Personalized vs. Fixed-Activity 177Lu-PSMA-617 Radiopharmaceutical Therapy (PRODIGY-2)

PROstate-specific Membrane Antigen DosImetry- Guided endoradiotherapY: A Randomized- Controlled, Single-blind, Pilot Study of Personalized vs. Fixed-activity 177Lu-PSMA-617 Radiopharmaceutical Therapy (PRODIGY-2)

The goal of this clinical trial is to assess if a personalized regime of 177Lu-PSMA-617 (Lutetium Lu 177 vipivotide tetraxetan, also known as Pluvicto) is feasible and safe in a population of patients with metastatic castrate-resistant prostate cancer (mCRPC). The main questions it aims to answer are:

1. Can the administered activity (cumulative or per-cycle) be increased in a majority of participants?
2. What is the incidence of some specific adverse reactions during the treatment?

Researchers will compare participants receiving a personalized regime to participants receiving the standard fixed-activity regime of 177Lu-PSMA-617 to see if the activity can be safely increased through personalization based on renal dosimetry (i.e. the measure of how much radiation is actually delivered to the kidney).

Participants will receive up to 6 treatments of 177Lu-PSMA-617 every 6 weeks and be regularly evaluated with imaging and laboratory tests, as well as with questionnaires.

Inclusion Criteria:

1. Patient aged ≥18 years with metastatic adenocarcinoma of the prostate, defined by documented histopathology of prostate adenocarcinoma;
2. Castration-resistant prostate cancer, as defined as disease progressing despite castration by orchiectomy or ongoing androgen deprivation therapy;
3. Progressive mCRPC with rising PSA level, defined by PCWG3 criteria (sequence of two rising values above a baseline at a minimum of 1-week intervals, with serum testosterone level ≤ 1.7 nmol/dL);
4. PSA ≥2 ng/mL ;
5. Prior treatment with at least one ARPI;
6. PSMA-expressing cancer, with significant PSMA expression defined as SUVpeak in at least one lesion that is superior to SUVmean of the liver on PSMA-PET (68Ga-PSMA-11 or 18F-DCFPyL), within 45 days prior to randomization;
7. ECOG Performance status 0 to 2;
8. Calculated eGFR (by CKD-EPI formula) ≥ 45 mL/min/1.73m^2;
9. Albumin ≥ 25 g/L;
10. Platelets ≥ 100x10^9/L;
11. Neutrophils ≥ 1.5x10^9/L;
12. Hemoglobin ≥ 90 g/L without transfusion in the past 4 weeks;
13. Signed, written informed consent

Exclusion Criteria:

1. PSMA-PET "superscan" (i.e. extensive/diffuse PSMA-positive bone involvement);
2. Site(s) of disease that are FDG-positive, defined as SUVpeak in at least one lesion that is superior to twice (2x) SUVmean of the liver, and PSMA-negative (as above), within 45 days prior to randomization;
3. Prior treatment with more than two lines of chemotherapy for mHSPC and/or mCRPC (adjuvant and neoadjuvant chemotherapy does not count) towards the maximum of two regimens);
4. Prior radiopharmaceutical therapy;
5. Known CNS metastasis unless they are deemed to be non-progressive, asymptomatic and off corticosteroid therapy for at least four weeks, as per investigator's assessment;
6. Active malignancy other than prostate cancer;
7. Patients who are sexually active and not willing/able to use medically acceptable forms of barrier contraception;
8. Any other condition, diagnosis or finding that may in the investigator's opinion interfere with trial conduct;
9. Known hypersensitivity to 177Lu-PSMA-617 or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container.