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Randomized phase III study of AAA817 plus an androgen receptor pathway inhibitor in adult men with PSMA‑positive metastatic castration‑resistant prostate cancer

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What is this trial about?

A plain-language summary of the goals, design and what participants do

The study focuses on Metastatic Castration-Resistant Prostate Cancer, an advanced form of prostate cancer that continues to grow even when the body’s testosterone level is very low. In this condition the cancer has spread to other parts of the body, and many tumors show a protein called PSMA-positive, which can be seen on special imaging scans.

The investigational treatment combines a new radioactive drug called AAA817 with an androgen receptor pathway inhibitor, a medicine that blocks the signals hormones use to help cancer grow. This combination will be compared with the usual medicines doctors give for this disease, such as enzalutamide, abiraterone, docetaxel and cabazitaxel. The radioactive drug is designed to seek out and deliver radiation directly to the cancer cells that have the PSMA protein, while the hormone‑blocking drug works throughout the body to stop cancer growth.

The purpose of the trial is to find out whether the new combination can keep the cancer from getting worse for a longer time than the standard treatments. Participants will be randomly placed into one of the two groups, will receive the assigned medicines for several months, and will have regular doctor visits, blood tests and imaging scans to track the disease and check for side effects. The study will continue until enough information is collected about how long the cancer stays under control and how safe the new treatment is.

The research process

The trial runs in 8 steps – from screening to follow-up. Each step says what happens and what the team monitors.

  1. Step 1

    Randomization and Baseline Assessments

    After joining the study you will be randomly assigned to one of two treatment groups. The study staff will record your medical history, perform physical examinations, and take baseline laboratory tests and imaging scans. These assessments establish the starting point for evaluating the effect of the treatment.

  2. Step 2

    First Administration of AAA817 (if assigned to the experimental group)

    If you are placed in the experimental group, you will receive AAA817 (vipivotide tetraxetan actinium‑225) as an intravenous infusion. The product is supplied as a solution for injection/infusion. The listed dose is 00 MBq (megabecquerel). The infusion is given according to the study schedule, which is defined by the trial protocol.

  3. Step 3

    Start of Androgen Receptor Pathway Inhibitor (ARPI) (experimental group)

    Along with AAA817, you will begin an androgen receptor pathway inhibitor (ARPI) taken by mouth. Possible ARPI options include:

    Enzalutamide – 160 mg oral tablet taken once daily.

    Abiraterone – 1000 mg oral tablet taken once daily.

    Flutamide – 750 mg oral tablets taken three times daily.

    Relugolix – 360 mg oral tablets taken once daily.

    The exact ARPI you receive will be chosen by the investigator and will follow the dosing schedule defined in the protocol.

  4. Step 4

    Standard‑of‑Care Treatment (if assigned to the comparator group)

    If you are placed in the standard‑of‑care group, you will receive one of the approved therapies for metastatic castration‑resistant prostate cancer, as selected by the investigator. Possible options and their doses are:

    Enzalutamide – 160 mg oral tablet taken once daily.

    Abiraterone – 1000 mg oral tablet taken once daily.

    Docetaxel – 75 mg/m² intravenous infusion given every three weeks.

    Cabazitaxel – 25 mg/m² intravenous infusion given every three weeks.

    Degarelix – 240 mg intravenous injection given as a single loading dose, followed by maintenance dosing per protocol.

    Other background medications such as Prednisone 10 mg oral daily or Prednisolone 10 mg oral daily may be prescribed to manage side effects, following the study protocol.

  5. Step 5

    Ongoing Treatment and Monitoring Visits

    You will continue to take the assigned oral medication each day and receive any required intravenous infusions on the schedule defined by the protocol. Regular clinic visits will be scheduled to:

    • Perform blood tests, including prostate‑specific antigen (PSA) measurements.

    • Conduct imaging studies (such as CT, MRI, or PSMA‑PET scans) to assess disease status.

    • Evaluate safety by recording any adverse events or side effects.

    • Complete questionnaires about quality of life and pain.

  6. Step 6

    Assessment of Treatment Effectiveness

    The primary goal of the study is to measure radiographic progression‑free survival (rPFS), which is the time from randomization until the first sign of disease progression on imaging or death from any cause. Secondary goals include overall survival, response rates, and safety assessments. These outcomes are evaluated during the scheduled monitoring visits.

  7. Step 7

    Continuation or Discontinuation of Therapy

    Treatment will continue until one of the following occurs:

    • Disease progression is documented on imaging.

    • Unacceptable toxicity or serious adverse events develop.

    • You withdraw consent to remain in the study.

    If treatment stops, you will still be asked to attend follow‑up visits to monitor your health.

  8. Step 8

    End‑of‑Study Visit

    At the conclusion of the study, a final visit will be performed. The study team will collect final laboratory results, imaging studies, and safety information, and will discuss any remaining health concerns.

Who can join the trial?

9 criteria

  • Provide a signed informed consent form, which means you agree in writing to join the study after understanding what it involves.
  • Be at least 18 years old.
  • Have an ECOG performance status of 0 to 2, a simple scale that measures how well you can carry out daily activities (0 = fully active, 2 = up and about more than half the day but unable to work).
  • If you have harmful or possibly harmful changes (mutations) in certain DNA‑repair genes called homologous recombination repair (HRR) genes, whether these changes are inherited (germline) or found only in the tumor (somatic), you may join if you have already taken a PARP inhibitor (PARPi) medication, as decided by your doctor.
  • Have a confirmed diagnosis of prostate adenocarcinoma based on tissue examination (histological) or cell examination (cytological). Patients whose cancer also contains neuroendocrine components are not eligible.
  • If you have previously received taxane‑based chemotherapy during the earlier stage called metastatic hormone‑sensitive prostate cancer (mHSPC), you can participate if your doctor believes this treatment line is appropriate for you now. Patients who received taxane chemotherapy for the later stage metastatic castration‑resistant prostate cancer (mCRPC) are not eligible.
  • Show disease that is positive on a PSMA‑PET scan using an approved imaging agent, meaning the scan clearly identifies cancer cells that have the PSMA protein.
  • Have metastatic castration‑resistant prostate cancer (mCRPC) that is getting worse while on an androgen‑receptor pathway inhibitor (ARPI) as your most recent treatment, and you must not have progressed on more than one ARPI. Progression must be documented by at least one of the following:
    • A rise in your blood prostate‑specific antigen (PSA) level, shown by two increases measured at least one week apart (starting value must be at least 2.0 ng/mL, or 1.0 ng/mL if PSA rise is the only sign of progression).
    • The appearance of two or more new bone lesions on a bone scan, which indicates the cancer is spreading in the bones.

Who cannot join the trial?

3 criteria

  • You cannot have had any previous cancer treatment that used a radioactive drug (called a radiopharmaceutical), such as [177Lu]Lu‑PSMA, [177Lu]‑DOTA, or Radium‑223.
  • You cannot have had any external beam radiotherapy (radiation delivered from a machine outside the body), including hemi‑body radiation, within a few weeks before you would be randomly assigned to a treatment group.
  • You cannot have taken any other cancer medicines that work throughout the whole body (systemic anti‑cancer therapy)—such as chemotherapy, experimental drugs, immunotherapy, or biological medicines like monoclonal antibodies—within a certain number of days before randomization (or a period based on the drug’s half‑life, which is the time it takes for half of the drug to leave your body).
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Investigated drugs

  • RELUGOLIX

    is an oral pill that lowers the amount of testosterone in the body. It works by blocking signals that tell the testes to make testosterone, which can help slow the growth of prostate cancer that depends on this hormone.

  • FLUTAMIDE

    is an oral medication that blocks the action of testosterone on prostate cancer cells. By preventing testosterone from binding to its receptor, it helps reduce the stimulation of cancer growth.

  • ENZALUTAMIDE

    is a tablet taken by mouth that blocks the androgen receptor, which is the part of the cell that responds to testosterone and other male hormones. This stops the hormones from helping prostate cancer cells grow.

  • ABIRATERONE

    is an oral drug that stops the body from making testosterone. It works by blocking an enzyme needed for hormone production, thereby lowering hormone levels that can feed prostate cancer.

  • DEGARELIX

    is given by injection under the skin. It blocks the release of hormones that tell the testes to produce testosterone, leading to a rapid drop in testosterone levels.

  • PIFLUFOLASTAT (18F)

    is a radioactive imaging agent injected into a vein. It helps doctors see where prostate cancer cells that have a specific protein (PSMA) are located by showing them on special scans.

What is already known about the treatment

  • Relugolix

    This medication is taken by mouth as a tablet and works by blocking the hormone signals that tell the body to make testosterone, quickly lowering hormone levels. It is an approved drug for treating advanced prostate cancer and is listed in current medical guidelines. Its main use is to help control the growth of prostate cancer that no longer responds to standard hormone therapy. Relugolix belongs to the class of GnRH receptor antagonists.

  • Flutamide

    Flutamide is an oral tablet that blocks the action of male hormones at their receptor sites, reducing the stimulation of prostate cancer cells. It has been used for many years in prostate cancer treatment, although newer drugs have largely replaced it. The drug is mainly indicated for prostate cancers that continue to grow despite low testosterone levels. It is classified as a non‑steroidal antiandrogen.

  • Enzalutamide

    Enzalutamide is taken as an oral tablet and works by preventing male hormones from activating their receptors inside cancer cells. It is an approved therapy for metastatic castration‑resistant prostate cancer and is widely referenced in clinical studies. The medication helps to slow tumor growth and extend survival in men whose disease has progressed. It is an androgen receptor inhibitor.

  • Abiraterone

    This drug is given as an oral tablet and blocks an enzyme needed for the body to make male hormones, leading to lower testosterone levels. Abiraterone is approved for metastatic castration‑resistant prostate cancer and is included in many treatment guidelines. It is used to delay disease progression after other hormone therapies have failed. The drug belongs to the class of androgen biosynthesis inhibitors.

  • Degarelix

    Degarelix is injected under the skin and works by quickly blocking the hormone signals that cause testosterone production. It is an approved GnRH antagonist for advanced prostate cancer and is listed in current treatment protocols. The medication is used to achieve rapid hormone suppression in men with resistant disease. It is classified as a GnRH receptor antagonist.

  • Piflufolastat (18F)

    This agent is given by intravenous injection and binds to a protein called PSMA that is abundant on prostate cancer cells, allowing doctors to see tumors on a PET scan. It is approved as a diagnostic radiopharmaceutical for imaging PSMA‑positive prostate cancer. Its purpose is to help locate cancer spread and guide treatment decisions. It is classified as a PSMA‑targeted PET imaging agent.

Investigated diseases

Metastatic castration‑resistant prostate cancer - This is prostate cancer that continues to grow even when testosterone levels are very low. The disease has spread beyond the prostate gland to distant sites such as bone, lymph nodes, or other organs. Cancer cells keep dividing and form new tumor lesions despite hormonal suppression. The spread can be detected by imaging or rising prostate‑specific antigen levels. As the tumor burden increases, patients may experience symptoms related to affected organs. The condition represents an advanced stage of prostate cancer with ongoing disease progression.
Trial detailsLast updated 12 Nov 2026
Age18+ yearsPhasePhase IIITrial ID2024-512340-32-01Protocol codeCAAA817B12301Estimated enrolment722 patientsSponsorNovartis Pharma AG

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