PSMAAddition: An International Prospective Open-label, Randomized, Phase III Study comparing 177LU-PSMA-617 in combination with Standard of Care, versus Standard of Care alone, in adult make patients with Metastatic Hormone Sensitive Prostate Cancer

Protocol # :
Prostatic Neoplasms
Disease Sites
Principal Investigator
Ravi, Praful, Kumar
Site Research Nurses
Bretta, Katherine, v.
Carey, Margaret, M.
Creaton, Eileen
Healy, Erin, C.
Kabarame, Liliane
Katica, Dean
Kelleher, Kaitlin
Kelleher, Kaitlin
Leisner, Claire
Mingrino, Sage
Prisby, Judith

Trial Description

The purpose of this study is to evaluate the efficacy and safety of 177Lu-PSMA-617 in
combination with Standard of Care, versus Standard of Care alone, in adult male patients with
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 have been enrolled in 20 countries.

Eligibility Requirements

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

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

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

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 prior therapy and are neurologically stable, asymptomatic and not
receiving steroids for CNS metastases, are allowed, baseline and subsequent
radiological imaging must include evaluation of the brain (magnetic resonance imaging
(MRI) preferred or CT with contrast).

10. Diagnosed with other malignancies that are expected to alter life expectancy or may
interfere with disease assessment. However, participants with a prior history of
malignancy that has been adequately treated and who have been disease free, treatment
free for more than 3 years prior to randomization, or participants with adequately
treated non-melanoma skin cancer, superficial bladder cancer are eligible.

11. Concurrent serious (as determined by the Principal Investigator) medical conditions,
including, but not limited to, uncontrolled infection, known active hepatitis B or C,
or other significant co-morbid conditions that in the opinion of the investigator
would impair study participation or cooperation. Participants with an active
documented COVID-19 infection (any grade of disease severity) at time of informed
consent may be included only when completely recovered (in accordance with local

12. Active clinically significant cardiac disease defined as any of the following:

- NYHA class 3/4 congestive heart failure within 6 months prior to ICF signature
unless treated with improvement and echocardiogram or MUGA demonstrates EF > 45%
with improvement in symptoms to class < 3.

- History or current diagnosis of ECG abnormalities indicating significant risk of
safety for participants in the study such as: Concomitant clinically significant
cardiac arrhythmias, e.g. sustained ventricular tachycardia, complete left bundle
branch block, high-grade atrioventricular (AV) block (e.g., bifascicular block,
Mobitz type II and third degree AV block)

- History of familial long QT syndrome or known family history of Torsades de

- Cardiac or cardiac repolarization abnormality, including any of the following:
History of myocardial infarction (MI), angina pectoris, or coronary artery bypass
graft (CABG) within 6 months prior to ICF signature

13. History of somatic or psychiatric disease/condition that may interfere with the
objectives and assessments of the study

14. Symptomatic cord compression, or clinical or radiologic findings indicative of
impending cord compression

15. Any condition that precludes raised arms position

16. Unmanageable concurrent bladder outflow obstruction or urinary incontinence. Note:
participants with bladder outflow obstruction or urinary incontinence, which is
manageable and controlled with best available standard of care (incl. pads, drainage)
are allowed.

17. Sexually active males unwilling to use a condom during intercourse while taking study
treatment and for 14 weeks after stopping study treatment. A condom is required for
all sexually active male participants to prevent them from fathering a child AND to
prevent delivery of study treatment via seminal fluid to their partner. In addition,
male participants must not donate sperm for the time period specified above. If local
regulations deviate from the contraception methods listed above to prevent pregnancy,
local regulations apply and will be described in the ICF