Abstract P5-13-08: Identification of PD-L1+ status as a candidate predictive biomarker of response to talazoparib (TALA) in the phase 3 EMBRACA study
Authors: Rugo Hope S. , Blum Joanne L. , Laird A. Douglas , Hurvitz Sara A. , Ettl Johannes , Mina Lida A. , Lee Kyung-Hun , Gonçalves Anthony , Yerushalmi Rinat , Im Young-Hyuck , Martin Miguel , Fehrenbacher Louis , Roché Henri H. , Chen Ying , Lanzalone Silvana , Chelliserry Jijumon , Eiermann Wolfgang , Litton Jennifer K. 
Published: March 2022

Abstract
Background: Loss-of-function mutations in genes encoding components of the homologous recombination DNA damage response (DDR) machinery, notably BRCA1/2, are associated with tumor sensitivity to poly(ADP-ribose) polymerase inhibitors (PARPi). In EMBRACA, the PARPi TALA improved progression-free survival (PFS) (HR [95% CI] 0.54 [0.41-0.71], P&lt;0.001) vs chemotherapy (CT) in germline BRCA-mutated (gBRCAm) HER2− advanced breast cancer. BRCA1/2 deficiency is associated with elevated PD-L1 expression in ovarian cancers, and PARP inhibition has been associated with PD-L1 upregulation in nonclinical models (Stewart et al, Cancer Res 2018;78:6717-25). Little is known about the potential for PD-L1 expression to modulate sensitivity to PARPi monotherapy in the clinic. Recently, a neoadjuvant study of olaparib in unselected, primary triple-negative breast cancer (TNBC), demonstrated a significant correlation between PD-L1 expression (using the 22C3 antibody) and response to olaparib (Eikesdal et al, Ann Oncol 2021;32:240-9). In contrast, this EMBRACA analysis assessed the contribution of PD-L1 status to TALA sensitivity in a uniformly gBRCAm patient (pt) population. Methods: Available baseline tumor tissue blocks from 120 of 431 EMBRACA pts (28% of intent-to-treat) were sectioned and slides immunostained using SP142/Ventana anti-PD-L1 at HistoGeneX (Naperville, Illinois). PD-L1 immunohistochemistry (IHC) status was assessed as the proportion of tumor area occupied by PD-L1 stained immune cells (IC) of any intensity, with ≥1% defined as PD-L1+. The overall response rate (ORR), defined as unconfirmed complete or partial response (CR/PR), was assessed by investigators. PFS was assessed by an Independent Review Facility. Results: 92/120 (77%) tumors were evaluable for PD-L1 IHC status. Of these 92 evaluable tumors, 9/36 (25%) TNBC and 15/56 (27%) hormone receptor-positive (HR+) tumors were PD-L1+ (24/92, 26% combined TNBC and HR+). In the TALA arm, the ORR was similar for PD-L1+ and PD-L1− tumors for TNBC pts: 2/5 (40%) and 6/19 (32%), respectively. In contrast, the ORR was higher for PD-L1+ vs PD-L1− tumors for HR+ pts: 11/12 (92%) vs 12/31 (39%), exact P value=0.002 (for combined TNBC and HR+, 13/17 [76%] vs 18/50 [36%], P=0.005). For the CT arm, the limited numbers evaluable for both PD-L1 and response (n=25 total), with only one response, precluded similar analysis. Based on the imbalanced results in ORR according to PD-L1 status in pts with HR+ disease, Cox regression analysis was used to explore potential associations of PD-L1 status with PFS. In the TALA arm, median PFS was similar for TNBC independent of PD-L1 status (6.3 mo and 7.0 mo, respectively; HR [95% CI] 1.207 [0.371-3.929]). Median PFS was numerically longer for PD-L1+ vs PD-L1− for HR+ tumors; this difference was not significant (20.2 mo vs 9.2 mo; HR [95% CI] 1.154 [0.395-3.367]). In the CT arm, PD-L1 status was not associated with PFS, although the PD-L1 subgroups were small (For HR+: PD-L1+, n=3; PD-L1−, n=10). Conclusions: Based on these exploratory, retrospective subgroup analyses, PD-L1 positivity by SP142/Ventana was lower in EMBRACA than previously reported in TNBC using the same scoring algorithm: 24/92 (26%) vs 369/902 (41%) in IMpassion130 (Schmid et al, Lancet Oncol 2020;21:44-59). PD-L1+ status was associated with higher ORR in HR+ EMBRACA pts receiving TALA. Interestingly, the enhanced responsiveness for PD-L1+ was not associated with improved PFS, although this assessment is complicated by low pt numbers. Further research is warranted to explore the relationship between baseline tumor PD-L1 status and sensitivity to PARPi, particularly in light of ongoing clinical studies evaluating combinations of immunotherapy and PARPi.
Citation Format: Hope S. Rugo, Joanne L. Blum, A. Douglas Laird, Sara A. Hurvitz, Johannes Ettl, Lida A. Mina, Kyung-Hun Lee, Anthony Gonçalves, Rinat Yerushalmi, Young-Hyuck Im, Miguel Martin, Louis Fehrenbacher, Henri H. Roché, Ying Chen, Silvana Lanzalone, Jijumon Chelliserry, Wolfgang Eiermann, Jennifer K. Litton. Identification of PD-L1+ status as a candidate predictive biomarker of response to talazoparib (TALA) in the phase 3 EMBRACA study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-13-08.