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Study Comparing AAA817+ARPI Versus Standard of Care in Adult Participants With PSMA-positive mCRPC

Clinicaltrials.gov ID: NCT06855277
db-list-check Status RECRUITING
b-loader Phase PHASE3
b-people Age 18 - 100 Years
b-bullseye-arrow Enrollments 605

Conditions

Prostate Cancer

Drugs

AAA817, ARPI, Standard of Care

Summary

The purpose of this study is to determine whether [225Ac]Ac-PSMA-617 (AAA817), given for up to 6 cycles at a dose of 10 Megabecquerel (MBq) +/- 10%, plus androgen receptor pathway inhibitor (ARPI), improves the radiographic progression free survival (rPFS) compared to investigator's choice of standard of care (SOC) (ARPI change or taxane-based chemotherapy) in adult participants with PSMA-positive metastatic castration resistant prostate cancer (mCRPC) treated with another ARPI as last treatment and who have not been exposed to a taxane-containing chemotherapy in the mCRPC setting nor have received any prior PSMA-targeting radioligand therapy.

Detailed Description

This is a phase III, open label, multicenter randomized study. The study aims at evaluating the superiority of 225Ac-PSMA-617 combined with androgen receptor pathway inhibitor (ARPI) over a change of ARPI or chemotherapy in prolonging progression free survival (rPFS).

Screening period: At screening, the participants will be assessed for eligibility and will undergo a positron emission tomography (PET)/computed tomography (CT) scan to evaluate PSMA positivity. Only participants with PSMA positive cancer and confirmed eligibility criteria will be randomized.

Participants randomized to the investigational arms will receive up to 6 doses of AAA817 10 Mbq +/- 10% given intravenously with or without an ARPI (oral enzalutamide or oral abiraterone) per investigator’s choice. Treatment with ARPI should continue as per protocol end of treatment criteria.

Participants randomized to SoC will be treated with an ARPI change (oral enzalutamide or oral abiraterone) or taxane-based chemotherapy (docetaxel or cabazitaxel) per investigator’s choice. Treatment with ARPI should continue as per protocol end of treatment criteria. Treatment duration with taxane-based chemotherapy will depend on the chosen regimen per the investigator’s discretion following local guidelines as per standard of care and product labels and adhere to the protocol end of treatment criteria.

Supportive care will be allowed in both arms at the discretion of the investigator and includes available care for the eligible participant according to best institutional practice for mCRPC treatment, including androgen deprivation therapy (ADT).

Safety will be assessed routinely during the study. Crossover is not allowed among study arms.

The study will be conducted in the USA among other countries globally.

Locations

2 locations Found with status Recruiting

Status

  • RECRUITING

Contact Person

Study Director

  • Novartis Pharmaceuticals

Status

  • RECRUITING

Contact Person

Study Director

  • Novartis Pharmaceuticals

Eligibility Criteria

Key Inclusion Criteria:

* Signed informed consent must be obtained prior to participation in the study.
* Participants must be adults ≥ 18 years of age.
* Participants must have an ECOG performance status of 0 to 2.
* Participants must have histological, and/or cytological confirmation of adenocarcinoma of the prostate. Participants with mixed histology (neuroendocrine) are not eligible.
* Participants who have received taxane-based chemotherapy in mHSPC setting are eligible if they are deemed appropriate for chemotherapy or ARPI change as the next line of therapy in the opinion of the Investigator. Note: Participants who have received taxane-based chemotherapy for mCRPC are excluded.
* Participants must not have received taxane-based chemotherapy in mCRPC setting (allowed in mHSPC setting).
* Participants must have PSMA-PET positive disease using a PSMA imaging agent that is approved as per protocol.
* Participant must have been diagnosed with mCRPC with documented progressive disease while on treatment with ARPI in mHSPC or earlier setting as their last treatment (and did not progress on more than one ARPI).

Key Exclusion Criteria:

* Previous treatment with any approved or investigational RLT, approved or investigational radioisotopes
* Previous treatment with any conventional external beam radiotherapy including hemi-body radiation within 6 weeks of randomization (within 2 weeks for radiotherapy of localized metastases).
* Participants with known or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer.
* Any approved or investigational agents/systemic anti-cancer therapy (e.g. other chemotherapy, investigational therapy, immunotherapy or biological therapy including monoclonal antibodies) within 28 days (or 5 times the half-life of that therapy whichever is longer) of the anticipated day C1D1.
* Diagnosed with other active malignancies that are expected to alter life expectancy or may interfere with disease assessment.

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

Investigational Arm: AAA817+ARPI (enzalutamide or abiraterone)

EXPERIMENTAL

Participants will receive AAA817 infusion directly into a vein with ARPIs.

  • DRUG:

    AAA817

    Description:

    AAA817 is being studied for treating PSMA positive mCRPC. Inside the body, it attaches itself to PSMA on the cell surface of the prostate cancer cells and emits radiation to kill them. This treatment is also called a radioligand therapy.

  • DRUG:

    ARPI

    Description:

    Androgen receptor pathway inhibitor (ARPI): An ARPI is approved for the treatment of prostate cancer. It works by blocking signals from male hormones, such as testosterone, that helps cancer cells grow. By blocking these signals, an ARPI slows down or stops the growth of prostate cancer cells. In this trial, participants will be given either enzalutamide or abiraterone.

Investigational Arm: AAA817

EXPERIMENTAL

Participants will receive AAA817 infusion directly into a vein.

  • DRUG:

    AAA817

    Description:

    AAA817 is being studied for treating PSMA positive mCRPC. Inside the body, it attaches itself to PSMA on the cell surface of the prostate cancer cells and emits radiation to kill them. This treatment is also called a radioligand therapy.

Control arm: Investigator's choice of SoC (ARPI or taxane-based chemotherapy)

ACTIVE_COMPARATOR

Participants will receive standard treatment as decided by the trial doctor either as a chemotherapy infusion directly into a vein or ARPI either as capsules or tablets.

  • DRUG:

    ARPI

    Description:

    Androgen receptor pathway inhibitor (ARPI): An ARPI is approved for the treatment of prostate cancer. It works by blocking signals from male hormones, such as testosterone, that helps cancer cells grow. By blocking these signals, an ARPI slows down or stops the growth of prostate cancer cells. In this trial, participants will be given either enzalutamide or abiraterone.

  • DRUG:

    Standard of Care

    Description:

    Standard treatment includes approved treatment for mCRPC. In this trial, the trial doctor will decide which available treatment participants will receive. The trial doctor will select either an ARPI of enzalutamide or abiraterone, or a taxane based chemotherapy of docetaxel or cabazitaxel.

Outcome Measures

Primary Outcome Measures

Radiographic Progression Free Survival (rPFS)

Time Frame: From the date of randomization to the date of the first documented radiographic disease progression using conventional imaging, or death due to any cause, whichever occurs first, assessed up to approximately 40.0 months.

Secondary Outcome Measures

Overall Survival (OS) (Key Secondary Endpoint)

Time Frame: From the date of randomization to the date of death due to any cause, assessed up to approximately 40 months.

Radiographic Progression Free Survival by PSMA PET/CT and (rPSF-PET)(Key Secondary)

Time Frame: From date of randomization to the date of the first documented radiographic disease progression or death due to any cause, whichever occurs first, assessed up to approximately 40.0 months.

Progression Free Survival (PFS)

Time Frame: From date of randomization to the first documented progression by investigator's assessment or death due to any cause, whichever occurs first, assessed up to approximately 40.0 months.

Progression Free Survival (PFS2)

Time Frame: From date of randomization until date of second progression or date of death from any cause, whichever comes first, assessed up to approximately 40.0 months.

Overall Response Rate (ORR)

Time Frame: From the date of randomization to the date of the first documented radiographic disease progression, or death due to any cause, whichever occurs first, assessed up to approximately 40.0 months.

Disease Control Rate (DCR)

Time Frame: From the date of randomization to the date of the first documented radiographic disease progression or death due to any cause, whichever occurs first, assessed up to approximately 40.0 months.

Duration of Response (DoR)

Time Frame: From the date of first documented response (CR or PR) for confirmed responders and the date of first documented radiographic progression in soft tissue or death due to any cause, whichever occurs first, assessed up to approximately 40.0 months.

Time to first radiographic soft tissue progression (TTSTP)

Time Frame: From the date of randomization to the date of radiographic soft tissue progression or death due to any cause, whichever occurs first, assessed up to approximately 40.0 months.

Time to first symptomatic skeletal event (TTSSE)

Time Frame: From the date of randomization to the date of the first documented radiographic disease progression, or death due to any cause, whichever occurs first, assessed up to approximately 40.0 months.

Prostate specific antigen response (PSA50 and PSA90)

Time Frame: From the date of randomization to the date of safety follow up, assessed up to approximately 40.0 months.

Time-concentration profiles and PK parameters of AAA817

Time Frame: From Cycle 1 Day 1 up to approximately cycle 5 days 11 (each cycle is 8 weeks).

Change from baseline on FACT-P Prostate Cancer Subscale (PCS)

Time Frame: From randomization to the first occurrence of worsening on the score or death due to any cause, whichever occurs first, assessed up to approximately 40.0 months.

Time to worsening on the Worst Pain

Time Frame: From randomization to the first occurrence of worsening from baseline, or death due to any cause, whichever occurs first, assessed up to approximately 40.0 months.

rPFS in participants treated with AAA817

Time Frame: From the date of randomization to the date of the first documented radiographic disease progression, or death due to any cause, whichever occurs first, assessed up to approximately 40.0 months.

OS in participants treated with AAA817

Time Frame: From the date of randomization to the date of death due to any cause assessed up to approximately 40.0 months.

Timeline

  • Last Updated
    November 12, 2025
  • Start Date
    March 3, 2025
  • Today
    December 20, 2025
  • Completion Date ( Estimated )
    November 4, 2032

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