Olaparib in HR-deficient (HRD), metastatic triple-negative breast cancer (TNBC) and relapsed ovarian cancer (ROC) without germline mutations in BRCA1 or BRCA2: Phase 2 EMBRACE trial.

Abstract

e15079 Background: Homologous recombination deficiency (HRD) caused by germline BRCA1/2 mutations (gBRCAm) sensitize high grade serous ovarian cancers (HGSOC) and TNBC to PARP inhibitors (PARPi) such as olaparib. Loss of function of BRCA1 or RAD51C, due to promoter methylation or mutation of non-BRCA HR genes may also confer sensitivity to PARPi. This investigator-initiated, proof-of-concept trial evaluated olaparib in platinum(Pt)-sensitive, relapsed HGSOC and metastatic TNBC, with HRD due to mechanisms other than gBRCAm. EMBRACE is the first trial evaluating PARPi in loss of function of BRCA1/ RAD51C by promoter methylation. Methods: Single-arm, phase 2 trial of olaparib 300 mg orally twice daily in adults with metastatic TNBC or Pt-sensitive relapsed HGSOC and HRD due to mechanisms other than gBRCAm. 1 line of prior Pt-chemotherapy was allowed (HGSOC); additional lines of non-Pt therapy were allowed (TNBC). Tumor BRCA1/RAD51C promoter methylation was determined by methylation-sensitive high-resolution melting PCR and next generation sequencing (NGS, Pillar Biosciences BRCA1 & RAD51C Methylation test, high methylation threshold 70%). Unmethylated cases underwent NGS HR gene mutation testing (Pillar Biosciences HRD test, paired tumor/normal). The primary outcome was objective tumor response rate (OTRR) at 6 months(m). Secondary objectives: progression-free survival (PFS), OTRR according to HR gene mutation type, safety. Tertiary: associations between biomarkers and clinical outcomes. Results: 22 participants (15 HGSOC, 7 TNBC) enrolled from 208 screened (Sep 2018 - Mar 2022). Methylation was detected in 8/15 HGSOC (all BRCA1) and 5/7 TNBC (4 BRCA1, 1 RAD51C). Both cohorts included mutations in gBRIP1 (1), gPALB2 (1), gRAD51C (3), sBRCA1 (2), with 1 COSMIC mutational signature 3, and 1 positive HRD score in HGSOC. OTRR at 6m was 40% in HGSOC (6/15: 5 partial, 1 complete), and 0% in TNBC (0/7). OTRR was 38% (3/8) in methylated tumors vs 43% (4/7) with other HRD. Stable disease at 6m was 47% (7) in HGSOC and 43% (3) in TNBC durations were 7m in HGSOC and 3m in TNBC. PFS was 53% at 6m and 25% at 12m in HGSOC, vs 17% at 6m and NE at 12m in TNBC. TNBC 2-3 prior lines of therapy. Conclusions: Olaparib demonstrated clinically relevant activity in HGSOC without gBRCAm. Objective responses were seen in HGSOC with methylated BRCA1. Olaparib had limited activity in heavily pre-treated TNBC. Further research is needed into the effects of non-Pt chemotherapy on methylation of BRCA1/RAD51C to improve selection of HGSOC and TNBC for PARPi. (ANZCTRN12617000855325) Acknowledgements: Funding from Cancer Australia and the NBCF(PS-15-048), provision of study drug plus an untied educational grant from AstraZeneca and its group of companies. EMBRACE was led by the NHMRC CTC, University of Sydney in collaboration with ANZGOG, BCT-ANZ, and GCCTI. Clinical trial information: ACTRN12617000855325 .