An Open-label, Randomized, Phase III Study Comparing 177Lu-PSMA-617 in Combination With Standard of Care, Versus Standard of Care Alone, in Adult Male Patients With Metastatic Hormone Sensitive Prostate Cancer (mHSPC)

Official Summary

The purpose of this study is to evaluate the efficacy and safety of 177Lu-PSMA-617 in combination with Standard of Care (SOC), versus Standard of Care alone, in adult male patients with Metastatic hormone sensitive prostate cancer (mHSPC). In this study, the SoC is defined as a combination of Androgen Receptor Directed Therapy + Androgen Deprivation Therapy. Approximately 1126 patients will be randomized in this study. As of 31-Jan-2024, 1144 participants were enrolled in 20 countries.

Eligibility Requirements

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

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 1,145 participants

Study Arms

• 177Lu-PSMA-617 (EXPERIMENTAL)
  Participant will receive 7.4 GBq (+/- 10%) 177Lu-PSMA-617, once every 6 weeks (+/- 1 week) for a planned 6 cycles, in addition to the Standard of Care (SOC); Androgen receptor-directed therapy (ARDT) + Androgen deprivation therapy (ADT) is considered as SOC and treatment will be administered per the physician's order
• Standard of Care (ACTIVE_COMPARATOR)
  For participants randomized to Standard of Care arm, ARDT +ADT is considered as SOC and treatment will be administered per the physician's order

Interventions

• DRUG: 177Lu-PSMA-617 — administered intravenously once every 6 weeks (1 cycle) for 6 cycles
• DRUG: 68Ga-PSMA-11 — Intravenous dose of approx. 150 Megabecquerel (MBq) at screening and at time of centrally confirmed rPD
• DRUG: ARDT — Administered orally on a continuous basis as per package insert and guideline
• DRUG: ADT — ADT are administered as per physician order

Primary Outcomes

• Radiographic Progression Free Survival (rPFS) (From date of randomization until date of radiographic progression or date of death from any cause, whichever comes first, assessed up to 50 months (estimated final OS analysis))

Secondary Outcomes

• Overall Survival (OS) (Key Secondary Endpoint) (From date of randomization until date of death from any cause, assessed up to 50 months (estimated final OS analysis))
• Prostate-specific antigen 90 (PSA90) response (From date of randomization till 30 days safety fup, assessed up to 50 months (estimated final OS analysis))
• time to development of mCRPC (From date of randomization till End Of Treatment (EOT) or death, which ever happen first, assessed up to 50 months (estimated final OS analysis))
• Progression Free Survival (PFS) (From date of randomization until date of progression or date of death from any cause, whichever come first, assessed up to 50 months (estimated final OS analysis))
• second 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 50 months (estimated final OS analysis))

Eligibility Criteria

Inclusion Criteria:

Participants eligible for inclusion in this study must meet all of the following criteria:

1. Signed informed consent must be obtained prior to participation in the study
2. Patients must be adults ≥18 years of age
3. Patients must have an ECOG performance status of 0 to 2
4. Patients must have a life expectancy \>9 months as determined by the study investigator
5. Patients must have metastatic prostate cancer with histologically or cytologically confirmed adenocarcinoma (current or prior biopsy of the prostate and/or metastatic site)
6. Patients must have evidence of PSMA-positive disease as seen on a 68Ga-PSMA-11 PET/CT scan, and eligible as determined by the sponsor's central reader
7. Patients must have at least one documented metastatic bone and/or soft tissue/visceral lesion documented in the following manners within 28 days prior randomization:

   1. Metastatic disease to the bone (in any distribution) visible on 99Tc-MDP bone scintigraphy on either pre-ADT scans or baseline scans AND/OR
   2. Lymph node metastases of any size or distribution. If lymph nodes are the only site of metastasis, then at least one must be at least 1.5 cm in short axis AND outside of the pelvis AND/OR
   3. Visceral metastases of any size or distribution. If a participant has a history of visceral metastases at any time prior to randomization, he should be coded as having visceral metastases at baseline (i.e., patients with visceral metastases prior to ADT that disappear at baseline will be counted as having visceral metastases and would therefore have high volume disease for stratification purposes).
8. Patients must have adequate organ function:

   * Bone marrow reserve ANC ≥1.5 x 109/L Platelets ≥100 x 109/L Hemoglobin ≥9 g/dL
   * Hepatic Total bilirubin ≤2 x the institutional upper limit of normal (ULN). For patients with known Gilbert's Syndrome ≤3 x ULN is permitted Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≤3.0 x ULN OR ≤5.0 x ULN for patients with liver metastases
   * Renal eGFR ≥ 50 mL/min/1.73m2 using the Modification of Diet in Renal Disease (MDRD) equation
9. Albumin ≥2.5 g/dL
10. Human immunodeficiency virus (HIV)-infected patients who are healthy and have a low risk of acquired immune deficiency syndrome (AIDS)-related outcomes can participate in this trial
11. Patients must be:

Treatment naïve OR minimally treated with:

* Up to 45 days of luteinizing hormone-releasing hormone (LHRH) agonist /antagonists or bilateral orchiectomy with or without first generation anti-androgen (e.g. bicalutamide, flutamide) for metastatic prostate cancer is allowed prior to ICF signature. If given, first generation anti-androgen must be discontinued prior to start of study therapy or after 45 days whatever happens first.
* If received, prior LHRH agonist/antagonist with or without first generation anti-androgen use in the adjuvant/neo-adjuvant setting must have been discontinued \> 12 months prior to ICF signature AND must not have exceeded 24 months of therapy AND must not have shown disease progression within 12 months of completing adjuvant/neo-adjuvant therapy.
* Up to 45 days of CYP17 inhibitor or ARDT exposure for metastatic prostate cancer is allowed prior to ICF signature. No CYP17 inhibitor or ARDT exposure for earlier stages of prostate cancer is allowed.

Exclusion Criteria:

Participants meeting any of the following criteria are not eligible for inclusion in this study.

1. Participants with rapidly progressing tumor that requires urgent exposure to taxane-based chemotherapy
2. Any prior systemic anti-prostate cancer therapy (with the exception of the drugs listed on inclusion criteria 11), including chemotherapy, Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, immunotherapy or biological therapy (including monoclonal antibodies).
3. Concurrent cytotoxicity chemotherapy, immunotherapy, radioligand therapy, PARP inhibitor, biological therapy or investigational therapy
4. Previous treatment with any of the following within 6 months of randomization: Strontium-89, Samarium-153, Rhenium-186, Rhenium-188, Radium-223, hemi-body irradiation. Previous PSMA-targeted radioligand therapy is not allowed
5. Ongoing participation in any other clinical trial
6. Use of other investigational drugs within 30 days prior to day of randomization
7. Known hypersensitivity to any of the study treatments or its excipients or to drugs of similar chemical classes
8. Transfusion for the sole purpose of making a participant eligible for study inclusion
9. Participants with CNS metastases that are neurologically unstable, symptomatic, or receiving corticosteroids for the purpose of maintaining neurologic integrity. Participants with epidural disease, canal disease and prior cord involvement are allowed if those areas have been treated, are stable, and not neurologically impaired. Participants with parenchymal CNS metastasis (or a history of CNS metastasis), that have received

Trial Locations

• Mayo Clinic - Arizona Mayo Clinic Hospital, Scottsdale, Arizona, United States
• Mayo Clinic Arizona, Scottsdale, Arizona, United States
• University of California San Diego - Moores Cancer Center, La Jolla, California, United States
• VA Greater LA Healthcare System, Los Angeles, California, United States
• University of California LA, Los Angeles, California, United States
• St. Joseph Hospital, Orange, California, United States
• Univ Cali Irvine ALS Neuromuscular, Orange, California, United States
• VA Palo Alto Health Care System, Palo Alto, California, United States
• Stanford University Medical Center, Palo Alto, California, United States
• Sansum Clinic, Santa Barbara, California, United States
• ...and 10 more locations

Study Officials

• Novartis Pharmaceuticals — STUDY_DIRECTOR
  Novartis Pharmaceuticals

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