Genotoxic antibody-drug conjugates combined with BCL-XL inhibitors enhance therapeutic efficacy in metastatic castration-resistant prostate cancer

Metastatic castration-resistant prostate cancer (mCRPC) is an aggressive subtype of prostate cancer (PC) without curative treatments. Antibody-drug conjugates (ADCs) emerged as promising cancer therapeutics that selectively deliver cytotoxic agents (payloads) to the tumors. Although ADCs have been successfully applied in the treatment of hematological and solid tumors, ADC monotherapy has not demonstrated durable responses in mCRPC, and the mechanisms of PC resistance to ADCs have not been thoroughly investigated. Our study aimed to improve ADC efficacy using a new integrated approach for the custom ADC design and multiplexing. To nominate rational combinations of ADC targets and ADC payloads, we (1) examined protein co-expression of three clinically relevant surface antigens - B7 homolog 3 (B7-H3), prostate specific membrane antigen (PSMA), and six-transmembrane epithelial antigen of prostate-1 (STEAP1) - in a series of human mCRPCs, and (2) screened established ADC payloads and their combinations in mCRPC cell lines with different molecular backgrounds. Identified synergistic interactions between DNA-damaging payloads and BCL-XL inhibitor A-1331852 as well as their coordinated induction of intrinsic apoptosis pathway were evaluated in a panel of PC cell lines. Functional relevance between isolated p53 loss and PC responses to three genotoxic ADCs - B7-H3 - seco-DUBA (vobramitamab duocarmazine), PSMA - SG3249, and STEAP1 – DXd and their combinations with A-1331852 was established using genetic knockout models. Lastly, enhanced in vivo antitumor activity of vobramitamab duocarmazine by systemic A-1331852 was shown. Collectively, our findings provide rationale for the development of ADC therapies combining genotoxic payloads with BCL-XL inhibitors for mCRPC.