# Synergistic combinatorial DNA damage response/repair inhibition and Sacituzumab Govitecan in triple-negative breast cancer

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2022 · $559,783

## Abstract

Project Summary
The long-term objective of this project is to identify new, more effective, and less toxic therapeutic approaches
for triple-negative breast cancer (TNBC), the most aggressive and poor-prognosis breast cancer subtype. Our
team recently led the clinical development of the first antibody-drug conjugate (ADC) for metastatic TNBC
(mTNBC), Sacituzumab Govitecan (SG, aka Trodelvy), achieving dramatically improved objective response
rates (ORRs), progression-free survival (PFS), and overall survival (OS), and resulting in accelerated FDA
approval in 2020. SG comprises the topoisomerase 1 (TOP1) inhibitor SN-38 (the active metabolite of
irinotecan) coupled to a humanized monoclonal antibody targeting Trop-2, a tumor antigen expressed in >90%
of mTNBC. While it represents a paradigm-changing therapy, only approximately 30% of mTNBC patients
experience a therapeutic response to SG, highlighting the need to identify combination therapies with SG that
will uniquely complement and enhance its efficacy. Our preliminary data lead to the hypothesis that PARP
inhibition (PARPi) is synergistic with SG in mTNBC. Accordingly, we are carrying out a funded investigator-
initiated phase 1b/2 clinical trial (NCT04039230) of SG and PARPi (talazoparib) for mTNBC, notably delivered
via a sequential dosing schedule to minimize toxicity and improve the therapeutic window. Here, our team of
clinical, translational, and basic science investigators seeks to move forward the rational therapeutic use of SG
and SG/PARPi, and to discover new combinatorial therapies incorporating SG. Our aims are: i) to establish the
association of therapeutic response with pre-treatment and pharmacodynamic markers of DNA damage and
repair with SG/talazoparib versus SG alone for mTNBC through analysis of clinical trial and other patient
samples; ii) to determine mechanisms of resistance to SG monotherapy and SG/PARPi through CRISPR
screens and analysis of post-progression patient samples, and to test select druggable targets to overcome
them; and iii) to optimize drug scheduling and in vivo efficacy for novel combinations to overcome SG/PARPi
resistance. Collectively, these studies will enable and inform the next generation of mechanism-based
therapeutic trials investigating SG-based combinatorial therapy for patients with mTNBC.

## Key facts

- **NIH application ID:** 10390503
- **Project number:** 1R01CA260890-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Aditya Bardia
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $559,783
- **Award type:** 1
- **Project period:** 2022-01-01 → 2026-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10390503

## Citation

> US National Institutes of Health, RePORTER application 10390503, Synergistic combinatorial DNA damage response/repair inhibition and Sacituzumab Govitecan in triple-negative breast cancer (1R01CA260890-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10390503. Licensed CC0.

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