevant genomic alterations.
In this multicenter, single-arm, phase II clinical trial, we used a Simon 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 a homologous recombination repair gene, a microsatellite instability status, or an endocrine resistance-related mutation were eligible. Primary endpoint was 24-week progression-free survival rate.
The 172 (100%) patients included received prior endocrine therapy for metastatic breast cancer and 86% received a CDK4/6 inhibitor, and 67 (39%) had a previously documented germline BRCA1/2 mutation (gBRCA1/2m). The 24-week progression-free survival rate was 66.7% [95% confidence interval (CI), 58.6-74.1] in the evaluable population and 76.3% (95% CI, 63.4-86.4) in gBRCA1/2m patients. The median progression-free survival was 9.3 months (95% CI, 7.5-12.7) and 12.6 months (95% CI, 8.2-16.7) in the intention-to-treat and gBRCA1/2m populations, respectively. The median overall survival was 30 months (95% CI, 26.6-not reached). Most common adverse events of any grade were nausea (59%) and asthenia (43%). No new toxicity warning was detected.
In patients with ER+/HER2- metastatic breast cancer and selected genomic alterations, this triplet combination was active and had an acceptable toxicity profile (NCT04053322).