Abstract P6-15-02: Synthetic lethality in TNBC mediated by an anti-Trop-2 antibody-drug conjugate, sacituzumab govitecan (IMMU-132), when combined with paclitaxel or the PARP inhibitor, olaparib
Authors: Goldenberg DM , Cardillo TM , Govindan SV , Zalath M , Arrojo R , Sharkey RM 
Published: May 2016

Background: In current clinical trials (ClinicalTrials.gov, NCT01631552), triple-negative breast cancer (TNBC) patients treated with IMMU-132, which is composed of the active metabolite of irinotecan, SN-38, conjugated to an anti-Trop-2 antibody, shows manageable toxicity and very encouraging responses in relapsed/refractory cases. Synthetic lethality is a concept in which a cell harboring one out of two possible gene or protein defects is viable, while a cell containing both defects is nonviable. BRCA1/2 mutations are linked to deficiencies in DNA repair and are associated with TNBC. Other repair mechanisms involve poly(adenosine diphosphoribose) polymerase (PARP), which can be used by cancer cells to overcome loss of BRACA1/2. Treatment of TNBC cells with either IMMU-132 or paclitaxel results in cleavage and deactivation of PARP, whereas the small molecule olaparib directly inhibits PARP. Therefore, the rationale of combining IMMU-132 with either paclitaxel or olaparib to effectively knock-out PARP activity was investigated in TNBC xenografts to ascertain if these combinations will result in synthetic lethality.

Methods: Mice bearing human TNBC xenografts (MDA-MB-468 or HCC1806) were treated with 15 mg/kg paclitaxel weekly for 5 weeks. IMMU-132 was administered either at 10 mg/kg or 12.5 mg/kg on days 1, 8, 22, and 29. In vitro, various human TNBC cell lines were incubated with either a constant amount of IMMU-132 in combination with various amounts of olaparib or constant olaparib with varying amounts of IMMU-132. A combination index number was calculated to determine whether the interaction was synergistic, additive, or antagonistic. Mice bearing TNBC tumors were treated with olaparib (50 mg/kg, qdx5d, for 4 wks), or IMMU-132 (10 mg/kg, 2xwkly x 4 wks), or the combination of both.

Results: Mice bearing MDA-MB-468 tumors treated with the combination of IMMU-132 and paclitaxel exhibited superior anti-tumor effects with &gt;11-fold shrinkage of tumors in comparison to 1.4-fold shrinkage in the IMMU-132 group alone (P=0.0003) or 11.4-fold increase in tumor size in those mice treated with paclitaxel alone (P&lt;0.0001). In the more aggressive HCC1806, the combination improved median survival from 17.5 and 17 days for paclitaxel and IMMU-132, respectively, to 38 days for those in the combination group (P&lt;0.0015). IMMU-132 and olaparib demonstrated synergy in all TNBC cell lines tested in vitro. In an ongoing experiment, this same combination is proving to be superior to single agent therapy in mice bearing MDA-MB-468 tumors (P&lt;0.0032). In all studies, the combination of IMMU-132 with either paclitaxel or olaparib was well tolerated, with no observable toxicities. DNA breaks as determined by TUNEL staining of excised xenografts are being assessed.

Conclusions: Targeting the PARP DNA repair pathway in BRCA1/2 mutant TNBC tumors by combining IMMU-132 therapy with either paclitaxel or olaparib achieved synthetic lethality in this disease model with no observable toxicity. These data provide the rationale for the clinical evaluation of IMMU-132 in combination with other chemotherapeutics that likewise target DNA-repair mechanisms in patients with TNBC.

Citation Format: Goldenberg DM, Cardillo TM, Govindan SV, Zalath M, Arrojo R, Sharkey RM. Synthetic lethality in TNBC mediated by an anti-Trop-2 antibody-drug conjugate, sacituzumab govitecan (IMMU-132), when combined with paclitaxel or the PARP inhibitor, olaparib. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-15-02.