SHR-A1921: A Next-Generation TROP2-Targeted Antibody-Drug Conjugate Shows Promise in Prostate Cancer

SHR-A1921, also known as tizetatug rezetecan, represents a significant advancement in targeted cancer therapeutics, specifically designed to exploit TROP2 overexpression in aggressive malignancies including prostate cancer. This novel antibody-drug conjugate (ADC) has demonstrated compelling preclinical activity in prostate cancer models and encouraging early clinical results across multiple solid tumors, positioning it as a potential therapeutic option for patients with metastatic castration-resistant prostate cancer (mCRPC).

The molecular design of SHR-A1921 incorporates several key innovations intended to improve upon first-generation TROP2-targeting agents like sacituzumab govitecan. The molecule consists of a humanized anti-TROP2 IgG1 monoclonal antibody conjugated to SHR9265, a novel topoisomerase I inhibitor from the exatecan derivative family. The payload SHR9265 exhibits enhanced lipophilicity and cellular permeability compared to SN-38 (used in sacituzumab govitecan), potentially enabling superior intracellular delivery and a more potent bystander effect that allows the agent to kill neighboring non-targeted tumor cells. Preclinical comparative studies demonstrated that SHR-A1921 exhibits stronger TROP2 binding affinity, improved plasma stability, superior in vivo efficacy, and a longer half-life compared to both sacituzumab govitecan and SKB264, another Chinese TROP2-ADC.

TROP2 is a good target in prostate cancer because its levels increase as the disease becomes more aggressive and advanced. It is low in normal prostate tissue, higher in localized prostate cancer, and very common in metastatic castration‑resistant prostate cancer (mCRPC). This means many men with late‑stage disease could, in theory, be candidates for a TROP2‑targeting drug like SHR-A1921.

In lab studies on prostate cancer, SHR-A1921 has shown strong activity. In cell experiments, it killed TROP2‑positive prostate cancer cells by binding to TROP2, entering the cells, and releasing its toxic payload, which caused DNA damage and triggered cell death. In mouse models with human prostate tumors, it slowed or shrank tumors, showing that it works in a living organism, not just in a dish. It has also been tested on patient‑derived organoids, 3D mini‑tumors grown from real patients’ prostate cancers, and it was able to kill TROP2‑positive organoids. These organoid results are important because they often mirror how real patients may respond.

Early human studies have tested SHR-A1921 in people with various advanced solid tumors (such as lung, ovarian, and breast cancers) who had already received many prior treatments. The drug produced tumor shrinkage in a meaningful fraction of patients, and the dose for further trials has been identified.

So far, prostate cancer patients have mainly been studied in preclinical (lab and animal) models rather than in large clinical trials, but the combination of: high TROP2 expression in mCRPC, strong lab and animal data, activity in patient‑derived prostate organoids, and a manageable side‑effect profile in other cancers, all point to SHR-A1921 as a promising future option for men with advanced TROP2‑positive prostate cancer. Clinical trials focused specifically on prostate cancer would be the next key step to understand how well it works and how best to use it in that setting.

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