Clinical, Radiometabolic and Immunologic Effects of Olaparib in Locally Advanced Triple Negative Breast Cancer: The OLTRE Window of Opportunity Trial

Abstract

IntroductionOlaparib is effective in metastatic triple negative breast cancer (TNBC) carrying germline mutations in DNA damage repair (DDR) genes BRCA1/2 (gBRCA-mut). The OLTRE window-of-opportunity trial preliminarily investigated potential pathologic, radiometabolic and immune biomarkers of early-response to olaparib in gBRCA-wild-type (wt) TNBC and, as proof-of-concept in gBRCA-mut HER2-negative BC.MethodsPatients received olaparib for 3 weeks (3w) before standard neoadjuvant chemotherapy and underwent multiple FDG18-PET/CT scan (basal, after olaparib), clinical assessments (basal, every 3w), tumor biopsies and blood samplings (baseline, after olaparib). Clinical and radiometabolic responses were evaluated according to RECIST1.1 and PERCIST criteria.Results27 patients with gBRCA-wt TNBC and 8 with gBRCA-mut BC (6 TNBC, 2 HR+/HER2-negative) were enrolled. Three (11.1%) patients showed mutations in non-BRCA1/2 DDR genes and 4 (14.8%) in other genes. 3w olaparib induced 16/35 and 15/27 partial clinical and radiometabolic responses, including in 40.7% and 50.0% gBRCA-wt patients. gBRCA-mut tumors presented numerically higher tumor-infiltrating lymphocytes (TILs) levels and PD-L1 positive tumors. Clinical responders experienced a reduction in T-regs/T-eff ratio (p=0.05), B and NK lymphocytes (p=0.003 both), with an average increase in T-helpers rate (p<0.001) and CD4/CD8 ratio (p=0.02). Ki67% and TILs did not vary significantly (p=0.67 and p=0.77). A numerical increase in PD-L1 positive cases after olaparib was observed, though non-significant (p=0.134). No differences were observed according to gBRCA status and type of response.ConclusionsEarly-stage TNBC might be a target population for olaparib, irrespective of gBRCA mutations. Future trials should combine TILs, PD-L1 and gBRCA status to better identify candidates for escalated/de-escalated treatment strategies including olaparib.

Clinico-Immunological Effects of a Single-Agent CDK4/6 Inhibitor in Advanced HR+/HER2− Breast Cancer Based on a Window of Opportunity Study

“…This study’s main objective was to investigate the biological effects of the CDK4/6 i administered alone in a window of opportunity fashion in metastatic BC patients [ 17 , 27 ]. The primary endpoint was the exploratory evaluation of early changes in circulating immune cells for the overall cohort of patients (n = 23) induced by each agent under investigation.…”

“…Patients were assigned to orally receive either abemaciclib (n = 8, 34.8%), palbociclib (n = 6, 26.1%), or ribociclib (n = 9, 39.1%) at a dose of 150 mg/bid daily, 125 mg/daily, and 600 mg daily, respectively (28 days of continuous treatment for abemaciclib, 21 days of treatment and one week off for palbociclib and ribociclib) before starting with the standard combination with letrozole 2.5 mg/daily [ 17 , 27 ]. Blood sampling was performed at baseline and after 28 days of treatment.…”

“…Abemaciclib, palbociclib, and ribociclib demonstrated increased progression-free survival from 5 to 10 months in crucial clinical trials [ 10 , 11 , 12 , 13 , 14 , 15 , 16 ]. Furthermore, a recent meta-analysis showed that CDK4/6 inhibitors in association with hormonal therapy improved overall survival (OS) (independent of endocrine sensitivity, menopausal status, visceral involvement, and age) when compared to ET alone [ 17 ]. For the reasons above, CDK4/6 therapy associated with ET is considered the gold-standard treatment for HR+/HER2− mBC with no extensive visceral involvement.…”

Updated Neoadjuvant Treatment Landscape for Early Triple Negative Breast Cancer: Immunotherapy, Potential Predictive Biomarkers, and Novel Agents

“…The clinical efficacy of PARP inhibitors for early stage TNBC irrespective of BRCA mutations, however, remains unclear, and their use is not routine in clinical practice. Encouraging results were observed in the OLTRE window of the opportunity trial [ 93 ], but results are awaited from larger ongoing trials (e.g., PARTNER trial–NCT03150576).…”

PARP Inhibition and Beyond in BRCA-Associated Breast Cancer in Women: A State-Of-The-Art Summary of Preclinical Research on Risk Reduction and Clinical Benefits

“…This particularly aggressive subtype of breast cancer, often in women below 40 years, has been associated with reduced expression of repair genes. The average prevalence of this mutation has been estimated as 35% for BRCA1 and 8% for BRCA2 [ 41 , 42 ].…”