In this international, open-label, prospective, phase III study, where approximately 1126
patients with treatment naïve or minimally treated PSMA-positive mHSPC will be randomized in
a 1:1 ratio to receive Standard of Care (SoC) with or without the radioligand 177Lu-PSMA-617.
The primary objective of the study is to determine whether the combination of 177Lu-PSMA-617
+ SoC improves rPFS over that obtained by administration of SoC alone in mHSPC patients.
The randomization will be stratified according to the following three factors: disease volume
(high v low), age >= 70 years (yes/no), and on Previous or planned treatment (prostatectomy
or radiation) to primary (prostate) tumor (yes/no).
Study duration: approximately 50 months. screening period: after signing ICF, patients will
be assessed for eligibility and will be scanned with 68Ga PSMA-11 to identify PSMA expression
status. Following completion of all required screening procedures and verifying participant
eligibility, the participant will be randomized via the interactive response technology (IRT)
- Up to 45 days of LHRH agonist/antagonists is allowed prior to ICF signature. If patient
did not start the ADT prior randomization, ADT should start as soon as possible and
ideally no later than 2 weeks after randomization.
- Up to 45 days of ARDT is allowed prior ICF signature. If patient did not start the ARDT
prior randomization, ARDT should start as soon as possible and ideally no later than 2
weeks after randomization. Patients will received ARDT as per label instructions.
The participant will be randomized in a 1:1 ratio to receive Standard of Care (SoC) with or
without the radioligand 177Lu-PSMA-617.
Patients randomized to the investigational arm (i.e. SoC+177Lu-PSMA-617): Patients will
receive SoC as per label instructions, after randomization, if not started earlier and in the
time frame allowed by the protocol. Patients must begin 177Lu-PSMA-617 dosing within 14 days
after randomization or as soon as possible after the product is received. 177Lu-PSMA-617 is
administered at the dose of 7.4 GBq (+/- 10%), once every 6 weeks (+/- 1 week) for a planned
Patients randomized to the control arm will begin receiving SoC as per label instructions
after randomization, if not started earlier and in the time frame allowed by the protocol.
The primary endpoint of rPFS will be assessed by a centralized blinded image review committee
(i.e., BIRC) using radiographic images provided by the treating physician.
An end of treatment (EOT) visit will be performed when participants permanently discontinue
After patients randomized to the SoC alone (i.e., control) arm experience radiographic
progression (the rPFS event) as confirmed by BIRC, they will be allowed to cross-over to
receive 177Lu-PSMA-617 +/- SoC per the discretion of the treating physician. If cross-over to
177Lu-PSMA-617 is selected, then 177Lu-PSMA-617 will be administered with the same
dose/schedule as participants who were initially randomized to receive 177Lu-PSMA-617 as
described above. Study cross-over participants for whom 177Lu-PSMA-617 is discontinued must
have a second End of Treatment (EOT2) visit performed =< 7 days and enter the Post-treatment
Post-Treatment Follow-Up (Safety, Efficacy):
After treatment discontinuation, all participants will be followed for safety with a 30-day
safety follow-up visit (FUP) as well as longer term safety follow-up assessments for a period
of approximately 12 months.
Participants who discontinue study treatment without having progressive disease confirmed by
BIRC, will continue to be assessed for efficacy (efficacy follow-up) during the
post-treatment follow-up period until the occurrence of their BIRC-confirmed radiographic
disease progression (rPFS) event , or if the total number of protocol-defined rPFS events has
occurred triggering the primary analysis, whichever occurs first.
After study treatment discontinuation, or post-treatment follow-up period discontinuation,
the participant's status will be collected every 90 days (via phone calls) as part of the
survival follow-up. Every effort should be made to comply with the survival follow-up
schedule and ensure collection of participant survival. The survival follow-up and the study
will end when the number of OS events required for final OS analysis will be reached.
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 documented metastatic disease to bone and/or soft tissue/visceral
sites documented in one of 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. 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. OR
3. Visceral metastases of any size or distribution. If a subject has a history of
visceral metastases at any time prior to registration, 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
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
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 therapy.
- If received, prior LHRH agonist/antagonist 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 exposure for earlier stages of prostate cancer is
Participants meeting any of the following criteria are not eligible for inclusion in this
1. Patients with rapidly progressing tumor that requires urgent exposure to taxane-based
2. Any systemic anti-prostate cancer therapy (with the exception of the drugs listed on
inclusion criteria 11), including chemotherapy, PARP inhibitors, immunotherapy or
biological therapy (including monoclonal antibodies).
3. Other concurrent cytotoxicity chemotherapy, immunotherapy, radioligand therapy, or
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 subject eligible for study inclusion
9. Patients with CNS metastases that are neurologically unstable, symptomatic, or
receiving corticosteroids for the purpose of maintaining neurologic integrity.
Patients with epidural disease, canal disease and prior cord involvement are eligible
if those areas have been treated, are stable, and not neurologically impaired. For
patients with parenchymal CNS metastasis (or a history of CNS metastasis), 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, patients with a prior history of
malignancy that has been adequately treated and who have been disease free for more
than 3 years are eligible, as are patients with adequately treated non-melanoma skin
cancer, superficial bladder cancer. Note: Patients with a history of CNS metastases
that have received prior therapy and are neurologically stable, asymptomatic and not
receiving corticosteroids are allowed.
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
guidance) and had no symptoms for at least 28 days before the first dose of study
12. No 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. Concurrent bladder outflow obstruction or unmanageable urinary incontinence
17. Sexually active males unwilling to use a condom during intercourse while taking study
treatment and for 6 months 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