The phase 3 ProstACT GLOBAL trial (NCT06520345) is currently underway to assess the safety and efficacy of 177Lu-TLX591 in combination with standard of care (SOC) compared to SOC alone in patients with metastatic castration-resistant prostate cancer (mCRPC). This study is investigating a PSMA-targeted radionuclide therapy using lutetium-177.
Mechanism of Action
177Lu-TLX591 (177Lu-DOTA-rosopatamab) delivers radiation directly to PSMA-positive cancer cells. Scott Tagawa, MD, MS, FACP, FASCO, a professor of medicine and urology at Weill Cornell Medicine, explains that the lutetium-177 emits beta radiation, leading to DNA damage in the targeted cells. If the radiation dose is sufficient, the cells are unable to repair themselves, resulting in cell death. The primary mechanism of action is believed to be radiation-induced damage to PSMA-positive cells.
Antibody Targeting
The antibody used in 177Lu-TLX591 binds to the external domain of PSMA, which allows it to target viable cells. Upon binding, the antibody is internalized and retained within the cell. This is a key difference from earlier PSMA-targeting antibodies like capromab, which only binds to the internal domain of PSMA and, therefore, can only target necrotic cells. The GFM1 antibody, used in this therapy, can bind to the external domain, internalize, and retain the lutetium-177 within the cancer cells.
Prior Clinical Trials
Previous early-phase clinical trials with 177Lu-TLX591 in pre-treated mCRPC patients have shown some efficacy, but also demonstrated toxicity, particularly myelosuppression. One pivotal study involving 17 patients at the maximum tolerated dose showed an overall survival of over 40 months. However, a significant proportion of patients (59%) experienced grade 4 thrombocytopenia. The ProstACT GLOBAL trial is designed to evaluate this therapy in an earlier line of therapy, potentially mitigating some of the observed toxicities.
Trial Design and Objectives
The ProstACT GLOBAL trial aims to determine if the addition of 177Lu-TLX591 to standard of care can improve outcomes for patients with mCRPC. The trial will also monitor the safety profile of the combination therapy. By targeting an earlier stage of the disease, researchers hope to maximize the therapeutic benefit while minimizing adverse effects such as myelosuppression.
