O (olaparib, Lynparza®) is approved for gBRCAm HER2(-) MBC based on the OlympiAD study. O-induced DNA damage may increase tumor antigen release, activate cGAS/STING, attract tumor-infiltrating lymphocytes and upregulate programmed cell death ligand-1 (PD-L1). In OlympiAD (single-agent olaparib), median duration of response (DoR) and median progression-free survival (PFS) were 6.4 months (m) and 7.0 m, respectively. MEDIOLA assessed the efficacy and safety of the combination of O and D (durvalumab, Imfinzi®), an anti-PD-L1 antibody, in gBRCAm HER2(-) MBC (NCT02734004). Early results were reported (SABCS 2017 PD6-11, 2018 PD5-04).
Pts with gBRCAm HER2(-) MBC were eligible; prior platinum was allowed; prior PARPi or anti-PD(L)1 was not. Pts received O 300 mg BID for a 4-wk run-in, then O 300 mg BID and D 1.5g IV q 4 wks until disease progression. Tumors were assessed at baseline, 4 wks, then every 8 wks. Dual primary endpoints were disease control rate (DCR) at 12 wks and safety. Secondary endpoints were 28-wk DCR, objective response rate (ORR), DoR, PFS, overall survival (OS), and biomarker analysis.
34 pts were in the safety, and 30 pts in the efficacy analyses. The 12-wk DCR was 24/30 (80%), greater than the target of 75%. The 28-wk DCR was 15/30 (50%). Other efficacy endpoints are presented below. The most common adverse events ≥Grade 3: anemia (Gr 3, 4 pts), neutropenia (Gr 3, 3 pts), and pancreatitis (Gr 3, 1pt, Gr 4, 1 pt). Efficacy and safety results with longer follow-up will be presented. Efficacy results correlated to genomic data and intrinsic subtypes will also be presented. 1191O IQR, interquartile range; NC, not calculable; TNBC, triple-negative breast cancerEndpoint Overall Cohort (n = 30) 0 prior lines n = 9 (7/9 TNBC) 1 prior line n = 11 (5/11 TNBC) 2 prior lines n = 10 (5/10 TNBC) mPFS (mo) (95% CI) 8.2 (4.6, 11.8) 9.9 (2.2, 13.8) 11.7 (1.9, NC) 6.5 (1.0, 8.2) mOS (mo) (95% CI) 20.5 (16.2, 23.9) 21.3 (9.0, NC) 22.7 (10.1, NC) 16.9 (4.6, NC) Responses 19 7 7 5 ORR (95% CI) 63.3% (43.9-80.1) 78% (40.0, 97.2) 64% (30.8, 89.1) 50% (18.7, 81.3) mDoR (mo) (IQR) 9.2 (5.5, 20.3) 9.2 (4.0, 12.9) NC (10.9, NC) 5.5 (5.4, 5.5)
The data suggest that pts with fewer prior lines of chemotherapy (0/1) had higher ORR, longer mDoR, mPFS and mOS than those with 2 prior lines. The chemo-free combination was well-tolerated, with safety consistent with the individual agent profiles. Confirmation of these results in early-line patients is warranted.
NCT02734004.
Writing assistance was provided by Martin Goulding, PhD, of Mudskipper Ltd and funded by AstraZeneca.
AstraZeneca and the authors.
AstraZeneca.
S. Domchek: Honoraria (self), Research grant / Funding (self): AstraZeneca; Honoraria (self), Research grant / Funding (self): Clovis Oncology; Honoraria (self): Bristol-Myers Squibb; Research grant / Funding (self): PharmaMar. S. Postel-Vinay: Research grant / Funding (self), Travel / Accommodation / Expenses, Non-remunerated activity/ies: AstraZeneca; Research grant / Funding (self), Non-remunerated activity/ies: Boehringer Ingelheim; Research grant / Funding (self), Non-remunerated activity/ies: Bristol-Myers Squibb; Research grant / Funding (institution): Janssen-Cilag; Advisory / Consultancy, Research grant / Funding (self), Non-remunerated activity/ies: Merck; Research grant / Funding (self): Novartis; Research grant / Funding (self), Non-remunerated activity/ies: Pfizer; Research grant / Funding (self), Non-remunerated activity/ies: Roche; Research grant / Funding (self): Sanofi; Non-remunerated activity/ies: Bayer; Non-remunerated activity/ies: Johnson & Johnson; Non-remunerated activity/ies: Lilly; Non-remunerated activity/ies: MedImmune; Non-remunerated activity/ies: NH TherAGuiX. S. Im: Advisory / Consultancy, Research grant / Funding (self): AstraZeneca; Advisory / Consultancy, Research grant / Funding (self): Pfizer; Advisory / Consultancy: Amgen; Advisory / Consultancy: Eisai; Advisory / Consultancy: Hanmi; Advisory / Consultancy: Novartis; Advisory / Consultancy: Roche. J. Alexandre: Honoraria (self): AstraZeneca; Honoraria (self): Roche; Honoraria (self): PharmaMar; Honoraria (self), Travel / Accommodation / Expenses: Novartis; Honoraria (self): Ipsen; Research grant / Funding (self), Travel / Accommodation / Expenses: Janssen. M.G. Krebs: Advisory / Consultancy, Research grant / Funding (self): Roche; Advisory / Consultancy: Janssen; Advisory / Consultancy: Octimet; Advisory / Consultancy: Achilles; Travel / Accommodation / Expenses: AstraZeneca; Research grant / Funding (self), Travel / Accommodation / Expenses: BerGenBio; Research grant / Funding (self): MSD. M. Lanasa: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. H.K. Angell: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. Z. Lai: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. C. Gresty: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. L.M. Opincar: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. P. Herbolsheimer: Shareholder / Stockholder / Stock options, Full / Part-time employment: AstraZeneca. B. Kaufman: Advisory / Consultancy: AstraZeneca. All other authors have declared no conflicts of interest.