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

Phase 3

Not yet recruiting

• Conditions: Prostate Cancer
• Interventions: Drug: AAA817; Drug: ARPI; Drug: Standard of Care

• Registration Number: NCT06855277
• Lead Sponsor: Novartis Pharmaceuticals

Brief 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.

Study Timeline

• Study First Submitted: 2025-02-18
• Study First Submitted QC: 2025-02-26
• Status Verified: 2025-03
• Study First Posted: 2025-03-03
• Last Update Submitted: 2025-03-03
• Last Update Posted: 2025-03-05
• Study Start: 2025-08-20
• Primary Completion: 2027-12-31
• Study Completion: 2032-11-04

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: Male
• Target Recruitment: 486

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 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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Investigational Arm: AAA817+ARPI (enzalutamide or abiraterone)	ARPI	Participants will receive AAA817 infusion directly into a vein with ARPIs.
Control arm: Investigator's choice of SoC (ARPI or taxane-based chemotherapy)	ARPI	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.
Control arm: Investigator's choice of SoC (ARPI or taxane-based chemotherapy)	Standard of Care	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.
Investigational Arm: AAA817	AAA817	Participants will receive AAA817 infusion directly into a vein.
Investigational Arm: AAA817+ARPI (enzalutamide or abiraterone)	AAA817	Participants will receive AAA817 infusion directly into a vein with ARPIs.

Primary Outcome Measures

Name	Time	Method
Radiographic Progression Free Survival (rPFS)	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.

Secondary Outcome Measures

Name	Time	Method
Overall Survival (OS) (Key Secondary Endpoint)	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.
Radiographic Progression Free Survival by PSMA PET/CT and (rPSF-PET)(Key Secondary)	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 PSMA PET/CT and (rPSF-PET), or death due to any cause.
Progression Free Survival (PFS)	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.
Progression Free Survival (PFS2)	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.
Overall Response Rate (ORR)	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.
Disease Control Rate (DCR)	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.
Duration of Response (DoR)	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.
Time to first radiographic soft tissue progression (TTSTP)	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.
Time to first symptomatic skeletal event (TTSSE)	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.
Prostate specific antigen response (PSA50 and PSA90)	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.
Time-concentration profiles and PK parameters of AAA817	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).
Change from baseline on FACT-P Prostate Cancer Subscale (PCS)	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.
Time to worsening on the Worst Pain	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.
rPFS in participants treated with AAA817	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.
OS in participants treated with AAA817	From the date of randomization to the date of death due to any cause assessed up to approximately 40.0 months.	OS is time to death due to any cause.