The investigational drug AZD0516 has entered human testing as the first antibody-drug conjugate targeting STEAP2, a protein highly expressed on prostate cancer cells. The ongoing Phase I/IIa clinical trial represents a significant advancement in precision medicine for patients with metastatic castration-resistant prostate cancer (mCRPC), a condition where current treatment options eventually fail and survival outcomes remain poor.

STEAP2, or six-transmembrane epithelial antigen of the prostate-2, stands out as an exceptional therapeutic target due to its unique expression pattern. Unlike many cancer targets that show variable expression, STEAP2 appears on more than 85% of prostate tumor cells across all disease stages while maintaining limited presence in healthy tissues outside the prostate. This selective expression profile makes it an ideal candidate for targeted therapy, potentially minimizing damage to normal cells while maximizing anti-cancer effects.

The engineering behind AZD0516 represents sophisticated drug design. The antibody-drug conjugate combines three essential components: an antibody that specifically recognizes STEAP2 on cancer cells, a specialized linker that remains stable in blood circulation but releases its cargo inside tumors, and exatecan, a highly potent cell-killing agent that damages cancer cell DNA. The β-glucuronidase-cleavable linker technology offers improved tumor selectivity compared to earlier generation ADCs, as it exploits enzymes that are overexpressed in the cancer environment.

Exatecan, the drug’s payload, belongs to a class of chemotherapy agents called topoisomerase I inhibitors but demonstrates superior potency compared to related drugs like irinotecan. Preclinical studies show it is 3-10 times more effective at trapping DNA repair enzymes and inducing cancer cell death. When delivered directly to cancer cells through the STEAP2-targeting antibody, exatecan can potentially achieve higher concentrations in tumors while reducing systemic toxicity.

The clinical trial design employs a modular approach that allows researchers to test both single-agent therapy and combination treatment. The second module evaluates AZD0516 paired with AZD9574, a brain-penetrant PARP1 inhibitor that prevents cancer cells from repairing DNA damage. This combination creates a complementary attack on cancer cells: exatecan breaks DNA strands while AZD9574 blocks repair mechanisms, potentially leading to enhanced cancer cell death through synthetic lethality.

Clinical trial.