179O Combination of olaparib, durvalumab and fulvestrant in patients with advanced ER-positive, HER2-negative breast cancer harboring homologous recombination repair (HRR) deficiency or microsatellite instability (MSI): Results of the international phase II DOLAF trial

BRCA germline pathogenic variants (PV) ordefects in other genes involved in HRR or MSI have been associated with sensitivity to PARP inhibitors in metastatic breast cancer (mBC). Studies suggested synergy between immune checkpoint blockade and PARP inhibition. The ER-pathway also remains a key target in this setting. We evaluated the combination of olaparib, durvalumab and fulvestrant in ER+/HER2- mBC and either somatic or germline PV in genes of the HRR pathway, or MSI status. Patients (pts) had received 1 prior line of endocrine therapy, including a CDK4/6 inhibitor and ≤ 1 line of chemotherapy for mBC. The primary objective was the progression-free survival rate at 24 weeks (24w PFSR). With a two-stage Simon design, the null hypothesis was a PFSR ≤ 50% among the first 149 evaluable pts. Secondary endpoints included safety, progression-free survival (PFS), overall survival (OS) and objective response rate (ORR). 552 pts were screened and 172 included. gBRCA1/2 were the most frequent mutated HRR genes (n=67; 39%) followed by ATM/ATR (16%), FANCA (12%), PALB2 (9%) and CHEK2 (6%). With a median follow-up of 24.6 months, 24w PFSR was 66% (95% CI: 58.2 – 73.6) in the 154 evaluable pts and 76% [95%CI: 63.4-86.4] in gBRCAm pts. Median PFS was 9.3 months (95%CI: 7.5-12.7), 12.6 months (95%CI: 8.2-16.7), and 9.0 months (95%CI: 6.7 – 11.2) in the whole, gBRCAm and non-gBRCAm populations respectively. ORR was 41% (95%CI: 33.3-49.0). Median OS was 30 months (95% CI: 26.6-NE). Most common adverse events (AE) of any grade were nausea (64%) and asthenia (53%). 33.9% of pts presented at least one AE of grade ≥ 3, the main being anemia (9%). 6 pts stopped all the drugs due to AE. No toxicity warning was encountered. In patients with ER+/HER2- mBC and molecular abnormalities predicting sensitivity to PARP inhibitors, the efficacy of a combination of olarapib, durvalumab and fulvestrant as 2d to 3rd line treatment compares well to current standards and has an acceptable toxicity profile (NCT04053322).