A Study of the Radioactive Drug AAA817 in Combination with an Androgen Receptor Signaling Pathway Inhibitor Compared to Standard Treatment for Metastatic Castration-Resistant Prostate Cancer

Prostate cancer (prostate carcinoma) usually arises from the glandular cells of the prostate (adenocarcinoma). Its growth is generally dependent on male sex hormones such as testosterone, which is why testosterone levels are usually lowered with medication in advanced stages of the disease (anti-hormone therapy, ADT). If the disease progresses despite this, it is referred to as castration-resistant prostate cancer. The approved standard treatment then includes androgen receptor pathway inhibitors (ARPI) such as enzalutamide or abiraterone, which are taken as capsules or tablets. They block the growth-promoting signals from male hormones. In addition, taxane-based chemotherapy with docetaxel or cabazitaxel can be administered as an intravenous infusion. These drugs inhibit the division of cancer cells. PSMA (prostate-specific membrane antigen) is a protein on the cell surface that, in most cases of prostate cancer, is present in significantly greater quantities on cancer cells than on healthy prostate tissue. In radioligand therapy, a molecule that binds to PSMA is linked to a radioactive substance. This allows the radiation to be delivered specifically to the PSMA-expressing cancer cells and their immediate surroundings. For example, Lutetium-177-PSMA-617 (AAA617), which is part of the standard treatment, works with the beta emitter Lutetium-177. In contrast, the study drug AAA817 (actinium-225-PSMA-617) contains the alpha emitter actinium-225, whose radiation penetrates only a few cell diameters into the tissue. It is therefore intended to target primarily the bound cancer cells and their immediate surroundings. The goal of this Phase 3 study is to investigate whether AAA817, in combination with an ARPI, can delay disease progression longer than standard treatment. After PSMA positivity is confirmed via a specialized imaging test (PSMA-PET/CT), patients are randomly assigned to one of two study arms or the control arm. In both study arms, they will receive AAA817 as an intravenous infusion for up to six cycles; in one of these arms, they will also receive enzalutamide or abiraterone orally. In the control arm, they receive standard treatment selected by the study physicians—that is, a change in ARPI, taxane-based chemotherapy, or AAA617. Switching between groups (crossover) is not permitted, but concomitant anti-hormone therapy is allowed. The study is open-label, meaning that both the patients and the study physicians know which treatment is being administered. The main objective (primary endpoint) is radiographic progression-free survival (rPFS), defined as the time during which the disease does not progress on imaging and the patients remain alive. Eligible participants are patients aged 18 to 100 years with PSMA-positive, metastatic, and castration-resistant prostate adenocarcinoma that has progressed during their most recent ARPI treatment. Prior taxane-based chemotherapy is permitted only if it was administered during the hormone-sensitive stage, when the tumor was still responding to hormone deprivation. Patients who have already received a radiopharmaceutical or another drug-based cancer therapy for mCRPC are ineligible to participate.