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

Official 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 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.

Eligibility Requirements

• Minimum Age: 18 Years
• Maximum Age: 100 Years
• Sex: MALE

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 940 participants

Study Arms

• Investigational Arm: AAA817+ARPI (enzalutamide or abiraterone) (EXPERIMENTAL)
  Participants will receive AAA817 infusion directly into a vein with ARPIs.
• Investigational Arm: AAA817 (EXPERIMENTAL)
  Participants will receive AAA817 infusion directly into a vein.
• Control arm: Investigator's choice of SoC (ARPI or chemotherapy or AAA617) (ACTIVE_COMPARATOR)
  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.

Interventions

• 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.
• 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.
• 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).

Primary Outcomes

• 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.)

Secondary Outcomes

• 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.)
• Radiographic Progression Free Survival by by Prostate Cancer Working Group 3 (PCWG3)-modified RECIST v1.1 (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.)
• Overall Survival in participants with PSMA-positive mCRPC treated with another ARPI. (Key Secondary) (From the date of randomization to the date of death due to any cause.)
• 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.)
• 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.)

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, 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.

Trial Locations

• Sansum Clinic, Santa Barbara, California, United States
• Rocky Mountain Cancer Centers, Denver, Colorado, United States
• Miami Cancer Institute at Bapt, Miami, Florida, United States
• AdventHealth, Orlando, Florida, United States
• Univ Of Iowa Hospitals And Clinics, Iowa City, Iowa, United States
• University of Kansas Hospital, Kansas City, Kansas, United States
• Wash U School of Medicine, St Louis, Missouri, United States
• Bassett Medical Center, Cooperstown, New York, United States
• Weill Cornell Medicine NY-Presb, New York, New York, United States
• University of Rochester Medical Ctr, Rochester, New York, United States
• ...and 10 more locations

Contact Information

• Novartis Pharmaceuticals — CONTACT
  Phone: 1-888-669-6682
  Email: novartis.email@novartis.com
• Novartis Pharmaceuticals — CONTACT
  Phone: +41613241111

Study Officials

• Novartis Pharmaceuticals — STUDY_DIRECTOR
  Novartis Pharmaceuticals

More Prostate Cancer Trials

View all Prostate Cancer clinical trials