A Study Comparing Radioligand Therapy with AAA817 to Standard Treatment for Metastatic Castration-Resistant Prostate Cancer Following Prior Lutetium-177-PSMA Therapy

Prostate cancer (prostate carcinoma) is a malignant disease of the prostate gland that, in the vast majority of cases, originates in the glandular tissue (adenocarcinoma). Its growth is typically stimulated by male sex hormones (androgens, primarily testosterone), which is why, in advanced stages of the disease, testosterone levels are often lowered to what is known as the “castration level” through medication or surgery. If the disease progresses despite this, it is referred to as castration-resistant prostate cancer. Metastases from prostate cancer most commonly form in the bones, but lymph nodes and other organs may also be affected. Treatment involves the use of androgen receptor pathway inhibitors (ARPI), which suppress the growth-promoting effect of male sex hormones on cancer cells, while taxane-based chemotherapy drugs disrupt cell division. Prostate-specific membrane antigen (PSMA) is a protein found on the surface of prostate cells. Prostate cancer cells often produce PSMA in greater quantities than healthy cells, which can be detected using a specialized imaging technique (PSMA-PET/CT). In PSMA radioligand therapy, a molecule (ligand) that binds to PSMA is linked to a radioactive substance so that the radiation specifically damages the PSMA-expressing cancer cells while sparing the surrounding healthy tissue as much as possible. The study drug AAA817 is a PSMA-binding radioligand that contains actinium-225. This emits alpha radiation, which travels only a few cell diameters within the tissue and releases its energy over this short distance. In contrast, lutetium-177—used in previous radioligand therapies—emits beta radiation, which has a greater range within the tissue. PSMA radioligand therapies are typically administered as an injection into a vein (intravenously).

The goal of this Phase 2/3 study is first to gather further information on the efficacy and tolerability of the intended dose of the study drug AAA817 and then to evaluate the efficacy of AAA817 compared to standard treatment. The study consists of two parts and is open-label. This means that both the patients and the study physicians know which treatment is being administered. In the Phase 2 part, patients are randomly assigned to receive AAA817 at one of two doses (Dose A or Dose B) to assess its efficacy and tolerability in advance. In the subsequent Phase 3 part, they are also randomly assigned to receive either AAA817 or a standard treatment selected by the study physicians. AAA817 is administered over several treatment cycles, each lasting eight weeks. The main objectives (primary endpoints) of the study in the Phase 2 portion are biochemical response, measured as a confirmed reduction in PSA levels of at least 50%, as well as the safety and tolerability of AAA817. To this end, adverse events, dose adjustments, and treatment discontinuations will be recorded. In the Phase 3 part, the study will evaluate radiologically defined progression-free survival—that is, the time without disease progression as determined by imaging studies—and overall survival.

Eligible participants are patients aged 18 to 100 years with prostate adenocarcinoma confirmed by tissue or cell analysis, in whom PSMA positivity has been demonstrated by PSMA-PET/CT. Patients must have at least one metastasis, and their testosterone level must be at castration levels (i.e., below 50 ng/dL). In addition, they must have already been treated with an androgen receptor pathway inhibitor (ARPI) and taxane-based chemotherapy, and their disease must have progressed during or after lutetium-177-PSMA therapy.