Pathol Res Pract 2025 Jun 04;272:156075. doi: 10.1016/j.prp.2025.156075.

Synergistic strategies: ADC-PARP inhibitor combinations in triple-negative breast cancer therapy.

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Triple-negative breast cancer (TNBC) continues to be a very aggressive subtype with few targeted therapy options. Antibody-drug conjugates (ADCs) and poly (ADP-ribose) polymerase inhibitors (PARPis) have been promising therapeutic strategies, each of which targets different vulnerabilities in TNBC cells. ADCs like sacituzumab govitecan (SG) and datopotamab deruxtecan (Dato-DXd) target cytotoxic payloads with specificity, whereas PARPis like olaparib, rucaparib, niraparib, and talazoparib cause synthetic lethality in homologous recombination repair (HRR)-deficient tumors. Recent clinical trials of SEASTAR and PETRA have evaluated ADC-PARPi combinations to enhance anti-tumor activity through DNA damage induction with the prevention of its repair. Early data demonstrate enhanced therapeutic outcomes, especially in BRCA-mutated and HRD-positive TNBC. Myelosuppression and adaptation of dosing regimens remain challenges to be addressed. Future directions include biomarker-driven patient selection, combination with immune checkpoint inhibitors, and advancement in next-generation ADCs. The synergistic potential of ADC-PARPi combinations provides a new avenue for overcoming TNBC resistance, enhancing treatment outcomes, and widening therapeutic strategies for this challenging disease.

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