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

February 20, 2026 updated by: Novartis Pharmaceuticals

A Phase III, Open-label, Multi-center, Randomized Study Comparing AAA817+ARPI Versus Standard of Care in Adult Participants With PSMA-positive Metastatic Castration Resistant Prostate Cancer

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 or [177Lu]Lu-PSMA-617 (AAA617)) 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.

Study Overview

Status

Recruiting

Conditions

Intervention / Treatment

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 or [177Lu]Lu-PSMA-617 (AAA617) 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) or [177Lu]Lu-PSMA-617 (AAA617)' per investigator's choice. Treatment with ARPI should continue as per protocol end of treatment criteria. Treatment duration with taxane-based chemotherapy or AAA617will 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.

Study Type

Interventional

Enrollment (Estimated)

940

Phase

  • Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Novartis Pharmaceuticals
  • Phone Number: +41613241111

Study Locations

  • Australia
    • New South Wales
      • Darlinghurst, New South Wales, Australia, 2010
        • Recruiting
        • Novartis Investigative Site
    • South Australia
      • Adelaide, South Australia, Australia, 5000
        • Recruiting
        • Novartis Investigative Site
  • Brazil
    • São Paulo
      • São Paulo, São Paulo, Brazil, 01308-050
        • Recruiting
        • Novartis Investigative Site
      • São Paulo, São Paulo, Brazil, 05652-000
        • Recruiting
        • Novartis Investigative Site
  • China
      • Beijing, China, 100036
        • Recruiting
        • Novartis Investigative Site
      • Beijing, China, 100034
        • Recruiting
        • Novartis Investigative Site
      • Guangzhou, China, 510060
        • Recruiting
        • Novartis Investigative Site
      • Shanghai, China, 200025
        • Recruiting
        • Novartis Investigative Site
      • Shanghai, China, 200127
        • Recruiting
        • Novartis Investigative Site
      • Shanghai, China, 200032
        • Recruiting
        • Novartis Investigative Site
    • Guangdong
      • Guangzhou, Guangdong, China, 510632
        • Recruiting
        • Novartis Investigative Site
    • Hubei
      • Wuhan, Hubei, China, 430022
        • Recruiting
        • Novartis Investigative Site
      • Wuhan, Hubei, China, 430030
        • Recruiting
        • Novartis Investigative Site
    • Jiangsu
      • Nanjing, Jiangsu, China, 210006
        • Recruiting
        • Novartis Investigative Site
      • Nanjing, Jiangsu, China, 210029
        • Recruiting
        • Novartis Investigative Site
    • Liaoning
      • Shenyang, Liaoning, China, 110011
        • Recruiting
        • Novartis Investigative Site
    • Sichuan
      • Chengdu, Sichuan, China, 610041
        • Recruiting
        • Novartis Investigative Site
    • Zhejiang
      • Hangzhou, Zhejiang, China, 310022
        • Recruiting
        • Novartis Investigative Site
  • Hong Kong
      • Hong Kong, Hong Kong, 999077
        • Recruiting
        • Novartis Investigative Site
      • Hong Kong, Hong Kong, 999999
        • Recruiting
        • Novartis Investigative Site
  • India
    • Haryana
      • Gurgaon, Haryana, India, 122 002
        • Recruiting
        • Novartis Investigative Site
    • Maharashtra
      • Mumbai, Maharashtra, India, 400 012
        • Recruiting
        • Novartis Investigative Site
  • Japan
      • Chiba, Japan, 260-8717
        • Recruiting
        • Novartis Investigative Site
      • Fukuoka, Japan, 811-0213
        • Recruiting
        • Novartis Investigative Site
      • Fukuoka, Japan, 812-0033
        • Recruiting
        • Novartis Investigative Site
      • Fukuoka, Japan, 8128582
        • Recruiting
        • Novartis Investigative Site
      • Hiroshima, Japan, 7348551
        • Recruiting
        • Novartis Investigative Site
      • Kyoto, Japan, 6068507
        • Recruiting
        • Novartis Investigative Site
    • Hokkaido
      • Sapporo, Hokkaido, Japan, 0608648
        • Recruiting
        • Novartis Investigative Site
    • Hyōgo
      • Kobe, Hyōgo, Japan, 6500047
        • Recruiting
        • Novartis Investigative Site
    • Kanagawa-ku
      • Yokohama, Kanagawa-ku, Japan, 236-0004
        • Recruiting
        • Novartis Investigative Site
    • Tokyo
      • Chuo Ku, Tokyo, Japan, 1040045
        • Recruiting
        • Novartis Investigative Site
  • Singapore
      • Singapore, Singapore, 169608
        • Recruiting
        • Novartis Investigative Site
      • Singapore, Singapore, 119074
        • Recruiting
        • Novartis Investigative Site
      • Singapore, Singapore, 168583
        • Recruiting
        • Novartis Investigative Site
  • South Korea
      • Seoul, South Korea, 06351
        • Recruiting
        • Novartis Investigative Site
    • Korea
      • Seoul, Korea, South Korea, 03080
        • Recruiting
        • Novartis Investigative Site
  • Taiwan
      • Kaohsiung City, Taiwan, 83301
        • Recruiting
        • Novartis Investigative Site
      • Taoyuan District, Taiwan, 33305
        • Recruiting
        • Novartis Investigative Site
  • United Kingdom
    • Surrey
      • Sutton, Surrey, United Kingdom, SM2 5PT
        • Recruiting
        • Novartis Investigative Site
  • United States
    • California
      • Santa Barbara, California, United States, 93105
        • Recruiting
        • Sansum Clinic
        • Contact:
        • Principal Investigator:
          • Mukul Gupta
    • Colorado
      • Denver, Colorado, United States, 80218
        • Recruiting
        • Rocky Mountain Cancer Centers
        • Principal Investigator:
          • Allen Cohn
        • Contact:
    • Florida
      • Miami, Florida, United States, 33173
      • Orlando, Florida, United States, 32804
        • Recruiting
        • AdventHealth
        • Principal Investigator:
          • Ravi Shridhar
        • Contact:
    • Iowa
      • Iowa City, Iowa, United States, 52242
        • Recruiting
        • Univ Of Iowa Hospitals And Clinics
        • Contact:
        • Principal Investigator:
          • Kristin Plichta
    • Kansas
      • Kansas City, Kansas, United States, 66160
        • Recruiting
        • University of Kansas Hospital
        • Principal Investigator:
          • Xinglei Shen
        • Contact:
    • Missouri
      • St Louis, Missouri, United States, 63110
        • Recruiting
        • Wash U School of Medicine
        • Principal Investigator:
          • Jeff Michalski
        • Contact:
    • New York
      • Cooperstown, New York, United States, 13326
        • Recruiting
        • Bassett Medical Center
        • Contact:
        • Principal Investigator:
          • Timothy Korytko
      • New York, New York, United States, 10021
        • Recruiting
        • Weill Cornell Medicine NY-Presb
        • Principal Investigator:
          • Scott Tagawa
        • Contact:
      • Rochester, New York, United States, 14642
      • Syracuse, New York, United States, 13210
        • Recruiting
        • Associated Med Professionals of NY
        • Principal Investigator:
          • Steven Finkelstein
        • Contact:
    • South Carolina
      • Myrtle Beach, South Carolina, United States, 29572
        • Recruiting
        • Carolina Urologic Research Center
        • Principal Investigator:
          • Neal D Shore
        • Contact:
    • Texas
      • San Antonio, Texas, United States, 78229
    • Washington
      • Seattle, Washington, United States, 98122-4379
        • Recruiting
        • Swedish Medical Center
        • Principal Investigator:
          • Song Zhao
        • Contact:
    • Wisconsin
      • Milwaukee, Wisconsin, United States, 53226
        • Recruiting
        • Medical College of Wisconsin
        • Principal Investigator:
          • Deepak Kilari
        • Contact:

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Description

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, ARPI change or AAA617 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).

    • Participants with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer, as per local testing, may be enrolled if they had prior exposure to PARPi.

Key Exclusion Criteria:

  • Previous anti-cancer treatment with any approved or investigational radiopharmaceuticals (for example, [177Lu]Lu-PSMA, [177Lu]-DOTA, or Radium- 223.)

  • Previous treatment with any external beam radiotherapy including hemi-body radiation within 6 weeks of randomization (within 2 weeks for radiotherapy of localized metastases).

    • Any prior PARP inhibitor or other systemic anticancer therapy administered for metastatic castration-resistant prostate cancer (mCRPC). Any other approved or investigational systemic therapy (including chemotherapy, immunotherapy, biologics, or monoclonal antibodies) is prohibited within 28 days or 5 half-lives (whichever is shorter) before randomization.

Note: Prior ARPI administered in the mHSPC setting or earlier may continue until C1D1.

Other protocol-defined inclusion/exclusion criteria may apply.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Diagnostic
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Investigational Arm: AAA817+ARPI (enzalutamide or abiraterone)
Participants will receive AAA817 infusion directly into a vein with ARPIs.
Drug: AAA817
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.
Other Names:
  • [225Ac]Ac-PSMA-617
Drug: ARPI
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.
Other Names:
  • Enzalutamide or Abiraterone
Experimental: Investigational Arm: AAA817
Participants will receive AAA817 infusion directly into a vein.
Drug: AAA817
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.
Other Names:
  • [225Ac]Ac-PSMA-617
Active Comparator: Control arm: Investigator's choice of SoC (ARPI or chemotherapy or AAA617)
Participants will receive standard treatment as decided by the trial doctor either as a taxane-based chemotherapy infusion directly into a vein or ARPI change either as capsules or tablets or AAA617 monotherapy infusion directly into a vein.
Drug: ARPI
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.
Other Names:
  • Enzalutamide or Abiraterone
Drug: Standard of Care
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 or [177Lu]Lu-PSMA-617 (AAA617).
Other Names:
  • ARPI enzalutamide
  • ARPI abiraterone
  • Taxane based chemotherapy of docetaxel
  • Taxane based chemotherapy of cabazitaxel
  • [177Lu]Lu-PSMA-617 (AAA617)

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
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.
Time to radiographic disease progression or death due to any cause.
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

Outcome Measure
Measure Description
Time Frame
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.
Time to death due to any cause.
From the date of randomization to the date of death due to any cause, assessed up to approximately 40 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.
Time to first documented progression or death due to any cause.
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.
Time to first documented progression on next line of antineoplastic therapy or death from any cause.
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.
The proportion of participants with best overall response (BOR) of confirmed complete response (CR) or partial response (PR) in soft tissue.
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.
The proportion of participants with BOR of confirmed CR, PR, stable disease (SD) or non-CR/non-progressive disease (PD) in soft tissue.
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 between the date of first documented response and the date of first documented radiographic progression or death due to any cause.
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 radiographic soft tissue progression.
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.
Time to date of first new symptomatic skeletal event of death due to any cause.
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.
The percentage of participants who achieved ≥ 50% and ≥ 90% decrease from baseline, respectively.
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).
Time-concentration profiles and PK parameters of AAA817 (e.g. AUC, Cmax).
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.
Change from baseline on FACT-P Prostate Cancer Subscale (PCS). FACT-P assesses symptoms/problems related to prostate carcinoma and its treatment.
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.
Time to worsening on the Worst Pain is defined as the time from randomization to the first occurrence of worsening on the Worst Pain item (BPI-SF) or death due to any cause, whichever occurs first.
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.
rPFS time to the date of first documented radiographic disease progression or death due to any cause, whichever occurs first.
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.
Radiographic Progression Free Survival by by Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1 (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.
Time to radiographic disease progression, using by blinded independent central review (BICR) using conventional imaging and Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1 criteria or death due to any cause.
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.
Overall Survival in participants with PSMA-positive mCRPC treated with another ARPI. (Key Secondary)
Time Frame: From the date of randomization to the date of death due to any cause.
Time to death due to any cause.
From the date of randomization to the date of death due to any cause.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Novartis Pharmaceuticals

Investigators

  • Study Director: Novartis Pharmaceuticals, Novartis Pharmaceuticals

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

July 1, 2025

Primary Completion (Estimated)

September 29, 2028

Study Completion (Estimated)

November 4, 2032

Study Registration Dates

First Submitted

February 18, 2025

First Submitted That Met QC Criteria

February 26, 2025

First Posted (Actual)

March 3, 2025

Study Record Updates

Last Update Posted (Actual)

February 24, 2026

Last Update Submitted That Met QC Criteria

February 20, 2026

Last Verified

February 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • CAAA817B12301
  • 2024-512340-32 (Registry Identifier: EU CTIS)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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