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 to treat hematological and solid tumors, ADC monotherapy has not demonstrated durable responses in mCRPC, and mechanisms of PC resistance to ADCs have not been thoroughly investigated. Our study aimed to improve ADC efficacy using an integrated approach for a custom ADC design and multiplexing. To nominate rational combinations of ADC targets and payloads, we (a) examined protein coexpression of 3 clinically relevant surface antigens - B7-H3, PSMA, and STEAP1 - in human mCRPCs and (b) screened established ADC payloads and their combinations in mCRPC cell lines with different molecular backgrounds. Identified synergistic interactions between DNA-damaging payloads and the BCL-XL inhibitor A-1331852 as well as their coordinated induction of the intrinsic apoptosis pathway were evaluated in PC cell lines. Functional relevance between isolated p53 loss and PC responses to 3 genotoxic ADCs - B7-H3-seco-DUBA, PSMA-SG3249, and STEAP1-DXd - and their combinations with A-1331852 were 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 development of ADC therapies combining genotoxic payloads with BCL-XL inhibitors for mCRPC.